Methods of treating, ameliorating and / or preventing kidney diseases, and methods of predicting kidney diseases risks

Abstract

Described herein is a method of treating, ameliorating and / or preventing a kidney disease in a subject in need thereof. The method comprises performing a genomic editing in the subject to replace a risk allele of a kidney disease SNP with a reference allele; or adjusting the expression or activity of a kidney disease gene. Also described herein is a method of predicting the risk of kidney disease in a subject. The method comprises detecting the presence or absence of a risk allele of a kidney disease SNP in the subject

Description

[0001] Attorney Docket No. 046483-7468W01(04021)

[0002] METHODS OF TREATING, AMELIORATING AND / OR PREVENTING KIDNEY DISEASES, AND METHODS OF PREDICTING KIDNEY DISEASES RISKS

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] The present application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63 / 692,601, filed September 09, 2024, which is incorporated herein by reference in its entirety.

[0005] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0006] This invention was made with government support under DK087635 awarded by the National Institutes of Health. The government has certain rights in the invention.

[0007] SEQUENCE LISTING

[0008] The XML text file named "046483-7468W01(04021)_Seq Listing. xml" created on September 9, 2025, comprising 2,462,478 bytes, is hereby incorporated by reference in its entirety.

[0009] BACKGROUND

[0010] Kidney disease encompasses a range of conditions and include, among others, chronic kidney disease (CKD), diabetic kidney disease (DKD), acute kidney injury (AKI), and related glomerular, and tubulointerstitial disorders. Kidney diseases affects the health of a significant percentage of the world population. For example, CKD is a global public health challenge, affecting more than 800 million people worldwide and contributing to nearly one million deaths annually.

[0011] Kidney diseases impair the kidney’s ability to filter blood effectively. This impairment can lead to the accumulation of toxins and excess fluids in the body, which may result in serious health complications, such as hypertension (high blood pressure), electrolyte abnormalities and cardiovascular disease. The increasing mortality rates associated with kidney disease underscore its significance as a major public health issue.

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[0013] 56242423.3 Attorney Docket No. 046483-7468W01(04021)

[0014] There is a need for methods of treating, ameliorating and / or preventing kidney diseases, as well as for the methods of predicting the risk of kidney diseases. The present study addresses this need.

[0015] SUMMARY

[0016] In some aspects, the present invention is directed to the following non-limiting embodiments:

[0017] Method of treating, ameliorating and / or preventing a kidney disease

[0018] In some aspects, the present invention is directed to a method of treating, ameliorating and / or preventing a kidney disease in a subject in need thereof

[0019] In some embodiments, the method comprises administering to the subject an effective amount of a compound down-regulating CHAC1 in the subject. In some embodiments, the compound down-regulating CHAC1 comprises an siRNA for CHAC1.

[0020] In some embodiments, the method comprises performing a genomic editing in a cell of the subject to replace a risk allele of a single nucleotide polymorphism (SNP) associated with the kidney disease with a reference allele associated with an absence of the kidney disease.

[0021] In some embodiments, the method comprises down-regulating a gene associated with the kidney disease, wherein the up-regulation of the gene in the subject as compared to a healthy subject causes or is associated with the kidney disease.

[0022] In some embodiments, the method comprises up-regulating a gene associated with the kidney disease, wherein the down-regulation of the gene in the subject as compared to a healthy subject causes or is associated with the kidney disease.

[0023] In some embodiments, the kidney disease is chronic kidney disease, diabetic kidney disease, or acute kidney injury.

[0024] Methods of predicting risk, stratifying patients, and / or selecting therapy

[0025] In some aspects, the present invention is directed to a method of predicting a risk of kidney disease in a subject.

[0026] In some aspects, the present invention is directed to stratifying the a subject based on a risk of kidney disease.

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[0029] In some aspects, the present invention is directed to selecting a therapy for a subject with kidney disease.

[0030] In some embodiments, the method comprises detecting the presence or absence of a risk allele in a single nucleotide polymorphism (SNP) associated with kidney disease in a sample of the subject, wherein a presence of the risk allele in the SNP indicates a heightened risk of kidney disease.

[0031] In some embodiments, detecting a CpG meQTL sites linked (LD r2 0.2) to a SNP associated with kidney disease.

[0032] In some embodiments, the detection is performed using PCR, sequencing, digital droplet PCR, or methylation-specific arrays.

[0033] Method of identifying a causal kidney disease gene

[0034] In some aspects, the present invention is directed to a method of identifying a causal kidney disease gene.

[0035] In some embodiments, the method comprises performing a genome-wide association study (GWAS) of kidney function in a population.

[0036] In some embodiments, the method further comprises performing a fine-mapping credible sets of variants from the GWAS.

[0037] In some embodiments, the method further comprises integrating the fine-mapped variants with kidney-specific molecular data selected from the group consisting of expression quantitative trait loci (eQTL), allele-specific expression (ASE), bulk allele-specific chromatin accessibility (bASA), single-nucleus allele-specific chromatin accessibility (snASA), methylation quantitative trait loci (meQTL), and single-cell multiome peak-to-gene mapping (Open4Gene).

[0038] In some embodiments, the method further comprises prioritizing one or more causal variants, genes, or regulatory elements associated with kidney disease.

[0039] BRIEF DESCRIPTION OF THE DRAWINGS

[0040] The following detailed description of exemplary embodiments will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating, nonlimiting embodiments are shown in the drawings. It should be understood, however, that the

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[0042] 56242423.3 Attorney Docket No. 046483-7468W01(04021) instant specification is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings.

[0043] The figures depict, among others, how genome-wide association signals are integrated with kidney-specific molecular datasets to produce the Kidney Disease Genetic Scorecard (KDGS), how KDGS assigns locus— >-gene—>cell-type relationships, and how these assignments support diagnostic stratification and therapeutic targeting. The figures are schematic and not to scale. The term “subject” used in the “BRIEF DESCRIPTION OF THE DRAWINGS” section refers to a human subject, unless otherwise indicated. Each figure may include lettered subpanels, and multiple panels may be described for a single figure.

[0044] In the figures herein, GWAS significance is displayed as -loglO(p). Fine-mapping credible sets are annotated by posterior inclusion probability curves. ASE indicates allelic imbalance of mRNA; bASA / snASA indicate allele-specific chromatin accessibility in bulk tissue or single nuclei; meQTL indicates DNA methylation association; Open4Gene indicates singlecell multiome peak-to-gene linkage. Locus-zooms combine association tracks, regulatory features, and gene models to support varian gene assignments. How each panel support the claimed KDGS platform, diagnostic methods, or therapeutic methods are also provided in this section.

[0045] Figs. 1 A-1H illustrate certain aspects of the eGFRcrea GWAS of 2.2 million individuals, in accordance with some embodiments. Fig. 1A shows Manhattan plots of eGFRcrea GWAS in a multi -ancestry cohort (-2,287,877 individuals) and a European-ancestry cohort (-1,785,582 individuals). Each dot represents a SNP; the x-axis denotes the chromosomal position, and the y- axis denotes the strength of association (-loglO p value). Lead SNPs at independent loci are highlighted; previously reported loci are indicated in green and newly identified loci in purple. Prioritized genes at novel loci are labeled. These plots demonstrate the saturated, well-powered association landscape that underpins the KDGS variant-to-gene pipeline. Fig. IB shows the fraction of known and novel loci identified across ancestries. The ancestry breakdown confirms additional discovery and supports generalizability of KDGS across populations. Fig. 1C shows the number of independent loci validated by complementary kidney function measures, including eGFR based on cystatin C (eGFRcys) and blood urea nitrogen (BUN). Orthogonal validation corroborates kidney-specific relevance of GWAS loci used by KDGS. Fig. ID shows the number of loci identified in down-sampled European GWAS at varying sample sizes and locus windows

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[0048] (35 kb, 50 kb, 100 kb), demonstrating locus-discovery saturation at large sample sizes. Downsampling establishes diminishing returns and informs KDGS thresholds for fine-mapping. Fig. IE shows overlap of credible sets from fine-mapping between multi-ancestry and European-only GWAS. Credible-set overlap demonstrates consistency of fine-mapped signals used by KDGS. Fig. IF shows enrichment of fine-mapped variants in functional categories (nonsynonymous coding variants, kidney enhancers, active promoters). Functional enrichment evidences convergence of coding and regulatory mechanisms that KDGS exploits for causal inference. Fig. 1G shows a locus-zoom of the IRF5 region with GWAS association, posterior inclusion probability, and fine-mapping credible sets. Locus-level integration exemplifies how KDGS combines association with regulatory context for variant ^-gene assignment. Fig. 1H shows pleiotropy maps indicating the number of loci shared between eGFRcrea GWAS and other complex traits (e.g., blood pressure, diabetes, lipid traits). Pleiotropy delineates shared etiologic architecture, guiding KDGS to consider cross-trait mechanisms relevant for diagnostics and therapy.

[0049] Figs. 2A-2G illustrate certain aspects of the allele-specific expression (ASE) analysis in human kidneys, in accordance with some embodiments. Fig. 2A shows Manhattan plots for ASE mapping in microdissected tubule and glomerular compartments. ASE captures cis-regulatory effects not fully detected by standard eQTLs, increasing KDGS sensitivity. Fig. 2B shows overlap between ASE genes in tubules and glomeruli. Compartment-specific and shared signals reveal micro-domain regulatory architecture used by KDGS. Fig. 2C compares ASE and eQTL discoveries, indicating additional genes uniquely detected by ASE. ASE adds independent discovery power to KDGS variant^gene assignments. Fig. 2D shows a locus-zoom for GATM, demonstrating colocalization between GWAS, ASE, and eQTL signals. Multi-omic colocalization supports causal linkage at the gene level for KDGS prioritization. Fig. 2E quantifies the number of fine-mapped GWAS variants linked to ASE and / or eQTL. Linking credible-set variants to ASE / eQTL strengthens causal inference used in KDGS scoring. Fig. 2F shows the number of genes with ASE / eQTL-GWAS colocalization and enrichment for validated nephropathy genes. Enrichment validates biological relevance of KDGS-prioritized genes. Fig. 2G shows a locus-zoom for SLC22A2, demonstrating strong ASE colocalization with eGFRcrea GWAS. ASE-specific colocalization illustrates locus resolution where eQTL is weaker, improving KDGS precision.

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[0052] Figs. 3A-3F illustrate certain aspects of the allele-specific accessibility analysis in human kidneys, in accordance with some embodiments. These figures relate to the Bulk allele-specific chromatin accessibility (bASA) study. Fig. 3A shows the bASA analytical workflow and a Manhattan plot of bASA variants. The workflow establishes a genome-wide map of regulatory accessibility that KDGS integrates. Fig. 3B shows enrichment of bASA peaks in kidney enhancers and active promoters. Enrichment pinpoints regulatory leverage points for disease risk that KDGS uses to weight variants. Fig. 3C shows correlation between bASA and meQTL effect sizes. Correlation supports mechanistic coupling between chromatin accessibility and methylation in KDGS models. Figs. 3D-3E illustrate prioritization of variants overlapping bASA, ASE, and meQTL, emphasizing multi-omic convergence. Convergence filters to high- confidence variants for KDGS causal nomination. Fig. 3F shows a locus-zoom ofUSP24, illustrating colocalization of GWAS with bASA, meQTL, and ASE in tubules. Fully integrated tracks guide KDGS variant^-gene^- cell-type assignments at specific loci.

[0053] Figs. 4A-4I illustrate certain aspects of the single-nucleus allele-specific chromatin accessibility (snASA) analysis in human kidneys, in accordance with some embodiments. Fig. 4A shows the snASA mapping workflow. snASA resolves cell-type specific regulatory variation that KDGS uses to assign “cell-type of action.” Fig. 4B quantifies snASA SNPs per cell type. Discovery across nephron and interstitial lineages ensures KDGS has comprehensive cell-type coverage. Fig. 4C shows the fraction of snASA SNPs within open chromatin peaks. Localization within peaks indicates direct regulatory impact of KDGS-linked variants. Fig. 4D shows distributions of cell-type-specific and shared snASA SNPs across 19 kidney cell types. Specificity / sharing patterns inform KDGS weighting of cell-type assignments. Fig. 4E validates snASA against bASA signals. Concordance across modalities confirms robustness of KDGS regulatory inputs. Fig. 4F shows correlation of effect sizes between proximal tubule snASA and bulk bASA. Strong correlation supports technical and biological reliability informing KDGS outputs. Fig. 4G shows TF motif enrichment (e.g., HNF4A / G, CTCF, NFKB1) disrupted by snASA SNPs. Motif enrichment implicates specific regulators KDGS may prioritize for therapeutic intervention. Fig. 4H shows enrichment of snASA SNPs overlapping GWAS variants in TF binding sites. Overlap with TFBS supports direct transcriptional mediation of risk. Fig. 41 shows examples of snASA GWAS variants overlapping cell-type specific peaks. Concrete genomic examples guide KDGS-directed functional validation.

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[0056] Figs. 5A-5G demonstrate that human kidney single cell multi -omics Open4Gene associations link GWAS variants to target genes (peak-to-gene linkage), in accordance with some embodiments. Fig. 5A shows the single-nucleus multiome (RNA+ATAC) and Open4Gene pipeline. The pipeline links accessible peaks to expressed genes at single-cell resolution for KDGS causal mapping. Fig. 5B shows cell counts and numbers of Open4Gene links per cell type. Link discovery scales with sampling, informing KDGS design and confidence. Fig. 5C shows the fraction of peaks targeting single versus multiple genes. Predominantly single-gene links simplify KDGS variant^gene assignment. Fig. 5D prioritizes genes linked to GWAS variants via Open4Gene. Peak-to-gene links enable KDGS gene-level prioritization informed by GWAS strength. Fig. 5E shows the relationship between GWAS significance and distance from variant to linked peak. Distance trends support KDGS weighting of regulatory proximity. Fig. 5F counts GWAS variants linked per gene, with top kidney genes labeled. Highly targeted genes suggest nodal regulators and druggable hubs for therapy. Fig. 5G shows a locus-zoom of LRP2, integrating GWAS, open chromatin, and expression. Locus integration demonstrates how KDGS contextualizes GWAS signals by gene and cell type.

[0057] Figs. 6A-6G demonstrate that Kidney Disease Genetic Scorecard (KDGS) indicates the convergence of coding and regulatory variants in GWAS loci, in accordance with some embodiments. Fig. 6A shows the KDGS workflow for prioritizing regulatory variants by integrating 32 data sources. KDGS operationalizes variant^gene^cell-type prioritization for diagnostics and therapy. Fig. 6B shows prioritization thresholds balancing number of variants, fraction of unique genes, and validated nephropathy genes. Thresholding balances discovery breadth with causal specificity. Fig. 6C shows the genomic distribution of prioritized regulatory variants. Distribution corroborates the regulatory architecture KDGS leverages. Fig. 6D shows enrichment of prioritized variants in genic regions and regulatory features. Enrichment supports focusing follow-up on enhancer / promoter elements. Fig. 6E shows convergence of regulatory and coding variants per locus. Coding-regulatory convergence yields high-confidence target sets for modulation. Fig. 6F shows validation of prioritized genes by eGFRcys and BUN GWAS. Orthogonal validation increases clinical relevance of KDGS outputs. Fig. 6G shows the KDGS heatmap of prioritized genes, highlighting expression and open chromatin by cell type, and indicating genes targeted by FDA-approved drugs. The KDGS gene-cell -type-druggability map guides diagnostic panels and therapeutic development.

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[0060] Figs. 7A-7J illustrate certain aspects of the eGFRcrea GWAS analysis, in accordance with some embodiments. Fig. 7A: Manhattan plots of eGFRcrea GWAS of 282,852 individuals of East Asian-ancestry and 67,943 individuals of Arica-ancestry. The x-axis is the chromosomal location of SNP. The y-axis is the strength of association -loglO(p value, GWAS meta-analysis). The nearest genes for top loci are shown. Fig. 7B: LD score regression intercepts and Mean !2 statistic for meta-analysis of eGFRcrea GWAS, each cohort, and UKBB traits. The color represents different kinds of traits. Fig. 7C: The strategy to identify independent loci and novel eGFRcrea GWAS loci. Fig. 7D: Overlap of eGFRcrea GWAS loci identified in the meta-analysis of 2,287,877 multi -ancestry individuals in this study and meta-analysis of 1,508,659 multiancestry individuals. Fig. 7E: Validation of eGFRcrea GWAS variants (N=2,287,877 individuals) using eGFRcys GWAS (N=421,714 individuals) and BUN GWAS (N=852,678 individuals). Scatter plot of effect sizes between eGFRcrea GWAS and eGFRcys GWAS and BUN GWAS. Significant eGFRcrea GWAS variants passing two-sided p < 5* 10'8in this study were used for the plot. The correlation coefficient was calculated using Spearman's rho (R) statistic, and the two-sided p value was calculated using asymptotic t approximation. Venn plot of eGFRcrea GWAS significant variants validated by eGFRcys GWAS or BUN GWAS. Fig. 7F: Function enrichment improved by novel loci. The X-axis is the significance of the GREAT hypergeometric test for known loci, and the Y-axis is the significance of all loci. Each dot is a gene ontology, and the color represents the class of biological process. Fig. 7G: Locus-zoom view of three novel independent loci, FOXC2, PKD2 and SIK3. Fig. 7H: Number and genome coverage of GWAS loci identified in down-sampled GWAS of multi-ancestry. Different lines represent the loci defined by different window sizes (35kb, 50kb, and lOOkb). Fig. 71: Overlap of significant variants and loci identified by the meta-analysis of eGFRcrea GWAS from different ancestries (left panel), and Locus-zoom view of an example locus only identified in multiancestry GWAS. Fig. 7J: Locus-zoom view of ancestry-specific independent loci, AFR-specific locus of APOL1, and EAS-specific locus of BICC1. In each locus-zoom view, the y-axis is the strength of association -loglO(two-sided p value from GWAS). Each triangle shows a variant, with an index variant in purple color and other variants colored using LD R2 to the index variant (low in blue and red in red).

[0061] Figs. 8A-8G illustrate certain aspects of the fine mapping of eGFRcrea GWAS loci, in accordance with some embodiments. Fig. 8A: Number of credible sets (y-axis) with different

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[0063] 56242423.3 Attorney Docket No. 046483-7468W01(04021) numbers of GWAS variants (x-axis) fine-mapped with and without PolyFun annotations in European-ancestry GWAS. Fig. 8B: Number of credible sets (y-axis) with different numbers of GWAS variants (x-axis) fine-mapped with and without PolyFun annotations in Multi-ancestry GWAS. Fig. 8CL Enrichment of credible set variants in non-synonymous coding variants, kidney enhancers, and active promoters. The y-axis is the odds ratio, and the chi-square test significance is presented in each bar. Figs. 8D-8E: Locus-zoom of eGFRcrea GWAS, fine mapping credible sets, and regulatory elements in IRF5 locus. In the locus-zoom plot of GWAS, the y-axis is the strength of association -loglO(p value). In the fine mapping credible set plot, the y-axis is the posterior inclusion probability (PIP) calculated by CARMA. Coloc PP.H4 is the posterior probability of colocalization between eQTL / ASE with eGFRcrea GWAS. Fig. 8F: Genes with colocalization between kidney eQTL (sample size N=686) and eGFRcrea GWAS of 2.2 million individuals and meta-analysis of 1.5 million individuals. Fig. 8G: CpG sites with colocalization between kidney meQTL (sample size N=443) and eGFRcrea GWAS of 2.2 million individuals and meta-analysis of 1.5 million individuals.

[0064] Figs. 9A-9I illustrate certain aspects of the pleiotropy maps of eGFRcrea and other traits, in accordance with some embodiments. Fig. 9A: Enrichment of eGFRcrea variants in GWAS Catalog traits. The x-axis is the odds ratio. The y-axis is enrichment significance -loglO(p value). The color represents kidney traits (cyan) and non-kidney traits (red). Fig. 9B: Number of HyperColoc colocalization events for each given number of traits on the x-axis. Figs. 9C-9E: Locus-zoom of eGFRcrea GWAS and other related traits in FGF5 and TNPO3 gene locus on chromosome 4. The x-axis is the chromosomal location of SNP. The y-axis is the strength of association -loglO(p value, GWAS). Fig. 9F: Mendelian Randomization of eGFRcrea and other traits. Forest plots showed the effect and standard error of eGFRcrea on other traits (red dot) and that of other traits on eGFRcrea (black dot), with significance for each test. The network plot showed the summary of Mendelian randomization analysis in which only significant effects were used. The color of the dots represents the disease type, and the color of the line represents the direction of effect size. Fig. 9G: Overlap of loci identified by colocalization and GSMR analysis between eGFRcrea GWAS and fasting insulin GWAS. Fig. 9H: Effect sizes of fasting insulin and eGFRcrea estimated by GSMR. The x-axis is the instrument from GWAS for fasting insulin, and the x-axis is the outcome from GWAS for eGFRcrea. The dashed line represents the linear regression association between fasting insulin and eGFRcrea. Fig. 91: Locus-zoom of eGFRcrea

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[0067] GWAS and fasting insulin in the GCKR locus. The x-axis is the chromosomal location of SNP. The y-axis is the strength of association -loglO(p-value, GWAS).

[0068] Figs. 10A-10H illustrate certain aspects of the ASE mapping and analysis, in accordance with some embodiments. Fig. 10A: Workflow of ASE mapping in tubule and glomeruli compartments. Fig. 10B: Association of effect sizes between two compartments’ ASEs (left panel) and between ASEs and eQTLs mapped using the same samples from the tubule compartment (right panel). The correlation of effect size is calculated by the Spearman correlation test. Fig. IOC: Overlap of ASE / eQTL genes identified in this study and the study described in Sheng et al. (Nat Genet 53, 1322-1333 (2021)) in each compartment. Fig. 10D: Locus-zoom of tubule ASE, glomeruli ASE, and kidney eQTL in HNF1A locus. The x-axis is the chromosomal location of SNP. The y-axis is the strength of association -loglO(p value). Fig. 10E: Violin plot of absolute effect size (y-axis) of ASEs grouped by minor allele frequency bins (x-axis). The left panel is for tubule ASEs, and the right is for glomeruli ASEs. P value is calculated by the ggplot stat summary to test the significance of median values between two groups. Fig. 10F: The number of eGFRcrea GWAS loci and genes prioritized using ASEs / eQTLs. Fig. 10G: Top 10 biological processes enriched by genes with colocalization between ASEs and eGFRcrea GWAS using PANTHER Overrepresentation Test. Fig. 10H: Locus-zoom of eGFRcrea GWAS, tubule ASE, glomeruli ASE, and kidney eQTL in the locus of SLC15A2. The x-axis is the chromosomal location of SNP. The y-axis is the strength of association -loglO(p value). PP.H4 is the posterior probability of colocalization between eGFRcrea GWAS and molecular traits.

[0069] Figs. 11A-11 J illustrate certain aspects of the bASA mapping and analysis in human kidneys, in accordance with some embodiments. Fig. 11A: Construction of comprehensive open chromatin maps in human kidneys. The left panel shows the datasets used for open chromatin peak calling and bASA analysis. The right panel shows the peaks and regulatory elements in the SLC47A1 locus. Fig. 1 IB: Population structure of 96 AT AC samples using genotype-based principal component analysis (PCA) with an additional 2,504 samples from the 1,000 Genomes Project Phase 3. The x-axis is principal component 1, and the y-axis is principal component 2. Fig. 11C: Outlier detection using Mahalanobis distance. The x-axis is principal component 1, and the y-axis is principal component 2. Outlier samples are shown in purple. Fig. 1 ID: The effect of the number of included PEER factors on the bASA discovery rate. The number of identified

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[0071] 56242423.3 Attorney Docket No. 046483-7468W01(04021) bASAs on chromosome 1 (y-axis) vs. the number of PEER factors (x-axis) included in the RASQUAL. Fig. 1 IE: The strength of association (y-axis) (-loglO(p value calculated using RASQUAL)) of the best SNPs (the lead bASA) decreases with the increasing distance (x-axis) from the bASA peak to the transcription start site (TSS). Fig. 1 IF: The strength of association (y- axis) (-loglO(p value calculated using RASQUAL)) of the best SNPs (the lead bASA) decreases with the increasing distance (x-axis) from the SNP to the bASA peak. Fig. 11G: Overlap of peaks with local bASAs (SNPs in peaks) and distal bASAs (SNPs outside of peaks). Fig. 11H: Association of absolute effect sizes between local bASAs (x-axis) and distal bASAs (y-axis). Each dot represents a peak with both local bASAs and distal bASAs. The correlation of effect size is calculated by the Spearman correlation test. Fig. I ll: Violin plot of absolute effect size (y- axis) of bASAs grouped by minor allele frequency bins (x-axis). P value is calculated by the ggplot stat_summary to test the significance of median values between two groups. Fig. 11J GWAS significance (-loglO(p, GWAS)) (y-axis) of top genetic variant associated with eGFRcrea and bASA for each peak (x-axis) ranked by GWAS significance. The size of dot represents the number of shared GWAS and bASA variants. The colored dot represents the peaks that have at least one variant associated with kidney meQTL and tubule ASE. The genes linked by tubule ASEs were labeled.

[0072] Figs. 12A-12B illustrates certain aspects of the cell types in snATAC and their associations with GWAS traits, in accordance with some embodiments. Fig. 12A: Cell composition (y-axis) of each kidney sample (x-axis) with snATAC-seq data. The samples were ordered based on the fraction of PT cells in each sample. Fig. 12B: Enrichment of heritability mediated by cell type open chromatin peaks to eGFRcrea GWAS and other GWAS traits. The x- axis shows the GWAS traits, while the y-axis shows the cell types. Gray; non-significant. White to red indicates enrichment (nominal two-sided p < 0.05 calculated by LDSC). The asterisk indicates enrichment passing FDR q < 0.05 (accounting for 836 tests for 19 cell types and 44 GWAS traits).

[0073] Figs. 13A-13H illustrate certain aspects of the snASA mapping and analysis in kidney cell types, in accordance with some embodiments. Fig. 13 A: Workflow of snASA mapping in human kidney cell types. Fig. 13B: Number of snATAC reads converging snASA variants identified in open chromatin peaks and outside of peaks, with control using SNPs shuffled from non-peak regions with the same number of non-peak snASA. Fig. 13C: Violin plot of absolute

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[0075] 56242423.3 Attorney Docket No. 046483-7468W01(04021) effect size (y-axis) of snASA grouped by minor allele frequency bins (x-axis). P value is calculated by the ggplot stat_summary to test the significance of median values between two groups. Fig. 13D: Association of effect sizes of snASAs across cell types. For each pair of cell types, the effect sizes of shared snASAs were used for the scatterplot (bottom panel). The correlation coefficient was calculated using Spearman's rho (R) statistic, and the two-sided p- value was calculated using asymptotic t approximation. The significance of the correlation was shown using “***” if the p-value is < 0.001. Fig. 13E: The left panel is the open chromatin peaks near snASA SNP rsl0875467. The middle panel is the number of snATAC reads on each allele of SNP rsl0875467 in PT, LOH, and injured PT. The p-value shows the significance of snASA of SNP rsl0875467. The right panel shows the normalized open chromatin level of peak (chr8: 142232807-142233922) for each genotype of rsl0875467. The p-value shows the significance of the association between SNP rsl0875467 and open chromatin of peak chr8: 142232807-142233922. Fig. 13F: eGFRcrea GWAS signals nearly by 29 genes coding TF motifs in Figure 4G. In the locus-zoom of eGFRcrea GWAS for five TF genes, the x-axis is the chromosomal location of SNP, and the y-axis is the strength of association -loglO(p value, GWAS). Fig. 13G: The number of eGFRcrea GWAS loci in which GWAS variants were also associated with snASA and / or bASA. Fig. 13H: Enrichment of GWAS & snASA SNPs on TFBSs. Significant TF enrichment was defined using enrichment score > 3 and p value < 2.6* 10’4, Bonferroni’s threshold accounting for 194 TFs).

[0076] Figs. 14A-14I illustrates certain aspects of the analysis of gene regulatory circuits using Open4Gene, in accordance with some embodiments. Fig. 14A; Bubble plots of expression (left panel) and open chromatin (right panel) of markers genes for each cell type. The x-axis is the maker genes, and the y-axis is cell types. The color of the dots represents the average expression / accessibility and the size for the percent of cells expressed / accessible. Fig. 14B: Distribution of snRNA read count. The y-axis is the number of cells with a given RNA read count on the x-axis. Fig. 14C: Validation of top peak-to-gene pairs using chromatin interactions detected by HiC-based profiling in multiple tissues and kidneys. The top 1% peak-to-gene pairs based on significance were selected for comparison for each method. Violin plot of absolute values of Spearman Rho (y-axis) calculated for top peak-to-gene pairs identified by different methods. The function stat compare means of package ggpubr was used to compare the Spearman Rho difference between different methods. Fig. 14D: ROC curve represents true

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[0078] 56242423.3 Attorney Docket No. 046483-7468W01(04021) positive rate (y-axis) and false positive rate (x-axis) of 0pen4Gene links. Fig. 14E: The number of 0pen4Gene peaks identified for each gene is ordered by the number of peaks. The y-axis is the number of 0pen4Gene peaks, and the x-axis shows the genes ordered by the number of peaks. The top genes and known kidney disease genes were labeled. Fig. 14F: 0pen4Gene links and regulatory elements in the locus of PKHD1, which has the most 0pen4Gene peaks. The curves showed the Open4Gene links between gene TSS and associated peaks. Fig. 14G: Effect size (x-axis, beta) and significance (y-axis, -loglO(p value)) of 0pen4Gene links. The colors of docs represent the links with significant positive beta (red), significant negative beta (blue), and non-significant links (gray). Fig. 14H: Fraction of 0pen4Gene links with significant positive beta (red) and those with significant negative beta (blue). Fig. 141: Association of effect sizes of Open4Gene links across cell types. For each pair of cell types, the effect sizes of shared 0pen4Gene links were used for the scatterplot (bottom panel). The correlation coefficient was calculated using Spearman's rho (R) statistic, and the two-sided p-value was calculated using asymptotic t approximation. The significance of the correlation was shown using “***” if the p- value is < 0.001.

[0079] Figs. 15A-15F demonstrate that Open4Gene links GWAS variants to disease genes, in accordance with some embodiments. Fig. 15 A: The number of eGFRcrea GWAS variants linked to target genes by Open4Gene associations. The y-axis is the number of GWAS variants with each number of target genes on the x-axis. Fig. 15B: The number of genes targeting one or multiple genes by Open4Gene associations. The y-axis is the number of genes with each number of GWAS variants on the x-axis. Fig. 15C: Phenotypes enriched by 253 genes with 10 GWAS variants. The x-axis is the significance (-loglO(FDR)) for each phenotype on the y-axis. Only the top 10 phenotypes were used for the plot. Fig. 15D: Locus-zoom of eGFRcrea GWAS, Open4Gene links, regulatory elements, and gene expression in loci of SLC47A1, DAB2, ACSM2A, and UMOD. In the locus-zoom plot, the y-axis is the strength of association -loglO(p value, GWAS). The tracks on the left panel showed the open chromatin in each cell type, and the right panel showed the expression of each gene in corresponding cell types. Fig. 15E: Gene expression analysis of ACSM2A in human kidneys (N=433). In the box plot, the x-axis is different groups of human kidney samples, and the y-axis is the expression of ACSM2A. ANOVA test was used to test the expression changes of ACSM2A in kidney disease. In the scatter plots, the y-axis is the expression of ACSM2A, and the x-axis is eGFRcrea or fibrosis.

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[0082] Spearman correlation test was used to test the correlation between ACSM2A expression and eGFRcrea and fibrosis. Fig. 15F: Gene expression analysis of Acsm2, the homologous gene of ACSM2A in mouse, in kidney disease models. DESeq2 was used to test the expression changes of Acsm2 between normal control and each disease model.

[0083] Figs. 16A-16F illustrate certain aspects of the prioritization of regulatory variants by multi-omics integration, in accordance with some embodiments. Fig. 16A: Number of GWAS loci prioritized using regulatory variants. The left y-axis is the number (bar chart) of GWAS loci prioritized using each prioritization score cutoff on the x-axis. The right y-axis showed the fraction (red dot plot) of loci targeting unique genes prioritized by each prioritization score cutoff on the x-axis. Fig. 16B: Number of disease genes prioritized using regulatory variants. The left y-axis is the number (bar chart) of disease genes prioritized using each prioritization score cutoff on the x-axis. The right y-axis showed the fraction (red dot plot) of genes uniquely targeted by regulatory variants prioritized by each prioritization score cutoff on the x-axis. Fig. 16C: Locuszoom of eGFRcrea GWAS and prioritization evidence at the SLC34A1 locus. In the locus-zoom plot, the y-axis is the strength of association -loglO(p value, GWAS). The variant tracks showed the genetic variants identified by different omics data. The tracks on the left panel showed the open chromatin in each cell type, and the right panel showed the expression of each gene in each cell type. The curves showed the regulatory associations between gene TSS and associated variants. Fig. 16D: Fraction of regulatory variants (prioritization score 10) in different genome features. Fig. 16E: Fraction of regulatory variants (prioritization score ^ 10) targeting host and distal genes. The host genes were determined if the regulatory variants were in the 5’UTR, 3’UTR, or intron of a gene. Fig. 16F: The fraction of regulatory variants (prioritization score 10) overlapped with TFBSs obtained from the ENCODE project.

[0084] Figs. 17A-17D: Distribution of eGFRcrea GWAS variants, in accordance with some embodiments. Fig. 17A: Fraction of genetic variants in different gene features, including CDS, 5’UTR, 3’UTR, intron, and intergenic regions. The number of significant variants associated with eGFRcrea in each feature was counted for comparison with non-significant variants and genome. Fig. 17B: Fraction of genetic variants in credible sets by fine mapping. The variants in exons and outside of exons were counted, respectively. The chi-square test was used to test the difference between exons and non-exon regions. Fig. 17C: Enrichment of eGFRcrea GWAS variants in kidney chromatin states. The x-axis is the log-transformed odds ratio, and the y-axis

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[0086] 56242423.3 Attorney Docket No. 046483-7468W01(04021) is the chromatin states estimated using histone modifications. The chi-square test was used to test the difference between each state and other states. Fig. 17D: LDSC enrichment of eGFRcrea GWAS variants in kidney genes and epigenetic elements. For each panel, the x-axis is the features ordered based on tissue categories with different colors, and the y-axis is the significance of LDSC enrichment.

[0087] Figs. 18A-18G illustrate some aspects of the identification of coding variants in saturated GWAS, in accordance with some embodiments. Fig. 18A: Number of coding variants identified by GWAS and ExWAS studies. The x-axis is the number of identified coding variants by each study on the y-axis. Fig. 18B: Association of effect sizes between GWAS (x-axis) and ExWAS studies (y-axis). The correlation of effect size is calculated by the Spearman correlation test. The genes with coding variants were labeled. Fig. 18C: The number of genes with coding variants identified by GWAS, PheWAS, and ExWAS studies. The x-axis is the number of identified genes with coding variants by each study on the y-axis. Fig. 18D: Overlap of genes with coding variants identified by GWAS, PheWAS, and ExWAS studies. The genes identified by GWAS and PheWAS / ExWAS were listed, and the genes identified by all three methods are in bold. Fig. 18E: Examples of coding variants identified by all GWAS, PheWAS, and ExWAS studies. For each panel, the tracks provide information on genes, GWAS, ExWAS, and PheWAS variants. Fig. 18F: Number of coding variants identified for each gene in eGFRcrea GWAS. The y-axis is the number of coding variants, and the x-axis shows the genes ordered by the number of coding variants. The genes validated by ExWAS / PheWAS are in red. The top genes and known kidney disease genes were labeled. Fig. 18G: Association of GWAS effect sizes (y-axis) and minor allele frequency (MAF, x-axis) of coding variants. The genes validated by ExWAS / PheWAS are in red. The top genes and known kidney disease genes were labeled.

[0088] Figs. 19A-19F illustrate certain aspects of the genes with converging coding and regulatory variants, in accordance with some embodiments. Fig. 19A: Number of eGFRcrea GWAS loci prioritized by regulatory variants (prioritization score ^ 10) and coding variants. Fig. 19B: Validation of 601 genes using eGFRcys and / or BUN GWAS. Fig. 19C: Phenotypes enriched by 601 genes prioritized by both coding variants and regulatory variants (prioritization score 10). The x-axis is the significance (-loglO(p-value)) for each phenotype on the y-axis. Only the top 10 phenotypes were used for the plot. Fig. 19D: Number of nephropathy genes prioritized by GWAS (coding variants and regulatory variants with prioritization score 10),

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[0091] ExWAS, and PheWAS. Labeled genes include six genes only prioritized by GWAS and 11 shared genes. Fig. 19E: Fraction of genes causing kidney phenotypes. Each bar represents the genes prioritized using different evidence in this study. Fig. 19F: Features of coding variants converged with regulatory variants with a control of coding variants without convergence.

[0092] Figs. 20A-20D illustrate the cell type-specificity and clinical applications of genes targeted by coding and regulatory variants, in accordance with some embodiments. Fig. 20A: Heatmap of expression of 601 genes prioritized by both coding and regulatory variants (prioritization score 10) and open chromatin of their regulatory variants. Each row is a gene, and each column is a cell type. Row-scaled gene expression or chromatin accessibility was used for the plot. The cell type-specificity determined by snRNA is given in the left column, and the Open4Gene link is given in the right column. Fig. 20B: The number of cell type-specific highly expression genes. The y-axis is the number of specific genes for each cell type on the x-axis. Fig. 20C: Locus-zoom of eGFRcrea GWAS and prioritization evidence at the KNG1 locus. In the locus-zoom plot, the y-axis is the strength of association -loglO(p value, GWAS). The variant tracks showed the genetic variants identified by different omics data. The tracks on the left panel showed the open chromatin in each cell type, and the right panel showed the expression of each gene in each cell type. The curves showed the regulatory associations between gene TSS and associated variants. Fig. 20D: Overlap of genes targeted by FDA-approved drugs based on DrugBank and DGIdb.

[0093] Figs. 21A-21D: Prioritization of CHAC1 as a kidney disease gene, in accordance with some embodiments. Figs. 21A-21B: Regional association plots for kidney eGFRcre GWAS data (CKDGen study), human kidney meQTL analysis (genotype-methylation, n = 443), eQTL data in kidney tubules and eQTL data in kidney glomeruli. (Tubule n = 121 or glomerulus n = 119). Each dot represents 1 SNP. The dots are colored according to their relationship to the index SNP (rs4924525). The red dots indicate high correlation (r2 > 0.8) (LD) with the index SNP. The left y axis indicates -loglO (P value). The right y axis indicates recombination rate (cM / Mb). The x axis indicates the genomic location on chromosome 15. Fig. 21C: Box plots: the x axis represents the SNP (rs4924525 genotype A / A, C / A, C / C), and the y axis shows relative CHAC1 expression (P = 1.9 x IO'43) in human kidney tubule samples and (P=2.3 xlO-9 in kidney glomeruli samples. Fig. 21D: Effect sizes of eGFR GWAS SNPs (y axis) were plotted against eQTL SNPs (x axis). Error bars show the standard errors of SNP effects. Red dot indicates the

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[0095] 56242423.3 Attorney Docket No. 046483-7468W01(04021) top eQTL signal. Fig. 2 IE: Human kidney AT AC seq data highlighting areas of open chromatin associated with the variant rs4924525. Top row shows the eGFR GWAS SNPs followed by open chromatin in kidney cell types. PT; proximal tubule, LOH; loop of Henle, DCT; distal convoluted tubule, CD-PC / IC; collecting duct, principal cells and intercalated cells, Podo; podocyte, endo; endothelial cells, immune; immune cells, stroma; stromal cells.

[0096] Figs. 22A-22F demonstrate that lowering CHAC1 protects from folic acid nephropathy, in accordance with some embodiments. Fig. 22A: Relative expression of Chad in kidneys of wildtype (WT) (red) and CHACH7- mice (blue). (n=5). Fig. 22B: Representative western blot of CHAC1 protein level in WT(n=5) and CHAC1+ / - mice (n=3). Fig. 22C: Experimental design. WT and CHAC1+ / - mice were injected with folic acid (FA) and sacrificed one week later. Red is WT control, blue is CHAC1+ / - control, purple is WT FA treated and green is CHACH7- FA treated mice. Fig. 22D: Representative kidney images for H&E, PAS and Sirius red staining. Scale bar: 20 pm. Fig. 22E: Profibrotic gene expression in whole kidney tissue samples: Fibronectin (Fn), Collagen 1 (Col 1 al) and Collagen 3 (Col3al). Gene expression levels were normalized to Gapdh. Control-treated group: WT (n = 3-5) CHACH7- (n = 3-5), WT FA treated (n = 9-11), CHACH7- FA treated (n = 8-11). Fig. 22F : Representative western blot of SMA and FN in whole kidney lysates, GAPDH is used as a loading control. Protein quantification of SMA and FN level in whole kidney lysates. *P < 0.05, **P < 0.01, ***P < 0.001, 1-way ANOVA and Tukey’s post hoc test except for A which was compared with an unpaired t test.

[0097] Figs. 23 A-23F demonstrate that lower Chacl levels protect mice from diabetic kidney disease, in accordance with some embodiments. Fig. 23A: Experimental design: WT and CHACH7- mice underwent uni nephrectomy and STZ injection. Fig. 23B: Urine albumin-to- creatinine ratio at 24 weeks of age. Red is WT control, blue is CHAC1+ / - control, purple is WT Unx-STZ treated, and green is CHAC1+ / - Unx-STZ treated. Blood glucose levels of sham- treated and Unx-STZ-treated groups. Fig. 23C: Blood glucose level in experimental groups. Fig. 23D: Representative images for H&E, PAS and Sirius red staining. Scale bar: 20 pm. Fig. 23E: Profibrotic gene expression in whole kidney tissue samples: Fibronectin (Fn), Collagen 1 (Col lai) and Collagen 3 (Col3al). Gene expression levels were normalized to Gapdh. Control- treated group: WT (n = 3), CHAC1+ / - (n = 3), WT Unx-STZ treatment group: WT (n = 5), CHAC1+ / - (n = 5). Fig. 23F: Representative western blot images of SMA and FN in whole

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[0099] 56242423.3 Attorney Docket No. 046483-7468W01(04021) kidney lysates, GAPDH was usedas a loading control. Quantification for SMA and FN levels *P < 0.05, **P < 0.01, ***P < 0.001, 1-way ANOVA and Tukey’s post hoc test.

[0100] Figs. 24A-24F demonstrate that lower Chad protects from adenine-induced chronic kidney disease, in accordance with some embodiments. Fig. 24A: Experimental design: WT and CHAC1+ / - mice were fed with 0.2% adenine. Fig. 24B: Creatinine, BUN, Cystatin C measurements. Red is WT control, blue is CHACU7- control, purple is WT Adenine treated, and green is CHACU7- Adenine treated. Fig. 24C: Representative images for H&E, PAS and Sirius red staining. Scale bar: 20 pm. Fig. 24D: Profibrotic gene expression in whole kidney tissue samples: Fibronectin (Fn), Collagen 1 (Collal), Collagen 3 (Col3al) and SMA. Gene expression levels were normalized to Gapdh. Fig. 24E: Representative images of SMA and FN Western blots in whole kidney lysates, GAPDH was used as a loading control. Quantification for SMA and FN levels *P < 0.05, **P < 0.01, ***P < 0.001, 1-way ANOVA and Tukey’s post hoc test.

[0101] Figs. 25A-25G: Elevated CHAC1 expression in various circumstances, in accordance with some embodiments. Fig. 25A: In situ hybridization and Immuno Histo Chemistry for CHAC1 expression in control mice and disease mice. The red indicates the Loop of henle (UMOD). Blue indicates the CHAC1 expression. Fig. 25B: In situ hybridization and Immuno Histo Chemistry for CHAC1 expression in healthy vs CKD conditions in human kidney sections. Blue indicates the CHAC1 expression. Scale bars: 20 pm. Fig. 25C: CHAC1 RNA expression in RPTECs with time dependent tunicamycin treatment (n=3). Fig. 25D: CHAC1 protein expression in tunicamycin treatment (n=3). Quantification for CHAC1 blot. GAPDH was used as an internal control (n=3). Fig. 25E: CHAC1 expression in TGF-[3 treated primary kidney tubule cells (n=3). Fig. 25F: CHAC1 expression in Erastin treated primary kidney tubule cells (n=3). Fig. 25G: CHAC1 expression in cysteine methionine deprived primary kidney tubule cells (n=3).

[0102] Figs. 26A-26E demonstrate that ectopic human Chacl expression is sufficient to induce ferroptosis, in accordance with some embodiments. Fig. 26A: LDH levels of control and CHAC1 overexpressed cells (n = 3). Fig. 26B: Quantitative gene expression for ferroptosis markers of FTH1 and ACSL4 in control and cells overexpressing CHAC1 (n = 4). Fig. 26C: Ferroptosis markers protein expression levels in control and cells overexpressing CHAC1 (n = 3). Fig. 26D: Apoptosis and Pyroptosis markers expression levels in control and cells overexpressing CHAC1 (n = 3). Fig. 26E: Glutathione levels in control and cells overexpressing CHAC1 (n = 3).

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[0105] Figs. 27A-27G demonstrate that lower CHAC1 ameliorated the consequences of Cysteine- Methionine deprivation, in accordance with some embodiments. Fig. 27A: Cell death measurement (% LDH release) of primary kidney tubule cells cultured in control or CMD (cystatin methionine deprived) medium (n = 3). Fig. 27B: LDH levels of WT cells with various cell death inhibitors cultured in control or CMD medium (n=3). Fig. 27C: Protein expression levels of Ferroptosis markers in cells cultured in CMD medium and Fer-1 (n = 3). Fig. 27D: LDH levels of WT and CHAC1+ / - cells with the CMD medium (n=3). Fig. 27E: Representative BODIPY 581 / 591 Cl 1 fluorescence of WT and CHACU7- cells with the CMD medium (n=3). Scale bar: 50 pm. Quantification of BODIPY staining. Fig. 27F: Glutathione levels in CMD condition wild type and CHAC1+ / - (n = 3). Fig. 27G: Gene expression levels of Ferroptosis markers in CHAC1 silencing cells cultured in CMDmedium (n = 3).

[0106] Figs. 28A-28D: lower ferroptosis in Chacl depleted mice, in accordance with some embodiments. Figs. 28A-28B: Expression of ferroptosis markers Acsl4, Acsl3 and Gpx4 in kidneys of mice FAN and STZ Unx model. Wild type control mice are shown in red, CHACU7- control mice in blue, wild type experimental animals are shown in purple, and CHAC1+ / - experimental animals are shown in green. (n=3-4 control groups, n=8-l 1 experimental groups). Fig. 28C: Representative GPX4 and ACSL4 western blot in kidneys of control FAN mice (n=3-4 per group). GAPDH is used as a loading control. Fig. 28D: GPX4 and ACSL4 protein expression in the STZ-Unx model (n=3-4 per group). GAPDH is used as a loading control.

[0107] Figs. 29A-29B: Higher CHAC1 and lower GPX4 in of patients with kidney disease, in accordance with some embodiments. Fig. 29A: Representative immunohistochemistry images of control and CKD human kidney sections stained for CHAC1, GPX4, ACSL4, FTH1 and SLC7A11. Scale bar 20 um. Fig. 29B: Representative CHAC1, GPX4 and ACSL4 and GAPDH immunoblots of whole human kidney protein lysates. Quantification of immunoblot.

[0108] Figs. 30A-30B: Locus zoom plot for CHAC 1 locus highlighted three genetic variants associated with eGFR creatinine in 1.75 M EUR population, in accordance with some embodiments.

[0109] Figs. 31 A- 3 IE demonstrate that the heterologous deletion of CHAC1 in mice has no baseline defect in kidney, in accordance with some embodiments. Fig. 31 A: Kidney injury markers such as Ngal and KIMI in chacU7- mice at baseline. Fig. 3 IB: Percentage of body weights recorded in at 6-week-old mice. (Right) serum urea in chacl+ / - mice at baseline. Fig.

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[0112] 31 C: Gene expression of fibrosis markers tested in Chacl+ / - mice. Fig. 31D: Gene expression of Loop of Henle markers such as UMOD, BST1, and SLC12A1 in chad + / -mice. Fig. 3 IE: Gene expression of Primary tubule cell markers such as SLC5A2, SLC5A12, SLC5A19, SLC27A2 and SLC34A1 in chacl+ / - mice.

[0113] Figs. 32A-32B: Gene expression of CHAC1 in various kidney disease models, in accordance with some embodiments. Fig. 32A: Bulk RNA-seq data for CHAC1 in kidney disease samples from TFAM (n=3), UUO (n=3), and FAN (n=3), Col4a3 (n=3), APOL1 G1 / G2 (n=4). Fig. 32B: CHAC1 gene expression tested in various kidney disease models in qRT-PCR.

[0114] Figs. 33A-33B: Chad + / - mice protects from kidney disease, in accordance with some embodiments. Fig. 33A: Serum creatinine measured in WT (n=4), and CHAC1+ / - (n=6) mice injected with folic acid (FA). Fig. 33B: Blood urea nitrogen levels measured in WT (n=4), and CHAC1+ / - (n=6) mice injected with folic acid (FA).

[0115] Figs. 34A-34B: Reduced expression of Ferroptosis markers in Chac+ / - cells, in accordance with some embodiments. Fig. 34A: Gene expression of CHAC1, FTH1, and PTGS2 expression in WT cells treated with erastin (20uM). Fig. 34B: Gene expression of CHAC1 genes in primary tubule cells isolated from WT and Chacl+ / - mice and treated with erastin.

[0116] Figs. 35A-35F: ChacH7- cells protected against TGF-P action, in accordance with some embodiments. Fig. 35A: LDH release assay for cell viability in WT and CHACH7- primary tubule cells treated with TGF-p. Fig. 35B: B0DIPY-C511 staining in WT and siCHACl transfected cells treated with TGF-P and its quantification. Fig. 35C: BODIPY-C511 staining in cells treated with TGF-P in the presence or absence of ferrostatin (Fer-1) and its quantification. Fig. 35D: Glutathione levels are tested in WT and siCHACl transfected cells and treated with TGF-p. Fig. 35E: Immunoblots of FN1, SMA, and GAPDH in WT cells transfected with siCHACl and treated with TGFp. Right, quantification. Fig. 35F: Gene expression of CHAC1, SMA, and FN1 in WT and ChacH7- cells treated with TGF-p.

[0117] Figs. 36A-36F: CHAC1 and ferroptosis gene signature in TAL in kidney patients, in accordance with some embodiments. Fig. 36A: Box plots showing the CHAC1 expression in TAL clusters between healthy reference and CKD subjects. P values were calculated with the Wilcoxon rank-sum test (for two group comparison). Fig. 36B: Box plots showing the FTH1 expression in TAL clusters between healthy reference and CKD subjects. Fig. 36C: Box plots showing the NC0A4 expression in TAL clusters between healthy reference and CKD subjects.

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[0120] Fig. 36D: Box plots showing the SLC7A1 1 expression in TAL clusters between healthy reference and CKD subjects. Fig. 36E: Box plots showing the HSPB1 expression in TAL clusters between healthy reference and CKD subjects. Fig. 36F: Box plots showing the ACSL3 expression in TAL clusters between healthy reference and CKD subjects.

[0121] Fig. 37 illustrates certain aspects of the efficiencies of some non-limiting Chad siRNA in knocking down Chac mRNA expression, in accordance with some embodiments.

[0122] DETAILED DESCRIPTION

[0123] The following disclosure provides many different embodiments, or examples, for implementing different features of the provided subject matter. Specific examples of components and arrangements are described below to simplify the present disclosure. These are, of course, merely examples and are not intended to be limiting. For example, the formation of a first feature over or on a second feature in the description that follows may include embodiments in which the first and second features are formed in direct contact, and may also include embodiments in which additional features may be formed between the first and second features, such that the first and second features may not be in direct contact. In addition, the present disclosure may repeat reference numerals and / or letters in the various examples. This repetition is for the purpose of simplicity and clarity and does not in itself dictate a relationship between the various embodiments and / or configurations discussed.

[0124] The present invention relates to genetics-guided diagnosis and treatment of kidney diseases. In some aspects, it relates to platforms and methods for prioritizing causal variants, genes, and cell types using integrated multi-omics, and to diagnostic and therapeutic interventions directed at such prioritized targets. In some aspects, the invention also relates to computer-implemented systems for generating the prioritization and clinical decision outputs.

[0125] Current therapies for kidney diseases, including inhibitors of the renin-angiotensin system and sodium-glucose cotransporter-2 (SGLT2) inhibitors, can slow progression but rarely halt or reverse disease. Once patients progress to end-stage renal disease (ESRD), dialysis or transplantation remain the only options. Accordingly, there is a critical need for approaches that identify causal mechanisms and enable precision diagnostics and therapies to delay progression and reduce the need for dialysis or transplantation.

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[0128] Genetics plays a major role in kidney function and disease. Genome-wide association studies (GWAS) have identified more than 1,000 independent loci associated with estimated glomerular filtration rate (eGFR) and kidney disease. However, more than 90% of sentinel variants lie in noncoding regions and thus cannot be directly assigned to causal genes or mechanisms. This long-standing variant-to-gene and variant-to-function bottleneck has historically limited the translation of GWAS discoveries into clinical diagnostics and therapies.

[0129] To address this challenge, the present study performed a multi-ancestry GWAS of kidney function in over 2.2 million individuals and developed the Kidney Disease Genetic Scorecard (KDGS). The Kidney Disease Genetic Scorecard (KDGS) is a systematic framework that integrates genome-wide association studies (GWAS) with fine-mapping, expression quantitative trait loci (eQTL), allele-specific expression (ASE), bulk and single-nucleus allele-specific chromatin accessibility (bASA, snASA), DNA methylation QTL (meQTL), and single-cell multiome peak-to-gene mapping (Open4Gene). The KDGS systematically prioritizes causal variants, effector genes, and cell types of action in the kidney and provides a unified framework for risk prediction, patient stratification, and therapeutic target discovery.

[0130] The present study, such as the KDGS study, enables the prioritization of causal variants, effector genes, and cell types of action in kidney disease, providing a ranked list of variant gene —■ cell-type triplets suitable for diagnostic and therapeutic decision-making.

[0131] The KDGS can be used for risk prediction, early diagnosis, prognosis, monitoring disease progression, patient stratification, and therapeutic target discovery, thereby supporting precision medicine for kidney disease.

[0132] Notably, the KDGS study identified and validated multiple kidney disease genes across diverse mechanistic pathways, demonstrating general applicability of this strategy. The kidney disease genes and mechanistic pathways include:

[0133] - DPEP1 / CHMP1A (ferroptosis and iron metabolism): At a chromosome 16 locus, risk alleles coordinate up-regulation of DPEP1 and CHMP1A in tubules. Functional studies showed that both genes promote ferroptotic cell death by disrupting iron trafficking and lipid peroxidation; mouse knockouts were protected from injury. DPEP1 encodes dipeptidase- 1, and a DPEP1 inhibitor (cilastatin) is under Phase II clinical evaluation for the prevention of acute kidney injury, highlighting the translational potential of KDGS outputs.

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[0136] - ACSS2 (lipid metabolism and pyroptosis): KDGS assigned a chromosome 20 locus to ACSS2, a regulator of de novo lipogenesis. Risk alleles increase ACSS2 expression in proximal tubules, resulting in lipid accumulation, NADPH depletion, oxidative stress, and NLRP3 inflammasome activation. Acss2 knockout mice show reduced fibrosis across models, and inhibition of fatty acid synthase provides similar protection, demonstrating therapeutic tractability of the lipogenesis axis.

[0137] - WHAMM (cytoskeletal remodeling): KDGS prioritized WHAMM, a regulator of actin and microtubule dynamics. WHAMM expression rises during kidney injury, and Whamm- deficient mice are protected in acute and chronic models. Mechanistic experiments indicate that WHAMM promotes actin-dependent cytochrome-c release and ASC inflammasome assembly; actin polymerization inhibitors ameliorate kidney injury, phenocopying WHAMM deficiency.

[0138] - TET2 (DNA repair and innate immune sensing): KDGS identified TET2, a DNA demethylation enzyme essential for genomic stability in tubules. Variants lowering TET2 expression associate with worse kidney function. Tubule-specific Tet2 knockout mice are protected from injury; loss of TET2 impairs DNA repair, causing micronuclei accumulation and activation of the cGAS-STING pathway. Genetic or pharmacologic STING inhibition prevents disease, directly linking a GWAS locus to a druggable innate immune pathway.

[0139] - DACH1 (fibrosis regulation): KDGS and transcriptome-wide association analyses implicated DACH1 as a protective transcription factor. Risk alleles decrease DACH1 expression in tubules. Dachl knockout mice exhibit more severe fibrosis, whereas tubule-specific overexpression is protective. Single-cell studies show that DACH1 restrains cell-cycle progression and pro-inflammatory chemokine signaling; loss of DACH1 results in macrophage infiltration and fibrosis.

[0140] - Epigenetic regulation at TNF'. Within the KDGS framework, an epigenome -wide study in diabetic kidney disease identified differential methylation in the TNF promoter. Higher methylation correlates with improved outcomes. Targeted demethylation using dCas9-TETl increases TNF expression in cell systems, whereas TNF overexpression in mice worsens albuminuria, establishing causal epigenetic regulation of an inflammatory driver.

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[0143] These discoveries illustrate that KDGS not only identifies causal genes but also delivers mechanistic insight across ferroptosis, lipid metabolism, cytoskeletal dynamics, DNA damage repair, transcriptional regulation, and inflammation, thereby translating genetic signals into actionable therapeutic pathways and into druggable targets and biomarkers. Indeed, several outputs are already translatable, including DPEP1 inhibition under clinical evaluation, STING inhibitors in development, and fatty acid synthesis inhibitors available from oncology pipelines.

[0144] Among these mechanisms, ferroptosis has emerged as a driver of tubular injury. Multiple KDGS-prioritized genes — DPEP1 , CHMP1A, and ACSS2 — converge on glutathione-dependent lipid peroxide detoxification. Within this context, CHAC1 (ChaC glutathione-specific y- glutamylcyclotransferase 1) is a prototypical effector gene. Risk alleles at the CHAC1 locus reduce DNA methylation and increase CHAC1 expression in tubules. CHAC1 degrades glutathione, diminishing tubular antioxidant defenses. Patients carrying risk alleles exhibit higher renal CHAC1 levels. Functionally, Chad haploinsufficient mice are resistant to folic-acid nephropathy, adenine nephropathy, and diabetic kidney disease. Mechanistically, reduced CHAC1 preserves glutathione, prevents lipid peroxidation, and blunts ferroptotic cell death; in human kidney biopsies, CHAC1 expression correlates with ferroptosis markers, linking genetic variation to disease progression. Indeed, heterozygous deletion of Chacl protects mice from kidney injury, and siRNA-mediated knockdown in human and mouse tubular cells reduces ferroptotic cell death.

[0145] These findings also position CHAC1 as a validated effector gene and an exemplar of how KDGS moves seamlessly from GWAS signals to causal gene identification, mechanistic insight, and therapeutic opportunity. While CHAC1 is described in detail herein, the invention is not limited to CHAC1, but extends to all KDGS-prioritized kidney disease genes and to generalized methods of diagnosing and modulating such genes using RNAi / ASO, gene editing, epigenome editing, antibodies, small molecules, and related modalities in a human subject.

[0146] Accordingly, in some aspects, the present invention is directed to methods, compositions, and platforms for identifying, prioritizing, and therapeutically targeting kidney disease genes in a subject, such as a human.

[0147] Indeed, the present study identified more than ten thousand single nucleotide polymorphisms (SNPs) associated with kidney diseases, as well as more than six hundred genes that are mutated in kidney disease patients.

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[0150] The detection of the risk alleles of the kidney diseases SNPs can reveal the genetic predisposition of a subject to kidney diseases. Accordingly, in some embodiments, the present invention is directed to methods of predicting kidney disease risk.

[0151] The genes associated with kidney diseases can be targeted to treat, ameliorate and / or prevent kidney diseases. Similarly, disease alleles of SNPs associated with kidney diseases can be corrected, such as with CRISPR method. Accordingly, the present invention is directed to a method is directed to methods of treating, ameliorating, and / or preventing kidney diseases.

[0152] Definitions

[0153] As used herein, each of the following terms has the meaning associated with it in this section. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Generally, the nomenclature used herein and the laboratory procedures in animal pharmacology, pharmaceutical science, peptide chemistry, and organic chemistry are those well-known and commonly employed in the art. It should be understood that the order of steps or order for performing certain actions is immaterial, so long as the present teachings remain operable. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting; information that is relevant to a section heading may occur within or outside of that particular section. All publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference.

[0154] In the application, where an element or component is said to be included in and / or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components and can be selected from a group consisting of two or more of the recited elements or components.

[0155] In the methods described herein, the acts can be carried out in any order, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process.

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[0158] In this document, the terms "a," "an," or "the" are used to include one or more than one unless the context clearly dictates otherwise. The term "or" is used to refer to a nonexclusive "or" unless otherwise indicated. The statement "at least one of A and B" or "at least one of A or B" has the same meaning as "A, B, or A and B."

[0159] "About" as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20% or ±10%, in certain embodiments ±5%, in certain embodiments ±1%, in certain embodiments ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[0160] Unless specified otherwise, the nomenclature of the single nucleotide polymorphisms (SNPs) herein follows those of the Single Nucleotide Polymorphism Database (dbSNP) hosted by the National Center for Biotechnology Information.

[0161] “Subject” as used herein refers to a mammal, such as a human, in need of diagnosis, risk prediction, prophylaxis, or treatment, such as of kidney disease.

[0162] “Kidney disease” as used herein includes but is not limited to chronic kidney disease (CKD), diabetic kidney disease (DKD), acute kidney injury (AKI), and glomerular and tubulointerstitial disorders that impair kidney structure and / or function.

[0163] “Treating” and “treatment” as used herein refer to any intervention that prevents, delays, arrests, or reduces the severity or progression of kidney disease, improves a clinical sign or laboratory marker (e.g., eGFR, ACR), or reduces the risk of progression to end-stage renal disease (ESRD).

[0164] “Preventing” and “prophylaxis” as used herein refer to reducing the risk, incidence, or rate of onset of kidney disease or disease progression in a subject at risk.

[0165] “Effective amount” and “therapeutically effective amount” as used herein refer to an amount sufficient to elicit a desired biological or clinical effect (e.g., reduction of tubular injury, fibrosis, albuminuria, or preservation of eGFR).

[0166] “Pharmaceutically acceptable carrier” and “excipient” as used herein refer to a non-toxic material suitable for the formulation and administration of therapeutic agents, including buffers, tonicity agents, cryoprotectants, and surfactants for parenteral delivery.

[0167] “Administering” or “route of administration” includes intravenous (IV), subcutaneous (SC), intraperitoneal (IP), intra-arterial (including renal artery), and other routes known in the art.

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[0170] “Kidney Disease Genetic Scorecard” or “KDGS” as used herein refer to a multi-omic integrative framework for prioritizing causal variants, genes, and cell types for kidney disease using GWAS fine-mapping and kidney-specific datasets, including eQTL, ASE, bASA, snASA, meQTL, Open4Gene, and colocalization. KDGS outputs include variant^gene^cell-type triplets and prioritization scores. (See, e.g., Figs. 1 - 6).

[0171] “Expression quantitative trait locus” or “eQTL” as used herein refers to a genomic locus associated with steady-state mRNA expression of a gene in kidney tissue or compartments (tubule, glomerulus).

[0172] “Allele-specific expression” or “ASE” as used herein refers to within-sample allelic imbalance of gene expression driven by cis-acting genetic variation.

[0173] “Bulk / single-nucleus allele-specific chromatin accessibility” or “bASA / snASA” as used herein refers to genotype-dependent differences in chromatin accessibility measured by ATAC- seq in bulk kidney or at single-nucleus resolution.

[0174] “Methylation QTL” or “meQTL” as used herein refers to the association between genotype and CpG DNA methylation levels in human kidney tissue.

[0175] “Open4Gene as used herein refers to a single-cell multiome peak-to-gene linkage framework that models associations between open chromatin peaks and gene expression at single-cell resolution. (See, e.g., Figs. 5A-5G).

[0176] “Ferroptosis” as used herein refers to iron-dependent programmed cell death characterized by lipid peroxidation, typically accompanied by ACSL4 f , GPX4 1 , 4-HNE staining, and increased BODIPY 581 / 591-C11 oxidation.

[0177] “Nucleic acid therapeutics” as used herein include siRNA, shRNA, antisense oligonucleotides (ASO), and gRNAs; may include chemical modifications (e.g., 2’-O-methyl, 2’- fluoro, locked nucleic acid (LNA), phosphorothioate linkages) to improve stability, potency, and pharmacokinetics.

[0178] “Genome editing” as used herein include CRISPR / Cas-based nucleases, base editors (ABE / CBE), and prime editors for sequence modification at fine-mapped variants; CRISPRi / CRISPRa for transcriptional repression / activation.

[0179] “Epigenome editing” as used herein include those using dCas9-based fusions (e.g., dCas9-TETl, dCas9-DNMT3A, dCas9-HDAC, dCas9-HAT) for targeted demethylation / methylation or histone modification at GWAS-linked regulatory elements.

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[0182] Method of Treating, Ameliorating and / or Preventing Kidney Disease

[0183] In some aspects, the present invention is directed to a method of treating, ameliorating and / or preventing a kidney disease in a subject thereof.

[0184] Non-limiting examples of the kidney disease comprises chronic kidney disease (CKD), diabetic kidney disease (DKD), acute kidney injury (AKI), and related glomerular, tubulointerstitial disorders, and the like.

[0185] In some embodiments, down-regulation of a KDGS-prioritized gene reduces tubular cell ferroptosis, endoplasmic reticulum (ER) stress, or inflammatory cytokine production. In some embodiments, the method prevents or delays progression to end-stage renal disease, reduce the need for dialysis or transplantation, and in some embodiments, the method is tailored based on the subject’ s genotype at an APOL1, UMOD, or CHAC1 locus, thereby enable patient-specific precision therapies.

[0186] In some embodiments, the method comprises altering the nucleotide in a singlenucleotide polymorphism (SNP) that is associated with the kidney disease in a cell of the subject.

[0187] In some embodiments, the method comprises replacing a risk allele of the SNP, which causes or is otherwise associated with the kidney disease, with a reference allele of the SNP, which is not associated with the kidney disease. In some embodiments, the reference allele of the SNP is present in the majority of the general population. In some embodiments, the risk allele of the SNP is present in subjects with reduced kidney function as compared to a comparable healthy subject.

[0188] In some embodiments, the SNPs, as well as the risk allele and the reference allele for each of the SNPs, are selected from the group consisting of those listed in Table 1 herein and rs4924525. In some embodiments, the risk alleles are those listed under “Allele 1” in Table 1. In some embodiments, the reference alleles are those listed under “Allele 2” in Table 1.

[0189] In some embodiments, the nucleotide in the SNP is altered in a kidney cell of the subject.

[0190] In some embodiments, the nucleotide in the SNP is altered with a genome editing method, optionally, a CRISPR based method, optionally a CRISPR / Cas9 method. Genome editing method is known in the art, and non-limiting examples of genome editing methods are described elsewhere herein.

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[0193] In some embodiments, the method comprises down-regulating or up-regulating a gene whose mis-regulation causes or is associated with the kidney disease.

[0194] In some embodiments, the gene whose mis-regulation causes or is associated with the kidney disease is a gene selected from the group consisting of those listed Table 2 and CHAC1.

[0195] In some embodiments, the method comprises up-regulating or down-regulating the misregulated gene. Methods of up- or down-regulating genes are known in the art. It is known that a gene can be regulated by altering the expression levels and / or the activity of the protein products thereof, and that the regulation can take place at the genomic level, the transcriptional level (e.g., mRNA level), the translational level (e.g., the protein level), the post-translational level (e.g., post-translational modification and / or degradation), and etc. Non-limiting examples of methods of up- and down-regulating genes are described elsewhere herein.

[0196] In some embodiments, the kidney disease causes a reduction in a filtration capacity of the kidney in the subject as compared to a healthy control subject. In some embodiments, the subject has an estimated glomerular filtration rate of about 90% or less, about 85% or less, about 80% or less, about 75% or less, about 70% or less, about 65% or less, about 60% or less, about 55% or less, about 50% or less, about 45% or less, about 40% or less, about 35% or less, about 30% or less, about 25% or less, about 20% or less, or about 15% or less.

[0197] In some embodiments, the subject is a human.

[0198] Altering Alleles of SNPs

[0199] In some embodiments, the method herein treats, ameliorates and / or prevents kidney diseases by altering nucleotides (or alleles) of SNPs, such as those listed in Table 1 herein and / or a genetic variation at the CHAC1 locus (optionally a CHAC1 SNP associated with increased CHAC1 expression, reduced glutathione, and / or heightened susceptibility to ferroptosis, such as rs4924525), in the subject, such as in the kidney of the subject.

[0200] In some embodiments, the method replaces an risk allele, which is associated with kidney disease, with a reference allele, which are found in healthy subjects.

[0201] In some embodiments, the method alters the SNPs using a genome editing method, such as by based editing or prime editing, such as by a CRISPR-Cas9 based method.

[0202] Genome editing method for altering nucleotide / alleles in SNPs are known in the art. Genome editing involves the precise manipulation of DNA sequences to modulate cellular

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[0204] 56242423.3 Attorney Docket No. 046483-7468W01(04021) phenotypes, offering a therapeutic strategy to cure diseases. CRISPR-Cas9, the most widely used genome editor, is an RNA-guided DNA-cutting enzyme complex that creates double stranded DNA breaks (DSBs) at target positions in the DNA of eukaryotic cells. Repair of these breaks most commonly occurs via error-prone non-homologous end joining (NHEJ), which leads to small insertions and deletions (indels) at the break site that may interrupt gene function. Early clinical data suggest that NHEJ-mediated gene knockout can reduce the expression of diseasecausing proteins or induce the expression of therapeutic proteins. Indeed, the FDA recently approved the first genome editing drugs that use CRISPR-Cas9 technology, CASGEVY™ and LYFGENIA™, for the treatment of sickle cell disease and transfusion-dependent betathalassemia.

[0205] CRISPR-Cas9, as well as other methods have been studied in the genome editing. Pickar- Oliver et al. (Nat Rev Mol Cell Biol. 2019 Aug; 20(8): 490-507) describes fusing catalytically dead forms of Cas9 with different effector proteins to manipulate DNA or gene expression. CRISPR-Cas9 mediated DNA base editing can convert undesired spontaneous point mutations to the wild-type nucleotide to correct disease-causative point mutations (see e.g., Gaudelli et al. Nature 551, 464-471). DNA base editing can be achieved by fusing a Cas9 nickase with a cytidine deaminase enzyme and uracil glycosylate inhibitor to achieve a C->T (or G->A) substitution. Similarly, a transfer RNA adenosine deaminase is fused to a catalytically dead Cas9 to generate A->G (or T->C) conversion. DNA editing-induced changes occur without a DSB and without the need for introduction of a donor template. Disease-relevant mutations in mammalian cells can be corrected with base editing strategies (Dandage et al. Genetics 212: 377-385.). Prime Editing based on the fusion of Cas9 and reverse transcriptase can be added to CRISPR editing to increase precision and flexibility (Anzalone et al. Nature 576: 149-157).

[0206] Down-regulating and Up-regulating Genes Associated with Kidney Diseases

[0207] In some embodiments, the method herein treats, ameliorates and / or prevents kidney diseases by down-regulating or up-regulating one or more genes associated with kidney diseases, such as those listed in Table 2 herein and / or CHAC1 (ChaC Glutathione-Specific y- Glutamylcyclotransferase 1), in the subject, such as in the kidney of the subject.

[0208] One of ordinary skill in the art would be able to determine which of the genes listed in Table 2 need to be down-regulated to treat, ameliorated and / or prevent the kidney disease, and

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[0210] 56242423.3 Attorney Docket No. 046483-7468W01(04021) which of the genes need to be up-regulated. CHAC1 is upregulated in kidney diseases and needs to be down-regulated.

[0211] For example, if a gene listed in table 2 is found to be presumed loss-of-function (“pLOF”) in kidney disease patients or having reduced chromatin accessibility, this gene should be up-regulated in order to treat, ameliorate and / or prevent kidney diseases. Similarly, if a gene is found to be contain a missense mutation that results in higher than usual activity or having increased chromatin accessibility, this gene should be up-regulated to treat, ameliorate and / or prevent the kidney disease.

[0212] Non-limiting examples of the compounds for down-regulating or up-regulating genes are described herein:

[0213] Downregulating genes associated with kidney disease by small molecule inhibitors

[0214] In some embodiments, the compound that downregulates a gene associated with kidney disease includes a small molecule that inhibits the activity of the gene associated with kidney disease (such as a protein product thereof). As used herein, the term “small molecule” refers to a molecule having a size of less than 2000, 1800, 1600, 1400, 1200, 1000, 800, or 600 daltons.

[0215] In some embodiments, the small molecule inhibitor comprises a PROTAC or a Proteolysis Targeting Chimeric Molecule. PROTACs are heterobifunctional nanomolecules that can target any protein for ubiquitination and degradation. In certain embodiments, the PROTAC contemplated in the present invention comprises a group that is recognized by the E3 ubiquitin ligase and a group that is recognized by a protein product of the gene associated with kidney disease. The PROTAC is able to simultaneously bind to the protein product and the E3 ligase. Formation of such trimeric complex formation leads to the transfer of ubiquitins to the protein product, marking it for degradation. PROTAC molecules possess good tissue distribution and the ability to target intracellular proteins, thus can be directly applied to cells or injected into animals without the use of vectors. PROTACS useful within the invention can be prepared using any known compound that binds to and / or recognizes and / or inhibits the protein product of the gene associated with kidney disease, which is linked through a linker to an E3 ubiquitin ligase, such as but not limited to those described in WO 2013 / 106643, WO 2013 / 106646, and WO 2019 / 148055.

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[0218] Downregulating genes associated with kidney disease by protein inhibitors of the genes

[0219] In some embodiments, the compound that downregulates a gene associated with kidney disease includes a protein that downregulates the gene associated with kidney disease, such as by downregulating the protein product of the gene.

[0220] In some embodiments, the protein inhibitor is an antibody for the protein product of the gene associated with kidney disease, such as a neutralizing antibody.

[0221] In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a polyclonal antibody. In some embodiments, the antibody is a antigen binding fragment of a full antibody such as an IgG. In some embodiments, the antibody is a heavy chain antibody or a nanobody. In some embodiments, the antibody is humanized. Antibodies for a given protein is well known in the art.

[0222] In some embodiments, the protein that downregulates the gene associated with kidney disease is administered in form of a protein. In some embodiments, the protein that downregulates the expression level and / or activity of gene associated with kidney disease is administered in form of a nucleic acid that expresses the protein, such as an expression vector. The expression vector is described in the “Vector” section elsewhere in the instant specification.

[0223] Downregulating genes associated with kidney disease by RNA Interference

[0224] In some embodiments, the compound that downregulates a gene associated with kidney disease includes a nucleic acid that downregulates the activity and / or expression level of the kidney disease gene by the means of RNA interreference.

[0225] In some embodiments, the nucleic acid that downregulates the gene associated with kidney disease by the means of RNA interreference includes an isolated nucleic acid. In other embodiments, the modulator is an RNAi molecule (such as but not limited to siRNA and / or shRNA and / or miRNAs) or antisense molecule, which inhibits the expression and / or activity of the gene associated with kidney disease. In yet other embodiments, the nucleic acid comprises a promoter / regulatory sequence, such that the nucleic acid is preferably capable of directing expression of the nucleic acid. Thus, the instant specification provides expression vectors and methods for the introduction of exogenous DNA into cells with concomitant expression of the exogenous DNA in the cells such as those described, for example, in Sambrook et al. (2012, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York), and in

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[0228] Ausubel et al. (1997, Current Protocols in Molecular Biology, John Wiley & Sons, New York) and as described elsewhere herein.

[0229] In certain embodiments, siRNA is used to decrease the level of the gene associated with kidney disease, such as the mRNA or protein product thereof. RNA interference (RNAi) is a phenomenon in which the introduction of double-stranded RNA (dsRNA) into a diverse range of organisms and cell types causes degradation of the complementary mRNA. In the cell, long dsRNAs are cleaved into short 21-25 nucleotide small interfering RNAs, or siRNAs, by a ribonuclease known as Dicer. The siRNAs subsequently assemble with protein components into an RNA-induced silencing complex (RISC), unwinding in the process. Activated RISC then binds to complementary transcript by base pairing interactions between the siRNA antisense strand and the mRNA. The bound mRNA is cleaved and sequence specific degradation of mRNA results in gene silencing. See, for example, U.S. Patent No. 6,506,559; Fire et al., 1998, Nature 391(19):306-311; Timmons et al., 1998, Nature 395:854; Montgomery et al., 1998, TIG 14 (7):255-258; Engelke, Ed., RNA Interference (RNAi) Nuts & Bolts of RNAi Technology, DNA Press, Eagleville, PA (2003); and Hannon, Ed., RNAi A Guide to Gene Silencing, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (2003). Soutschek et al. (2004, Nature 432: 173-178) describes a chemical modification to siRNAs that aids in intravenous systemic delivery. Optimizing siRNAs involves consideration of overall G / C content, C / T content at the termini, Tm and the nucleotide content of the 3' overhang. See, for instance, Schwartz et al., 2003, Cell, 115: 199-208 and Khvorova et al., 2003, Cell 115:209-216. Therefore, the instant specification also includes methods of decreasing levels of kidney disease genes using RNAi technology.

[0230] In certain embodiments, the instant specification provides a vector comprising an siRNA or antisense polynucleotide. In other embodiments, the siRNA or antisense polynucleotide inhibits the expression of the gene associated with kidney disease. The incorporation of a desired polynucleotide into a vector and the choice of vectors is well-known in the art.

[0231] In certain embodiments, the expression vectors described herein encode a short hairpin RNA (shRNA) inhibitor. shRNA inhibitors are well known in the art and are directed against the mRNA of a target, thereby decreasing the expression of the target. In certain embodiments, the encoded shRNA is expressed by a cell, and is then processed into siRNA. For example, in certain instances, the cell possesses native enzymes (e g., dicer) that cleaves the shRNA to form siRNA.

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[0234] The siRNA, shRNA, or antisense polynucleotide can be cloned into a number of types of vectors as described elsewhere herein. For expression of the siRNA or antisense polynucleotide, at least one module in each promoter functions to position the start site for RNA synthesis.

[0235] In order to assess the expression of the siRNA, shRNA, or antisense polynucleotide, the expression vector to be introduced into a cell can also contain either a selectable marker gene or a reporter gene or both to facilitate identification and selection of expressing cells from the population of cells sought to be transfected or infected using a viral vector. In certain embodiments, the selectable marker may be carried on a separate piece of DNA and used in a cotransfection procedure. Both selectable markers and reporter genes may be flanked with appropriate regulatory sequences to enable expression in the host cells. Useful selectable markers are known in the art and include, for example, antibiotic-resistance genes, such as neomycin resistance and the like.

[0236] Following the generation of the siRNA polynucleotide, a skilled artisan will understand that the siRNA polynucleotide has certain characteristics that can be modified to improve the siRNA as a therapeutic compound. Therefore, in some embodiments, the siRNA polynucleotide is further designed to resist degradation by modifying it to include phosphorothioate, or other linkages, methylphosphonate, sulfone, sulfate, ketyl, phosphorodithioate, phosphoramidate, phosphate esters, and the like (see, e.g., Agrwal et al., 1987, Tetrahedron Lett. 28:3539-3542; Stec et al., 1985 Tetrahedron Lett. 26:2191-2194; Moody et al., 1989 Nucleic Acids Res. 12:4769-4782; Eckstein, 1989 Trends Biol. Sci. 14:97-100; Stein, In: Oligodeoxynucleotides. Antisense Inhibitors of Gene Expression, Cohen, ed., Macmillan Press, London, pp. 97-117 (1989)).

[0237] In some embodiments, the RNA interreference oligonucleotides are specifically designed to increase the cellular uptake of these oligonucleotides. Methods of designing oligonucleotides having desirable cellular uptake are described in, e.g., Geary et al., Adv Drug Deliv Rev 87, 46- 51 (2015) and Crooke et al., Nature biotechnology 35, 230-237 (2017).

[0238] Any polynucleotide may be further modified to increase its stability in vivo. Possible modifications include, but are not limited to, the addition of flanking sequences at the 5' and / or 3' ends; the use of phosphorothioate or 2' O-methyl rather than phosphodiester linkages in the backbone; and / or the inclusion of nontraditional bases such as inosine, queosine, and wybutosine

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[0240] 56242423.3 Attorney Docket No. 046483-7468W01(04021) and the like, as well as acetyl- methyl-, thio- and other modified forms of adenine, cytidine, guanine, thymine, and uridine.

[0241] In certain embodiments, an antisense nucleic acid sequence expressed by a plasmid vector is used to inhibit the protein expression of the kidney disease genes. The antisense expressing vector is used to transfect a mammalian cell or the mammal itself, thereby causing reduced endogenous expression of the genes.

[0242] Antisense molecules and their use for inhibiting gene expression are well known in the art (see, e.g., Cohen, 1989, In: Oligodeoxyribonucleotides, Antisense Inhibitors of Gene Expression, CRC Press). Antisense nucleic acids are DNA or RNA molecules that are complementary, as that term is defined elsewhere herein, to at least a portion of a specific mRNA molecule (Weintraub, 1990, Scientific American 262:40). In the cell, antisense nucleic acids hybridize to the corresponding mRNA, forming a double-stranded molecule thereby inhibiting the translation of genes.

[0243] The use of antisense methods to inhibit the translation of genes is known in the art, and is described, for example, in Marcus-Sakura (1988, Anal. Biochem. 172:289). Such antisense molecules may be provided to the cell via genetic expression using DNA encoding the antisense molecule as taught by Inoue, 1993, U.S. Patent No. 5,190,931.

[0244] Alternatively, antisense molecules of the instant specification may be made synthetically and then provided to the cell. Antisense oligomers of between about 10 to about 30, and more preferably about 15 nucleotides, are preferred, since they are easily synthesized and introduced into a target cell. Synthetic antisense molecules contemplated by the instant specification include oligonucleotide derivatives known in the art which have improved biological activity compared to unmodified oligonucleotides (see U.S. Patent No. 5,023,243).

[0245] It is worth noting that RNA interference molecule designs that accumulates in the kidney are available, are available and described in, for example, Biscans et al. (J Control Release. 2019 May 28:302: 116-125), Yamada et al. (Nat Biotechnol. 2024 Aug 1), Yang et al. (J Transl Med. 2015 Feb 1: 13:39), Molitoris et al. (J Am Soc Nephrol . 2009 Aug;20(8): 1754-64), Hamar et al. (Proc Natl Acad Sei USA. 2004 Oct 12; 101 (41 ): 14883-8), and Biscans et al. (Nucleic Acids Res. 2019 Feb 20;47(3): 1082-1096). Therefore, in some embodiments, the RNA interference molecule is designed for kidney accumulation.

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[0248] Non-limiting examples of the sequences of the RNA interference molecules for regulating the kidney disease genes herein are listed in Table 3.

[0249] Downregulating genes associated with kidney disease by ribozyme

[0250] In some embodiments, the compound that down regulates a gene associated with kidney disease includes a ribosome that inhibits the protein expression of the gene associated with kidney disease.

[0251] A ribozyme is used to inhibit gene expression. Ribozymes useful for inhibiting the expression of a target molecule may be designed by incorporating target sequences into the basic ribozyme structure which are complementary, for example, to the mRNA sequence produced from the gene associated with kidney disease. Ribozymes are antisense RNAs which have a catalytic site capable of specifically cleaving complementary RNAs. Therefore, ribozymes having sequence complementary to the mRNA sequences are capable of downregulating the expression of the gene associated with kidney disease by reduces the level of the mRNA. Ribozymes targeting the gene associated with kidney disease may be synthesized using commercially available reagents (Applied Biosystems, Inc., Foster City, CA) or they may be genetically expressed from DNA encoding them. In some embodiments, the DNA encoding the ribozymes are incorporated in a vector, which is described in the “Vector” section elsewhere in the instant specification.

[0252] Downregulating genes associated with kidney disease by CRISPR knockout / knockdown and other knockouts / knockdown techniques

[0253] In some embodiments, the compound that down regulates the activity or expression level of a gene associated with kidney disease comprises a nucleic acid that down regulates the expression level of the gene associated with kidney disease by the means of CRISPR knockout.

[0254] In some embodiments, the compound down regulates the activity or expression level of the gene associated with kidney disease comprises a CRISPR / Cas9 system for knocking out the gene.

[0255] The CRISPR / Cas9 system is a facile and efficient system for inducing targeted genetic alterations. Target recognition by the Cas9 protein requires a “seed” sequence within the guide RNA (gRNA) and a conserved di-nucleotide containing protospacer adjacent motif (PAM)

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[0257] 56242423.3 Attorney Docket No. 046483-7468W01(04021) sequence upstream of the gRNA-binding region. The CRISPR / Cas9 system can thereby be engineered to cleave virtually any DNA sequence by redesigning the gRNA in cell lines (such as 293T cells), primary cells, and CAR T cells. The CRISPR / Cas9 system can simultaneously target multiple genomic loci by co-expressing a single Cas9 protein with two or more gRNAs, making this system uniquely suited for multiple gene editing or synergistic activation of target genes.

[0258] The Cas9 protein and guide RNA form a complex that identifies and cleaves target sequences. Cas9 is comprised of six domains: REC I, REC II, Bridge Helix, PAM interacting, HNH, and RuvC. The Reel domain binds the guide RNA, while the Bridge helix binds to target DNA. The HNH and RuvC domains are nuclease domains. Guide RNA is engineered to have a 5' end that is complementary to the target DNA sequence. Upon binding of the guide RNA to the Cas9 protein, a conformational change occurs activating the protein. Once activated, Cas9 searches for target DNA by binding to sequences that match its protospacer adjacent motif (PAM) sequence. A PAM is a two or three nucleotide base sequence within one nucleotide downstream of the region complementary to the guide RNA. In one non-limiting example, the PAM sequence is 5'-NGG-3'. When the Cas9 protein finds its target sequence with the appropriate PAM, it melts the bases upstream of the PAM and pairs them with the complementary region on the guide RNA. Then the RuvC and HNH nuclease domains cut the target DNA after the third nucleotide base upstream of the PAM.

[0259] One non-limiting example of a CRISPR / Cas system used to inhibit gene expression, CRISPRi, is described in U.S. Patent Appl. Publ. No. US2014 / 0068797. CRISPRi induces permanent gene disruption that utilizes the RNA-guided Cas9 endonuclease to introduce DNA double stranded breaks which trigger error-prone repair pathways to result in frame shift mutations. A catalytically dead Cas9 lacks endonuclease activity. When coexpressed with a guide RNA, a DNA recognition complex is generated that specifically interferes with transcriptional elongation, RNA polymerase binding, or transcription factor binding. This CRISPRi system efficiently represses expression of targeted genes.

[0260] CRISPR / Cas gene disruption occurs when a guide nucleic acid sequence specific for a target gene and a Cas endonuclease are introduced into a cell and form a complex that enables the Cas endonuclease to introduce a double strand break at the target gene. In certain embodiments, the CRISPR / Cas system comprises an expression vector, such as, but not limited to, an pAd5F35-CRISPR vector. In other embodiments, the Cas expression vector induces

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[0262] 56242423.3 Attorney Docket No. 046483-7468W01(04021) expression of Cas9 endonuclease. Other endonucleases may also be used, including but not limited to, T7, Cas3, Cas8a, Cas8b, CaslOd, Csel, Csyl, Csn2, Cas4, CaslO, Csm2, Cmr5, Fokl, other nucleases known in the art, and any combinations thereof.

[0263] In certain embodiments, inducing the Cas expression vector comprises exposing the cell to an agent that activates an inducible promoter in the Cas expression vector. In such embodiments, the Cas expression vector includes an inducible promoter, such as one that is inducible by exposure to an antibiotic (e.g., by tetracycline or a derivative of tetracycline, for example doxycycline). However, it should be appreciated that other inducible promoters can be used. The inducing agent can be a selective condition (e.g., exposure to an agent, for example an antibiotic) that results in induction of the inducible promoter. This results in expression of the Cas expression vector.

[0264] In certain embodiments, guide RNA(s) and Cas9 can be delivered to a cell as a ribonucleoprotein (RNP) complex. RNPs are comprised of purified Cas9 protein complexed with gRNA and are well known in the art to be efficiently delivered to multiple types of cells, including but not limited to neurons, stem cells and immune cells (Addgene, Cambridge, MA, Minis Bio LLC, Madison, WI).

[0265] The guide RNA is specific for a genomic region of interest and targets that region for Cas endonuclease-induced double strand breaks. The target sequence of the guide RNA sequence may be within a loci of a gene or within a non-coding region of the genome. In certain embodiments, the guide nucleic acid sequence is at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 or more nucleotides in length.

[0266] Guide RNA (gRNA), also referred to as "short guide RNA" or "sgRNA", provides both targeting specificity and scaffolding / binding ability for the Cas9 nuclease. The gRNA can be a synthetic RNA composed of a targeting sequence and scaffold sequence derived from endogenous bacterial crRNA and tracrRNA. gRNA is used to target Cas9 to a specific genomic locus in genome engineering experiments. Guide RNAs can be designed using standard tools well known in the art.

[0267] In the context of formation of a CRISPR complex, "target sequence" refers to a sequence to which a guide sequence is designed to have some complementarity, where hybridization between a target sequence and a guide sequence promotes the formation of a CRISPR complex.

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[0270] Full complementarity is not necessarily required, provided there is sufficient complementarity to cause hybridization and promote formation of a CRISPR complex. A target sequence may comprise any polynucleotide, such as DNA or RNA polynucleotides. In certain embodiments, a target sequence is located in the nucleus or cytoplasm of a cell. In other embodiments, the target sequence may be within an organelle of a eukaryotic cell, for example, mitochondrion or nucleus. Typically, in the context of an endogenous CRISPR system, formation of a CRISPR complex (comprising a guide sequence hybridized to a target sequence and complexed with one or more Cas proteins) results in cleavage of one or both strands in or near (e.g., within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50 or more base pairs) the target sequence. As with the target sequence, it is believed that complete complementarity is not needed, provided this is sufficient to be functional.

[0271] In certain embodiments, one or more vectors driving expression of one or more elements of a CRISPR system are introduced into a host cell, such that expression of the elements of the CRISPR system direct formation of a CRISPR complex at one or more target sites. For example, a Cas enzyme, a guide sequence linked to a tracr-mate sequence, and a tracr sequence could each be operably linked to separate regulatory elements on separate vectors. Alternatively, two or more of the elements expressed from the same or different regulatory elements may be combined in a single vector, with one or more additional vectors providing any components of the CRISPR system not included in the first vector. CRISPR system elements that are combined in a single vector may be arranged in any suitable orientation, such as one element located 5' with respect to ("upstream" of) or 3' with respect to ("downstream" of) a second element. The coding sequence of one element may be located on the same or opposite strand of the coding sequence of a second element, and oriented in the same or opposite direction. In certain embodiments, a single promoter drives expression of a transcript encoding a CRISPR enzyme and one or more of the guide sequence, tracr mate sequence (optionally operably linked to the guide sequence), and a tracr sequence embedded within one or more intron sequences (e.g., each in a different intron, two or more in at least one intron, or all in a single intron).

[0272] In certain embodiments, the CRISPR enzyme is part of a fusion protein comprising one or more heterologous protein domains (e.g. about or more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more domains in addition to the CRISPR enzyme). A CRISPR enzyme fusion protein may comprise any additional protein sequence, and optionally a linker sequence between any two

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[0274] 56242423.3 Attorney Docket No. 046483-7468W01(04021) domains. Examples of protein domains that may be fused to a CRISPR enzyme include, without limitation, epitope tags, reporter gene sequences, and protein domains having one or more of the following activities: methylase activity, demethylase activity, transcription activation activity, transcription repression activity, transcription release factor activity, histone modification activity, RNA cleavage activity and nucleic acid binding activity. Additional domains that may form part of a fusion protein comprising a CRISPR enzyme are described in U.S. Patent Appl. Publ. No. US20110059502, incorporated herein by reference. In certain embodiments, a tagged CRISPR enzyme is used to identify the location of a target sequence.

[0275] Conventional viral and non-viral based gene transfer methods can be used to introduce nucleic acids in mammalian and non-mammalian cells or target tissues. Such methods can be used to administer nucleic acids encoding components of a CRISPR system to cells in culture, or in a host organism. Non-viral vector delivery systems include DNA plasmids, RNA (e.g., a transcript of a vector described herein), naked nucleic acid, and nucleic acid complexed with a delivery vehicle, such as a liposome. Viral vector delivery systems include DNA and RNA viruses, which have either episomal or integrated genomes after delivery to the cell (Anderson, 1992, Science 256:808-813; and Yu, et al., 1994, Gene Therapy 1 : 13-26).

[0276] In certain embodiments, the CRISPR / Cas is derived from a type II CRISPR / Cas system. In other embodiments, the CRISPR / Cas system is derived from a Cas9 protein. The Cas9 protein can be from Streptococcus pyogenes, Streptococcus thermophilus, or other species.

[0277] In general, Cas proteins comprise at least one RNA recognition and / or RNA binding domain. RNA recognition and / or RNA binding domains interact with the guiding RNA. Cas proteins can also comprise nuclease domains (i . e. , DNase or RNase domains), DNA binding domains, helicase domains, RNAse domains, protein-protein interaction domains, dimerization domains, as well as other domains. The Cas proteins can be modified to increase nucleic acid binding affinity and / or specificity, alter an enzymatic activity, and / or change another property of the protein. In certain embodiments, the Cas-like protein of the fusion protein can be derived from a wild type Cas9 protein or fragment thereof. In other embodiments, the Cas can be derived from modified Cas9 protein. For example, the amino acid sequence of the Cas9 protein can be modified to alter one or more properties (e.g., nuclease activity, affinity, stability, and so forth) of the protein. Alternatively, domains of the Cas9 protein not involved in RNA-guided cleavage can be eliminated from the protein such that the modified Cas9 protein is smaller than the wild

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[0279] 56242423.3 Attorney Docket No. 046483-7468W01(04021) type Cas9 protein. In general, a Cas9 protein comprises at least two nuclease (i.e., DNase) domains. For example, a Cas9 protein can comprise a RuvC-like nuclease domain and a HNH- like nuclease domain. The RuvC and HNH domains work together to cut single strands to make a double-stranded break in DNA. (Jinek, et al., 2012, Science, 337:816-821). In certain embodiments, the Cas9-derived protein can be modified to contain only one functional nuclease domain (either a RuvC-like or a HNH-like nuclease domain). For example, the Cas9-derived protein can be modified such that one of the nuclease domains is deleted or mutated such that it is no longer functional (i.e., the nuclease activity is absent). In some embodiments in which one of the nuclease domains is inactive, the Cas9-derived protein is able to introduce a nick into a double-stranded nucleic acid (such protein is termed a "nickase"), but not cleave the doublestranded DNA. In any of the above-described embodiments, any or all of the nuclease domains can be inactivated by one or more deletion mutations, insertion mutations, and / or substitution mutations using well-known methods, such as site-directed mutagenesis, PCR-mediated mutagenesis, and total gene synthesis, as well as other methods known in the art.

[0280] In one non-limiting embodiment, a vector drives the expression of the CRISPR system. The art is replete with suitable vectors that are useful in the instant specification. The vectors to be used are suitable for replication and, optionally, integration in eukaryotic cells. Typical vectors contain transcription and translation terminators, initiation sequences, and promoters useful for regulation of the expression of the desired nucleic acid sequence. The vectors of the instant specification may also be used for nucleic acid standard gene delivery protocols. Methods for gene delivery are known in the art (U.S. Patent Nos. 5,399,346, 5,580,859 & 5,589,466, incorporated by reference herein in their entireties).

[0281] Further, the vector may be provided to a cell in the form of a viral vector. Viral vector technology is well known in the art and is described, for example, in Sambrook et al. (4th Edition, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York, 2012), and in other virology and molecular biology manuals. Viruses, which are useful as vectors include, but are not limited to, retroviruses, adenoviruses, adeno-associated viruses, herpes viruses, Sindbis virus, gammaretrovirus and lentiviruses. In general, a suitable vector contains an origin of replication functional in at least one organism, a promoter sequence, convenient restriction endonuclease sites, and one or more selectable markers (e.g., WO 01 / 96584; WO 01 / 29058; and U.S. Patent No. 6,326,193).

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[0284] In some embodiments, the compound that down regulates the gene associated with kidney disease comprises a nucleic acid that down regulates the expression level of the gene by the means of CRISPR knockdown. CRISPR knockdown includes, but not limited to, CRISPR Casl3 knockdown. (See e.g., Mendez-Mancilla et al., Cell Chemical Biology 29, 1-7, 2021 Jul 27, and Kushawah et al., Dev Cell. 2020 Sep 28;54(6):805-817. The entireties of which are incorporated herein by reference).

[0285] In some embodiments, the present invention includes any other methods for effecting gene knockdown and / editing, which allow for deletion and / or inactivation of the gene associated with kidney disease such as but not limited to those described in WO 2018 / 236840 (which is incorporated herein in its entirety by reference).

[0286] Downregulating genes associated with kidney disease by inactivating and / or sequestering

[0287] In some embodiments, the compound that downregulates a gene associated with kidney disease includes a protein that downregulates the gene associated with kidney disease by inactivating and / or sequestering a protein product of the gene associated with kidney disease. In some embodiment, the compound includes a nucleic acid that express the protein that downregulates the activity of the gene by inactivating and / or sequestering the protein product. In some embodiments, the compound includes an expression vector that express the protein that downregulates the protein product by inactivating and / or sequestering protein product (see “Vector” section for descriptions on vectors).

[0288] In some embodiments, the compound that downregulates the protein product is a transdominant negative mutant of the protein product, and / or a nucleic acid or a vector expressing the trans-dominant negative mutant of the protein product.

[0289] Down regulating genes associated with kidney disease by targeted epigenome editing

[0290] In some embodiments, the compound down-regulates the gene associated with kidney disease via a therapeutic epigenome editing method.

[0291] Down-regulating genes by targeted epigenome editing can be achieved by alter CpG methylation and / or chromatin state linked to disease variants, such as employing dCas9-TETl, dCas9-DNMT3A, dCas9-HDAC / HAT, to tune gene expressions.

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[0294] In some embodiments, the compound down-regulates CHAC1 through epi genome editing at risk-linked CpGs (e g., cg05124934), thereby recapitulating the protective phenotype.

[0295] Targeted epigenome editing is described in, for example, Cappelluti et al. (Nature. 2024 Mar;627(8003):416-423).

[0296] It is worth noting that therapeutic epigenome editing can also be used to upregulate genes.

[0297] Upregulating genes associated with kidney disease

[0298] In some embodiments, the compound that upregulates a gene associated with kidney disease.

[0299] In some embodiments, the compound up-regulates the gene associated with kidney disease by increasing the mRNA product and / or protein product of the gene.

[0300] In some embodiments, the compound comprises the gene associated with kidney disease, the mRNA product thereof, the protein product thereof, or a functional equivalent such as a fragment or variant.

[0301] In some embodiments, the compound comprises an expression vector comprising the gene, and / or for expressing the mRNA / protein products (or the functional equivalent).

[0302] In some embodiments, the compound up-regulates the gene associated with kidney disease via a therapeutic epigenome editing method, which is described in, for example, Cappelluti et al. (Nature. 2024 Mar;627(8003):416-423).

[0303] Vectors

[0304] Vectors can increase the stability of the nucleic acids, make the delivery easier, or allow the expression of the nucleic acids or protein products thereof in the cells.

[0305] Therefore, in some embodiments, the compounds for modulating the genes associated with kidney diseases herein is incorporated into a vector.

[0306] In some embodiments, the instant specification relates to a vector, including the nucleic acid sequence of the instant specification or the construct of the instant specification. The choice of the vector will depend on the host cell in which it is to be subsequently introduced. In certain embodiments, the vector of the instant specification is an expression vector. Suitable host cells include a wide variety of prokaryotic and eukaryotic host cells. In certain embodiments, the

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[0308] 56242423.3 Attorney Docket No. 046483-7468W01(04021) expression vector is selected from the group consisting of a viral vector, a bacterial vector and a mammalian cell vector. Prokaryote- and / or eukaryote-vector based systems can be employed for use with the instant specification to produce polynucleotide, or their cognate polypeptides. Many such systems are commercially and widely available.

[0309] In some embodiments, the vector is a viral vector. Viral vector technology is well known in the art and is described, for example, in virology and molecular biology manuals. Viruses, which are useful as vectors include, but are not limited to, retroviruses, adenoviruses, adeno- associated viruses, herpes viruses, and lentiviruses. In general, a suitable vector contains an origin of replication functional in at least one organism, a promoter sequence, convenient restriction endonuclease sites, and one or more selectable markers. (See, e.g., WO 01 / 96584; WO 01 / 29058; and U.S. Pat. No. 6,326,193.

[0310] In some embodiments, the viral vector is a suitable adeno-associated virus (AAV), such as the AAV1-AAV8 family of adeno-associated viruses. In some embodiments, the viral vector is a viral vector that can infect a human. The desired nucleic acid sequence, such as the nucleic acids that modulate the genes herein, can be inserted between the inverted terminal repeats (ITRs) in the AAV. In various embodiments, the viral vector is an AAV2 or an AAV8. The promoter can be a thyroxine binding globulin (TBG) promoter. In various embodiments, the promoter is a human promoter sequence that enables the desired nucleic acid expression in the kidney. The AAV can be a recombinant AAV, in which the capsid comes from one AAV serotype and the ITRs come from another AAV serotype. In various embodiments, the AAV capsid is selected from the group consisting of a AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, and a AAV8 capsid. In various embodiments, the ITR in the AAV is at least one ITR selected from the group consisting of a AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, and an AAV8 ITR. In various embodiments, the instant specification contemplates an AAV8 viral vector (recombinant or non-recombinant) containing a desired nucleic acid expression sequence and at least one promoter sequence that, when administered to a subject, causes elevated systemic expression of the desired nucleic acid. In some embodiments, the viral vector is a recombinant or non-recombinant AAV2 or AAV5 containing any of the desired nucleic acid expression sequences described herein.

[0311] In some embodiments, the vector in which the nucleic acid sequence is introduced is a plasmid that is or is not integrated in the genome of a host cell when it is introduced in the cell.

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[0314] Illustrative, non-limiting examples of vectors in which the nucleotide sequence of the instant specification or the gene construct of the instant specification can be inserted include a tet-on inducible vector for expression in eukaryote cells.

[0315] The vector may be obtained by conventional methods known by persons skilled in the art (Sambrook et al., 2012). In certain embodiments, the vector is a vector useful for transforming animal cells.

[0316] In certain embodiments, the recombinant expression vectors may also contain nucleic acid molecules which encode a peptide or peptidomimetic inhibitor of the instant specification, described elsewhere herein.

[0317] A promoter may be one naturally associated with a gene or polynucleotide sequence, as may be obtained by isolating the 5’ non-coding sequences located upstream of the coding segment and / or exon. Such a promoter can be referred to as "endogenous." Similarly, an enhancer may be one naturally associated with a polynucleotide sequence, located either downstream or upstream of that sequence. Alternatively, certain advantages will be gained by positioning the coding polynucleotide segment under the control of a recombinant or heterologous promoter, which refers to a promoter that is not normally associated with a polynucleotide sequence in its natural environment. A recombinant or heterologous enhancer refers also to an enhancer not normally associated with a polynucleotide sequence in its natural environment. Such promoters or enhancers may include promoters or enhancers of other genes, and promoters or enhancers isolated from any other prokaryotic, viral, or eukaryotic cell, and promoters or enhancers not "naturally occurring," i.e., containing different elements of different transcriptional regulatory regions, and / or mutations that alter expression. In addition to producing nucleic acid sequences of promoters and enhancers synthetically, sequences may be produced using recombinant cloning and / or nucleic acid amplification technology, including PCR™, in connection with the compositions disclosed herein (U.S. Patent 4,683,202, U.S. Patent 5,928,906). Furthermore, it is contemplated the control sequences that direct transcription and / or expression of sequences within non-nuclear organelles such as mitochondria, chloroplasts, and the like, can be employed as well.

[0318] It will be important to employ a promoter and / or enhancer that effectively directs the expression of the DNA segment in the cell type, organelle, and organism chosen for expression. Those of skill in the art of molecular biology generally know how to use promoters, enhancers,

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[0320] 56242423.3 Attorney Docket No. 046483-7468W01(04021) and cell type combinations for protein expression. The promoters employed may be constitutive, tissue-specific, inducible, and / or useful under the appropriate conditions to direct high-level expression of the introduced DNA segment, such as is advantageous in the large-scale production of recombinant proteins and / or peptides. The promoter may be heterologous or endogenous.

[0321] The recombinant expression vectors may also contain a selectable marker gene which facilitates the selection of transformed or transfected host cells. Suitable selectable marker genes are genes encoding proteins such as G418 and hygromycin which confer resistance to certain drugs, P-galactosidase, chloramphenicol acetyltransferase, firefly luciferase, or an immunoglobulin or portion thereof such as the Fc portion of an immunoglobulin preferably IgG. The selectable markers may be introduced on a separate vector from the nucleic acid of interest.

[0322] Methods of Diagnosing Kidney Disease, Predicting Kidney Disease Risk or Prognosis, Stratifying Patients, Predicting Prognosis, and / or Selecting Patients

[0323] In some embodiments, the instant specification is directed to a method of diagnosing kidney disease in a subject.

[0324] In some embodiments, the instant specification is directed to a method of predicting a risk or prognosis of kidney disease in a subject.

[0325] In some embodiments, the instant specification is directed to a method of stratifying patients at risk for kidney disease, such as for guiding clinical management.

[0326] In some embodiments, the instant specification is directed to a method of selecting of kidney disease patients most likely to benefit from targeted therapies.

[0327] In some embodiments, the method comprises detecting the presence or absence of an risk allele in a single nucleotide polymorphism (SNP) associated with kidney disease in a sample of the subject.

[0328] In some embodiments, a presence of the risk allele in the SNP indicates a heightened risk of kidney disease.

[0329] In some embodiments, the sample is a sample that comprises the genomic DNA of the subject. In some embodiments, the sample comprises a kidney cell of the subject.

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[0332] In some embodiments, the SNPs, as well as the risk allele for each of the SNPs, are selected from the group consisting of those listed in Table 1 herein and rs4924525 (a genetic variation at the CHAC1 locus).

[0333] In some embodiments, the method comprises detecting abnormal CpG methylation states of the risk genes herein (e.g., cg05124934 for CHAC1).

[0334] In some embodiments, the method further comprises collecting the sample from the subject.

[0335] In some embodiments, the kidney disease causes a reduction in a filtration capacity of the kidney in the subject as compared to a healthy control subject. In some embodiments, the subject has an estimated glomerular filtration rate of about 90% or less, about 85% or less, about 80% or less, about 75% or less, about 70% or less, about 65% or less, about 60% or less, about 55% or less, about 50% or less, about 45% or less, about 40% or less, about 35% or less, about 30% or less, about 25% or less, about 20% or less, or about 15% or less.

[0336] In some embodiments, the subject is a human.

[0337] In some embodiments, the method prevents or delays progression to end-stage renal disease, reduce the need for dialysis or transplantation, and enable patient-specific precision therapies.

[0338] Examples

[0339] The instant specification further describes in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only, and are not intended to be limiting unless so specified. Thus, the instant specification should in no way be construed as being limited to the following examples, but rather, should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

[0340] Example 1: Overview

[0341] In one embodiment, the invention provides the Kidney Disease Genetic Scorecard (KDGS), a multi-omic, computer-implementable platform that integrates genome-wide association studies (GWAS) with kidney-specific regulatory and transcriptomic datasets to prioritize causal variants, effector genes, and cell types of action for kidney disease.

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[0344] As shown in Figs. 1A - 1H, the GWAS discovery map (n~2,287,877) provides the association substrate. Figs. 2A - 3F contribute cis-regulatory and chromatin accessibility evidence (ASE, bASA). Figs. 4A - 41 resolve cell-type specificity (snASA). Figs. 5A - 5G link peaks to genes (0pen4Gene), and Figs. 6A - 6G operationalize KDGS scoring, thresholds, and druggability. KDGS outputs — variant^gene^cell-type triplets with prioritization scores — are used for diagnostics, risk prediction, patient stratification, and therapeutic nomination (see Examples 2-1 to 2-5).

[0345] GWAS discovery and saturation

[0346] In one embodiment, a multi-ancestry GWAS (n~2,287,877) identifies 1,026 independent eGFR loci (see Fig. 1 A). In another embodiment, down-sampling analyses (see Fig. ID) demonstrate that locus discovery saturates in European cohorts beyond ~1.5 million participants, while additional ancestry-specific signals (e.g., APOL1, BICC1) are uncovered in diverse populations (Fig. IB, 1H). In certain embodiments, these association results form the primary input to KDGS fine-mapping.

[0347] Fine-mapping and regulatory enrichment

[0348] In one embodiment, KDGS applies fine-mapping to construct 99% credible sets for each locus and to estimate posterior inclusion probabilities (see Fig. IE, 1G). In another embodiment, credible-set variants are enriched for nonsynonymouscoding changes and for kidney regulatory elements (enhancers, active promoters) (see Fig. IF), supporting a joint coding-regulatory mechanism at many loci. This enrichment is used as a prioritization feature in KDGS scoring.

[0349] ASE, bASA / snASA, and meQTL integration

[0350] In one embodiment, KDGS integrates allele-specific expression (ASE) from tubule and glomerulus (Figs. 2A-2G) to capture cis-regulatory effects that may not appear in standard eQTL analyses (see Fig. 2C). In another embodiment, KDGS incorporates bulk and single-nucleus allele-specific chromatin accessibility (bASA / snASA) (Figs. 3A-3F; 4A-4I) to pinpoint celltype-specific regulatory variants (e.g., proximal tubule and loop of Henle; enriched transcription factor motifs including HNF4A / G and CTCF; Fig. 4G). In certain embodiments, methylation

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[0353] QTL (meQTL) evidence is added to capture genotype-CpG effects (see Fig. 3C). In a further embodiment, colocalization across GWAS and molecular traits is computed to identify shared causal signals, which are then up-weighted in KDGS.

[0354] Open4Gene peak-to-gene linkage

[0355] In one embodiment, KDGS integrates Open4Gene (single-cell multiome RNA+ATAC peak-to-gene linkage) to connect accessible regulatory peaks to expressed target genes at singlecell resolution (Figs. 5A-5G). In certain embodiments, the predominance of single-gene links (see Fig. 5C) simplifies variant^gene assignment; the distance - significancerelationship (see Fig. 5E) and the number of GWAS variants per gene (see Fig. 5F) are used as additional features for KDGS scoring. A representative locus integration for LRP2 is shown in Fig. 5G.

[0356] KDGS scoring, thresholds, and outputs

[0357] In one embodiment, KDGS computes a prioritization score for each candidate variant^ gene^cell-type triplet based on weighted evidence from: (i) fine-mapping, (ii) ASE / eQTL, (iii) bASA / snASA, (iv) meQTL, (v) Open4Gene, and (vi) colocalization and functional enrichment (see Fig. 6A). In another embodiment, thresholds are selected to balance the number of retained variants, the fraction of unique genes, and coverage of validated nephropathy genes (Fig. 6B). In certain embodiments, KDGS outputs include approximately 24,437 regulatory variants targeting -1,060 genes, with -601 genes showing convergence of coding and regulatory evidence and proximal tubule enrichment (see Figs. 6C-6E). In a further embodiment, -124 genes overlap with targets of FDA-approved drugs (Fig. 6G), enabling repurposing and accelerated development. KDGS outputs are used for diagnostic panels, risk stratification, and therapeutic target nomination (see Examples 2-1 and 2-5).

[0358] KDGS fine-mapped variants (diagnostic panel)

[0359] In some embodiments, the KDGS-prioritized variant set comprises the fine-mapped SNPs enumerated in Table 1 (KDGS Variant Panel). The rsIDs of Table 1 provide a diagnostic / risk backbone and may be used singly or in combination with linked CpG meQTLs for risk prediction and patient stratification.

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[0362] KDGS convergence genes (therapeutic set)

[0363] In some embodiments, KDGS-prioritized genes with coding-regulatory convergence are enumerated in Table 2 (KDGS Convergence Genes). Non-limiting examples include UMOD, LRP2, ACSM2A, SLC22A2, DAB2, SLC34A1, FOXC2, PKD2, KNG1, and USP24. These genes are suitable targets for the modalities in Section 4 (RNAi, CRISPR, epigenome editing, biologies, small molecules).

[0364] Representative siRNA sequences by gene

[0365] In certain embodiments, representative siRNA sequences for CHAC1 and additional KDGS genes (e.g., DPEP1, ACSS2) are provided in Table 3 (KDGS siRNA Sequences). The sequences listed in Table 3 serve as species enabling RNAi embodiments across KDGS targets.

[0366] Therapeutic logic and cell-type of action

[0367] In one embodiment, KDGS provides (i) a prioritized target list with causal support and (ii) a cell-type map to guide delivery and modality selection (e.g., tubule-directed siRNA, ASO, CRISPR, or epigenome editing; see Section 4). In certain embodiments, this enables targeted therapy in the proximal tubule or loop of Henle, consistent with KDGS cell-type enrichment (Figs. 4D, 6G). In another embodiment, KDGS outputs inform combination strategies (e.g., ferroptosis + lipogenesis axes) when multiple prioritized genes converge on a pathway (see Example 2-5).

[0368] Computer-implemented KDGS embodiments

[0369] In one embodiment, KDGS is implemented as software executing on a computing system that: (i) ingests GWAS summary statistics and kidney-specific molecular datasets; (ii) performs fine-mapping and colocalization; (iii) integrates ASE, bASA / snASA, meQTL, and Open4Gene; (iv) calculates prioritization scores for variant --gene^- cell-type triplets; and (v) outputs a ranked list with supporting evidence and confidence metrics. In certain embodiments, the output is used to design diagnostic assays and to select therapeutic modalities, as claimed (see Claims 1-3, 7- 8).

[0370] Clinical utilities supported by KDGS

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[0373] In one embodiment, KDGS outputs are used to: (i) predict risk via detection of fine- mapped variants or risk-linked CpG methylation states; (ii) select patients for therapy or clinical trials; and (iii) guide modality choice and delivery route for gene modulation (e.g., siRNA / LNP or GalNAc; CRISPR / AAV or RNP; dCas9-TETl for demethylation). In a further embodiment, KDGS-guided interventions prevent or delay progression to end-stage renal disease and reduce dialysis or transplantation needs (see Support and Enablement — Utility).

[0374] CHAC1: Genetic-epigenetic link

[0375] In one embodiment, the invention provides that the CHAC1 locus contains fine-mapped variant rs4924525, which colocalizes with kidney methylation QTL (meQTL) (e.g., cg05124934), allele-specific expression (ASE), and eQTLsignals. In another embodiment, rs4924525 lies within an open chromatin region identified by single-nucleus ATAC-seq in loop of Henle cells. In certain embodiments, the risk allele of rs4924525 increases CHAC1 expression, decreases kidney function, and stratifies patient outcomes (see Fig. CHAC1 locus panel; Example 3).

[0376] CHAC1: Mechanistic role in ferroptosis

[0377] In one embodiment, CHAC1 encodes ChaC glutathione-specific y- glutamylcy cl otransf erase 1, which degrades glutathione, the principal cellular antioxidant. In tubular epithelial cells, up-regulation of CHAC1 reduces glutathione reserves, thereby sensitizing cells to ferroptosis, an iron-dependent cell death pathway characterized by lipid peroxidation (ACSL4 t , GPX4 I ) and oxidative injury (see Fig. CHAC1 ferroptosis assays; Example 3).

[0378] CHAC1: In vivo proof (mouse haploinsufficiency)

[0379] In one embodiment, heterozygous Chad knockout mice (Chacl+ / -) show no baseline renal defects but exhibit protection across diverse kidney injury models:

[0380] • Folic acid nephropathy: serum creatinine and BUN were lower; fibrosis markers (Fnl, Collal, Col3al) were reduced; histology showed decreased a-SMA and fibronectin.

[0381] • Adenine chronic kidney disease: creatinine, BUN, and cystatin C improved; fibrosis was reduced on H&E, PAS, and Sirius red staining; profibrotic gene expression diminished.

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[0384] • Uninephrectomy-STZ diabetic nephropathy: urinary albumin-to-creatinine ratio (UACR) was reduced; fibrosis decreased; ferroptosis markers normalized (ACSL4 1 , GPX4 f ).

[0385] These results provide in vivo validation of therapeutic benefit from CHAC 1 modulation (see Fig. CHAC1 mouse protection panels; Example 3).

[0386] CHAC1: In vitro proof (human and mouse tubular cells)

[0387] In one embodiment, CHAC1 is strongly induced in HKC8 cells, RPTECs, and primary mouse proximal tubules exposed to ER stress, TGF-P, cysteine / methionine deprivation, or erastin. In another embodiment, siRNA knock-down of CHAC1 reduces LDH release, lipid peroxidation (BODIPY 581 / 591-C11), and restores GPX4 / ACSL4 balance. In certain embodiments, siRNA also blunts TGF-P-induced profibrotic responses (see Fig. CHAC1 siRNA rescue panels; Example 4). Representative siRNAs validated in HKC8 and RPTECs include siRNA 316, 355, 356, 708, 1026, 1028, and 1522 described in Example 4 section.

[0388] CHAC1: Therapeutic opportunity

[0389] Together, genetic association (rs4924525), in vivo mouse haploinsufficiency, and in vitro siRNA rescue establish CHAC1 as a validated kidney disease effector gene. In one embodiment, CHAC1 is targeted therapeutically with siRNA delivered via lipid nanoparticles or GalNAc conjugates. In another embodiment, CHAC1 is modulated by CRISPR editing of rs4924525 to replace the risk allele with the protective allele.

[0390] Epigenome editing

[0391] Although epigenome editing was not yet performed for CHAC1, in one embodiment, targeted methylation or demethylation is used to modulate KDGS-prioritized genes whose expression is regulated by CpG methylation. For example, at the TNF locus in diabetic kidney disease, targeted demethylation increased TNF expression and worsened disease, whereas higher methylation correlated with protection (see Example 3). These findings demonstrate the feasibility of applying dCas9-TETl / DNMT3A approaches to KDGS-identified loci, including but not limited to CHAC1.

[0392] RNA interference (RNAi)

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[0395] In one embodiment, prioritized kidney disease genes are modulated by RNA interference (RNAi). Agents include small interfering RNAs (siRNA), short hairpin RNAs (shRNA), and microRNA mimics or antagomirs. In some embodiments, RNAi molecules are chemically modified for improved stability, nuclease resistance, and pharmacokinetics. Examples of chemical modifications include 2’-O-methyl (2’-0-Me), 2’-fluoro (2’-F), locked nucleic acids (LNA), phosphorothioate backbones, and terminal capping.

[0396] In another embodiment, CHAC1 is silenced by siRNAs validated in human tubular cells, including those described in Example 4, which reduce ferroptotic death in HKC8 and RPTECs. In some embodiments, additional siRNAs targeting KDGS-prioritized genes (e.g., DPEP1, ACSS2, WHAMM, TET2, DACH1, TNF) are designed as described in Table 3.

[0397] Delivery vehicles include lipid nanoparticles (LNPs), polymeric nanoparticles, peptide conjugates, GalNAc conjugates (for proximal tubule targeting), adeno-associated viral vectors (AAVs), exosomes, and implantable depots. In one embodiment, dosing regimens for CKD, AKI, and proteinuric diseases range from about 0.01-100 mg / kg, delivered intravenously or subcutaneously, depending on formulation and indication.

[0398] CRISPR editing

[0399] In another embodiment, prioritized kidney disease genes are targeted by genome editing. In certain embodiments, fine-mapped causal SNPs (e.g., rs4924525 at the CHAC1 locus) are corrected by clustered regularly interspaced short palindromic repeats (CRISPR) / Cas-based methods. Editors include:

[0400] • SpCas9 / HiFi Cas9 for double- stranded breaks,

[0401] • Base editors (ABE / CBE) for single-nucleotide substitutions, and

[0402] • Prime editors for precise small insertions, deletions, or substitutions without doublestrand breaks.

[0403] In one embodiment, editing reagents are delivered as ribonucleoprotein complexes (RNPs) to minimize off-target effects.

[0404] On-target activity is confirmed by sequencing, while off-target activity is minimized by high-fidelity Cas variants and guide RNA optimization. Functional readouts include changes in target gene expression, ferroptosis markers (e.g., ACSL4, GPX4), and kidney injury biomarkers.

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[0407] Epigenome editing

[0408] In another embodiment, prioritized genes are modulated by targeted editing of epigenetic marks. Catalytically inactive Cas proteins (dCas9) are fused to effector domains, including:

[0409] • dCas9-TETl (for CpG demethylation),

[0410] • dCas9-DNMT3A (for CpG methylation), and

[0411] • dCas9-HAI7HDAC fusions (for histone modification).

[0412] In one embodiment, editing sites are CpGs colocalizing with fine-mapped kidney GWAS variants and validated by kidney meQTL analysis. For example, CpG cg05124934 (targeted by mQTL with rs4924525 near CHAC1) serves as a model locus where targeted methylation / demethylation alters gene expression.

[0413] Although CHAC1 epigenome editing is presented as a prophetic example, functional proof-of-principle is provided at the TNF locus, where dCas9-TETl demethylation increased TNF expression and worsened kidney injury in diabetic models. Thus, the invention provides a generalizable strategy for epigenome editing of KDGS-prioritized loci, including CHAC1 and TNF, to modulate gene expression without inducing double-strand breaks.

[0414] Antisense oligonucleotides, ribozymes, PROTACs, antibodies, and small molecules

[0415] In certain embodiments, prioritized kidney disease genes are targeted by alternative therapeutic modalities, including:

[0416] • Antisense oligonucleotides (ASOs): complementary nucleic acids that hybridize to target transcripts and reduce expression.

[0417] • Ribozymes: catalytic RNA molecules that cleave target mRNAs.

[0418] • Proteolysis-targeting chimeras (PROTACs): bifunctional molecules that direct ubiquitin ligase activity to target proteins for degradation.

[0419] • Monoclonal antibodies, antibody fragments, and nanobodies: directed against extracellular or secreted products of prioritized genes.

[0420] • Small molecule inhibitors or activators: designed to block or enhance enzymatic activity (e.g., inhibitors of DPEP1 to prevent ferroptotic inflammation, or modulators of lipid metabolism enzymes linked to ACSS2).

[0421] These modalities provide therapeutic redundancy and increase the range of KDGS- prioritized genes that can be clinically addressed.

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[0424] Vectors and delivery systems

[0425] In one embodiment, therapeutic nucleic acids (e.g., siRNA, ASO, CRISPR guides) are delivered by viral vectors, including adeno-associated virus (AAV) serotypes 2, 5, and 8, as well as engineered kidney-tropic AAV capsids. In another embodiment, non-viral systems are employed, including lipid nanoparticles (LNPs), polymeric carriers, biodegradable implants, and extracellular vesicles (e.g., exosomes).

[0426] Kidney-specific uptake. In one embodiment, siRNA or ASO molecules are conjugated to ligands for receptor-mediated uptake in proximal tubules. Examples include:

[0427] • N-acetylgalactosamine (GalNAc) conjugates, which are efficiently internalized and accumulate in renal tubules.

[0428] • Megalin / LRP2-targeted conjugates, such as peptides, antibodies, or small molecules that bind megalin and promote receptor-mediated endocytosis into proximal tubular cells.

[0429] • Apolipoprotein- or lipid-conjugated siRNAs, including cholesterol-modified siRNAs, fatty acid conjugates (e.g., docosahexaenoic acid), or novel ionizable lipids, which increase plasma protein binding and renal filtration / uptake.

[0430] Chemical modifications. In another embodiment, therapeutic oligonucleotides are chemically modified to enhance uptake and stability. Modifications include 2 ' -O-methyl, 2 ' - fluoro, phosphorothioate backbones, locked nucleic acid (LNA) segments, terminal capping, or lipid-tail conjugates. In certain embodiments, dual conjugation (e.g., GalNAc + lipid tail) further increases renal accumulation.

[0431] Tissue-specific promoters. For viral vectors, in one embodiment, expression is restricted by use of kidney- or tubule-specific promoters, optionally in combination with capsids engineered for kidney tropism.

[0432] Formulations. In some embodiments, formulations include pharmaceutically acceptable carriers, buffering agents, cryoprotectants, tonicity agents, and surfactants optimized for parenteral administration. Dosing regimens may include loading and maintenance phases, with routes including intravenous, subcutaneous, or direct renal artery administration.

[0433] Utility. These delivery strategies ensure that KDGS-prioritized therapeutic agents (RNAi, ASO, CRISPR editors, epigenome modulators, antibodies, ribozymes, PROTACs, or small

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[0435] 56242423.3 Attorney Docket No. 046483-7468W01(0402f) molecules) are selectively delivered to the proximal tubule and other nephron cell types identified as causal sites of action by KDGS.

[0436] In some embodiments, the cell is obtained ex vivo from the subject, modified by RNAi, genome editing, or epigenome editing, and subsequently readministered to the subject, thereby providing an autologous cell therapy approach.

[0437] Example 2: Saturating Genetic Map and Integrating Kidney Multiome Reveal Convergent Coding and Regulatory Variants

[0438] Kidney dysfunction is a major cause of mortality, but its genetic architecture remains elusive. Here, the present study conducted a multi -ancestry genome-wide association study in 2.2 million individuals and identified 1,026 (97 newly reported) independent loci. Ancestry-specific analysis indicated a saturation of signals on common variants in European ancestry populations and the power of population diversity for further discoveries. The present study defined genotype effects on allele-specific gene expression and regulatory circuitries in over 1,000 kidneys and 237,000 cells. The present study found 1,363 coding variants disrupting 782 genes, with 601 genes also targeted by regulatory variants and convergence in 161 genes. Integrating 32 types of genetic information, the present study presents the ‘Kidney Disease Genetic Scorecard’ for prioritizing potentially causal genes, cell types, and druggable targets for kidney disease.

[0439] Example 2-1:

[0440] Kidney disease encompasses a range of conditions impairing the kidney’s ability to filter blood effectively. This impairment can lead to the accumulation of toxins and excess fluids in the body, which may result in serious health complications, such as hypertension (high blood pressure), electrolyte abnormalities, and cardiovascular disease. The increasing mortality rates associated with kidney disease underscore its importance as a major public health issue.

[0441] The etiology of kidney disease is complex, with contributing factors ranging from genetic disorders like polycystic kidney disease, to comorbidities including diabetes, high blood pressure, and autoimmune diseases. Although each cause affects the kidneys differently, they all contribute to a diminished fdtration capacity. Glomerular fdtration rate (GFR) is a critical measure used to assess this capacity and is typically estimated by measuring serum creatinine

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[0443] 56242423.3 Attorney Docket No. 046483-7468W01(04021) levels in the blood. Low eGFR is not only a marker of kidney function decline but it defines kidney disease.

[0444] Kidney function has strong heritable components. Pathogenic variants in the coding regions are primarily associated with monogenic forms of kidney disease, which are more commonly observed in children but very rarely detected in adults as they are presumed deleterious and subjected to the action of purifying selection at a population level. Recent exome-wide association studies (ExWAS) utilizing whole exome sequencing data have cataloged rare coding variants associated with kidney disease. While coding variants provide a strong indication of candidate causal genes - making these studies potentially fruitful for dissecting the molecular pathways underlying kidney function - they ultimately explain a very small fraction of common disease heritability in the population. In contrast, common variants identified by genome-wide association studies (GWAS) explain most of the heritability of common disease conditions. Prior GWAS have uncovered associations between common single nucleotide polymorphisms (SNPs) and kidney function. More than 90% of GWAS-identified common variants are situated in non-coding regions of the genome. Therefore, pinpointing their target genes and regulatory functions is challenging — a problem often referred to as the ‘variant-to- gene’ or ‘variant-to-function’ issue.

[0445] Chromatin accessibility is pivotal for gene regulation. Single nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq) has identified cell typespecific regulatory elements in human kidneys. However, investigating cell type-specific genetic effects on chromatin accessibility and their roles in regulating genes related to kidney disease remains a formidable challenge, often due to the absence of paired transcriptomic and open chromatin information at single cell level. Therefore, simultaneous profiling of chromatin accessibility and gene expression within the same cell could enhance the understanding of the regulatory variants implicated in human diseases.

[0446] The current study aimed to define the genetic architecture of GFR and use a multitude of complimentary omics datasets and tools to nominate regulatory variants, genes, and cell types for kidney function regulation. The present study shows that each type of multiomic information can prioritize partially overlapping genes, cell types, and regulatory variants for each locus. The present study shows the convergence of common non-coding and rare coding variants in specific genes and the key role of proximal tubules in kidney function maintenance. The present study

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[0448] 56242423.3 Attorney Docket No. 046483-7468W01(04021) proposes the development and use of a probabilistic approach by integrating 32 genomic annotation and prioritization tools, as the present study presents the Kidney Disease Genetic Scorecard that can be applied for disease diagnostic and therapeutic development.

[0449] The current study aimed to define the genetic architecture of GFR and use a multitude of complimentary omics datasets and tools to nominate regulatory variants, genes, and cell types for kidney function regulation. The present study shows that each type of multiomic information can prioritize partially overlapping genes, cell types, and regulatory variants for each locus. The present study shows the convergence of common non-coding and rare coding variants in specific genes and the key role of proximal tubules in kidney function maintenance. The present study proposes the development and use of a probabilistic approach by integrating 32 genomic annotation and prioritization tools, as the present study presents the Kidney Disease Genetic Scorecard that can be applied for disease diagnostic and therapeutic development.

[0450] Example 2-2: Genetic discovery from 2.2 million individuals

[0451] The present study conducted a genetic analysis of kidney function, as measured by the estimated glomerular filtration rate based on serum creatinine (eGFRcrea), by integrating data from millions of individuals across 19 cohorts. First, the present study mapped genetic associations in 861,840 individuals (including 639,074 European, 136,620 East Asian, and 34,879 African individuals) from nine cohorts (MVP, TWB, All of Us, MGB, GHS, BioMe, PMBB, eMERGE-III, and CCPM). Then, the present study performed a meta-analysis by combining summary data comprising 1,413,622 individuals from ten previously published studies (CKDGen, Pan-UK Biobank, HUNT, BioVU, MGI, TOPMed, UKHLS, PAGE, SUMMIT, and BBJ). Through sample size-weighted meta-analysis of z-scores using METAL(19) (materials and methods), the present study developed a catalog of eGFRcrea associations genome-wide for European-ancestry (n = 1,785,582), East Asian-ancestry (n = 282,852), African-ancestry populations (n = 67,943) as well as across all ancestries (n = 2,287,877; Figs. 1A and 7A). To assess the extent of population stratification in these GWAS meta-analyses, the present study applied linkage-disequilibrium (LD) score regression. The LD score intercepts ranged from 0.912 to 1.109 with low attenuation ratios (Fig. 7B), which is consistent with the expectations under polygenicity, suggesting that there was no obvious excess inflation due to population stratification.

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[0454] Within the multi -ancestry GWAS encompassing 13,700,391 variants, the present study identified 99,595 genome-wide significant variants (P < 5* 10'8), excluding 12,895 significant variants from the major histocompatibility complex locus. Further, the present study identified 1,026 independent loci, including 97 loci situated at least 500 kb away from any previously reported eGFRcrea-associated variants (Figs. IB, 7C and 7D). Most (86.8%, 891 / 1,026) of these eGFRcrea-associated loci have been validated as kidney function loci by at least one variant associated with complementary kidney function measurements, serum cystatin C-based eGFR (eGFRcys) or blood urea nitrogen (BUN)(6) (Figs. 1C and 7E). These independent (including the newly identified) loci were significantly (FDR < 0.05) enriched near genomic regions associated with genes critical for kidney development and function (Fig. 7F). More than half (42 / 78) of the prioritized genes in the 97 new loci have been previously reported as related to kidney function or disease, including Forkhead Box C2 (FOXC2), Polycystin 2 (PKD2), and Salt-Inducible Kinase 3 (SIK3) (Fig. 1G).

[0455] Down-sampling analysis indicated that the number of identified loci rose with sample size; however, this upward trend began to plateau for sample sizes exceeding 1.5 million in European-ancestry GWAS (Figs. ID and 7H). This suggests a saturation of the eGFRcrea GWAS map for common autosomal variants used in this study for European-ancestry populations. Although the European-ancestry GWAS accounted for most (85.4%) of the loci identified in the multi-ancestry GWAS, the present study identified ancestry-specific loci in African (3 loci near the APOL1 gene, known to be associated with kidney disease) and East Asian populations (2 loci near the BICC1 and HCRTR2 genes) (Figs. 71 and 7J), highlighting the value of increased population diversity. The GWAS provides a genetic link between the BICC1 gene and eGFRcrea, two decades after the recognition of BICCl's role in kidney development and disease.

[0456] Example 2-3: Fine-mapping and characterizing eGFRcrea-associated loci

[0457] To identify putative causal variants at eGFRcrea loci, the present study performed fine- mapping using CARMA, a Bayesian model for fine-mapping in meta-analyses, separately for European-ancestry and multi-ancestry GWAS. In the European-ancestry GWAS, the present study delineated 1,818 sets comprising 99% credible intervals, 45.7% (830 / 1,818) of which had single putative causal variants when including PolyFun annotations (Figs. IE and 8A). These

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[0459] 56242423.3 Attorney Docket No. 046483-7468W01(04021) credible sets included 8,901 putative causal variants, which were significantly enriched for non- synonymous variants (P < 1* 1O'300), kidney enhancers (P = 7.7><1 O'252), and promoters (P = 1.2x 10’96) (Fig. IF). Most (82.0%) of these sets were also observed in the multi-ancestry GWAS (Fig. IE, 8B and 8C). For instance, at a chromosome 7 locus (q32.1), the present study identified two statistically distinct signals with credible sets with distinct regulatory features: one proximal to the promoter of the IRF5 (Interferon Regulatory Factor 5) gene and colocalized with eQTLs of IRF5 (Fig. 1G), and another adjacent to an enhancer and colocalized with allelic expression of the TNPO3 (Transportin 3) gene (Figs. 8D-8E). Additionally, the colocalization analyses with eQTL and meQTL datasets led to the prioritization of 387 genes and 4,363 CpG sites, which exhibited shared genetic predispositions with kidney function (Figs. 8F and 8G).

[0460] To evaluate the shared genetic basis between kidney disease and other conditions, the present study conducted a genome-wide multi-trait colocalization analysis between eGFRcrea and 23 GWAS traits potentially related to kidney function (Fig. 9A) utilizing HyPrColoc (36). This analysis resulted in the identification of pleiotropy maps across 351 loci where eGFRcrea colocalized with other traits with regional probability > 0.8, 64.4% (226 / 351) of which colocalized with known kidney function traits. The number of colocalizations per signal varied, ranging from four loci with fasting glucose to 183 loci with eGFRcys (Fig. 1H). Within these loci, eGFRcrea colocalized with a single trait at 164 loci, while 187 loci demonstrated colocalization with multiple traits, including loci of GCKR (15 traits including type 2 diabetes, T2D), FGF5 (11 traits including systolic blood pressure, SBP), and APOE (5 traits including parental longevity) (Figs. 9B-9E). To explore causal relationships, the present study applied the Mendelian randomization analysis using the method GSMR, which revealed multiple traits, including CAD, fasting insulin, SBP, high-density lipoprotein, and low-density lipoprotein, that are potentially implicated in the etiology of kidney disease (Figs. 9F-9I).

[0461] Example 2-4: Allele-specific expression in bulk human kidneys (bASE)

[0462] To elucidate the genetic impact on gene expression within the kidney, the present study conducted an allele-specific expression (ASE) analysis on two distinct kidney compartments: the tubule (with a sample size of 613 individuals) and glomeruli (with a sample size of 522 individuals). This analysis was performed using RASQUAL, with adjustments for technical and clinical variables as well as probabilistic estimation of expression residuals (PEER) factors (Fig.

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[0465] 2A and 10A-10B). The present study identified 10,398 ASE genes, with 8,573 in the tubule and 8,725 in the glomeruli, while maintaining a 1% false discovery rate (FDR) (Fig. 2B). As a validation, the present study also performed typical eQTL mapping using MatrixeQTL in the same dataset. The effect sizes estimated by the two methods were significantly correlated; with RASQUAL identifying 389 additional genes not reported by typical eQTL mapping (FDR < 0.01) (Figs. 2C and 10B-10C). Approximately 60% of ASE genes showed allele-specific expression in AlleleDB, an allele-specific annotation for the 1000 Genomes variant catalog, compared to 45.6% for genes identified solely through typical eQTL (Fig. 2C). Among these ASE genes, 1,773 (17.1%) had not been previously detected by kidney eQTL studies. This subset includes genes that are already known to play roles in kidney function, such as Glycine Amidinotransferase (GATM) and HNF1 Homeobox A (HNF1A) (Figs. 2D andlOD). Furthermore, the present study observed that variants with minor allele frequency (MAF) < 10% tended to exhibit a greater impact on gene expression, which is consistent with the eQTL studies (Fig. 10E).

[0466] Furthermore, the present study used the ASE associations to prioritize variants identified in eGFRcrea GWAS. This led to the nomination of 32,610 variants targeting 1,212 genes across 470 (45.8% of 1,026) eGFRcrea loci improving the eQTL-eGFRcrea annotation (Figs. 2E and 10F). To further refine the list of potential causal genes, the present study carried out a colocalization analysis and highlighted 531 genes whose ASE associations colocalized with eGFRcrea GWAS signals (Fig. 2F). These genes were significantly enriched in metabolic processes (P = 2.4* 10'7, Fig. 10G). While most (76.7%, 407 / 531) of ASE-GWAS colocalization genes also showed eQTL-GWAS colocalization (Figs. 2F and 10H), 124 genes did not show colocalization between eQTLs and eGFRcrea GWAS (Fig. 2F). For instance, SLC22A2 (also known as OCT2, a kidney function gene) exhibited significant ASEs (top variant rs8177512, P = 3.5x 1 O’40) and eQTLs (top variant rs316018, P = 1 ,7x 1 O’7); however, colocalization was observed exclusively between ASEs and eGFRcrea GWAS (Fig. 2G), underscoring the efficacy of ASE analysis in uncovering signals related to kidney function.

[0467] Example 2-5: Allele-specific chromatin accessibility in bulk kidneys (bASA)

[0468] Chromatin accessibility is vital for gene regulation, yet the genotype influence on chromatin accessibility within the kidney has not been characterized. To address this gap, the

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[0470] 56242423.3 Attorney Docket No. 046483-7468W01(04021) present study conducted whole-genome sequencing paired with high-throughput transposase- accessible chromatin sequencing (ATAC-seq) on human kidney samples. Initially, the present study established comprehensive maps of chromatin accessibility, which included 446,385 open chromatin peaks (Fig. 11A). Following stringent quality control measures (Figs. 1 IB-11C), the present study mapped allele-specific chromatin accessibility in 82 bulk kidney samples (bASA). This was done using RASQUAL, with adjustments for both technical and clinical variables, as well as PEER factors (Fig. 1 ID). The analysis identified 19,083 peaks with 523,700 single nucleotide polymorphisms (SNPs) with MAF > 5% that were associated with changes in chromatin accessibility by RASQUAL with validation by at least one of two other models, MatrixeQTL and stratAS (FDR < 0.05, Fig. 3A). This effort provided the first understanding of the genotype effect on open chromatin across the human kidney.

[0471] Human kidney bASA peaks were significantly enriched in regions identified as kidney enhancers, with an odds ratio (OR) of 1.7 (chi-square test P = 2.4* 10’171), and active promoters, with an OR of 2.2 (chi-square test P = 2.3^ 1 O'259), in comparison to non-bASA peaks (Figs. 3B and 1 IE). Most of the bASA SNPs identified above were found within 50 kb of the associated peaks (Fig. 1 IF). The present study discovered that 8,317 bASA peaks had associations with both local (within peak) and distal (outside peak) SNPs, which exerted consistent effects on the same peak (Figs. 11G-11H). Variants with MAF < 10% had a more substantial impact on chromatin accessibility, aligning with the findings from the ASE analysis in this study (Fig. 1 II). Furthermore, the effect sizes of bASA negatively correlated with methylation QTLs (correlation = -0.78, P < 2.2xl0'16) and positively correlated with ASEs (correlation = 0.51, P < 2.2x l0’16), suggesting a regulatory effect of open chromatin on gene expression (Figs. 3C-3D).

[0472] Furthermore, the present study used bASA associations to prioritize open chromatin peaks affected by variants from the eGFRcrea GWAS. The present study identified 20,035 SNPs that were associated with both eGFRcrea and human kidney chromatin accessibility within 997 bASA peaks across 445 eGFR GWAS loci (Fig. 3E). Most bASA SNPs (88.9%) also had substantial associations with DNA methylation and / or allele-specific expression.

[0473] To investigate the shared genetic architecture between open chromatin and kidney function, the present study carried out a colocalization analysis, which identified 209 loci where eGFRcrea GWAS signals colocalized with the accessibility of 268 peaks (Fig. 3E). Notably, most (82.3%) of these also colocalized with meQTLs and / or ASEs (Fig. 3E). Specifically, the

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[0475] 56242423.3 Attorney Docket No. 046483-7468W01(04021) present study found colocalization of eGFRcrea with all three molecular traits (bASA, meQTL, and ASE) at 79 loci for 104 genes, which include genes previously linked to kidney disease (such as UMOD and UNCX) as well as potential new disease genes (like USP24 and ACSM2A) (Fig. 11 J). For instance, genetic variants at the USP24 locus showed significant associations with eGFRcrea (P = 7.9 IO'20), open chromatin (P = 2.4* 10'26), CpG methylation (P = 6.3 x 10’88), and gene expression (P = 2.6 10’46) at shared variant rs2802865 (Fig. 3F). Most (91.9%, 192 / 209) of these eGFRcrea~bASA colocalization loci have been validated as kidney function loci by complementary kidney function measurements (eGFRcys and / or BUN), underscoring the intersection of genetic variation and epigenetic regulatory elements in influencing kidney function.

[0476] Example 2-6: Allele-specific chromatin accessibility in kidney cell types

[0477] A critical limitation of bulk open chromatin and gene expression analysis is its constraint in nominating cell type-specific changes. This is particularly challenging given the intricate complexity of the kidney, which has more than 30 cell types. To discern the genotype effects on chromatin accessibility in specific kidney cell types, the present study profiled individual cells using single nuclear ATAC sequencing (snATAC-seq) in human kidneys (17 newly profiled and 13 publicly available). Following rigorous quality control, the present study compiled an extensive atlas of open chromatin across 237,274 cells, spanning 19 cell types, with a median of 5,302 cells per type (Fig. 12A). The present study found a significant enrichment of eGFRcrea GWAS variants within proximal tubule-specific open chromatin peaks (FDR = 0.021), correcting for 836 tests performed across 19 cell types and 44 GWAS traits (Fig. 12B).

[0478] The present study then assessed the allelic impact on chromatin accessibility within each cell type by conducting snATAC -based allele-specific chromatin accessibility (snASA) analyses (Figs. 4A and 13 A). In total, the present study identified 25,766 SNPs exhibiting significant snASA (FDR < 0.05) in at least one cell type (Fig. 4B). Most of these snASA SNPs (93.2%, or 24,015 out of 25,766) were located within open chromatin peaks (Fig. 4C), and non-peak snASA SNPs showed significantly higher read coverage than shuffled SNPs from non-peak regions (Wilcoxon ranked sum test P = 6.8* IO'307, Fig. 13B). Furthermore, the present study observed that variants with MAF < 10% tended to exhibit a greater impact on chromatin accessibility

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[0481] (Wilcoxon ranked sum test P < 1 x IO'140), which is consistent with the ASE and bASA analysis (Fig. 13C).

[0482] Most of the snASA SNPs (22,151 out of 25,766, 86%) were specific to individual cell types, while 3,615 snASA SNPs were shared across at least two cell types (Fig. 4D). The present study then assessed the potential of snASA to identify new regulatory variants by analyzing 18,727 common SNPs that were tested in both snASA and bulk kidney allele-specific accessibility (bASA) in the 82 bulk kidney samples mentioned earlier. While most (68.4%) of the snASA SNPs that were common across cell types were also detected by bASA, a large proportion (58.7%) of cell type-specific snASA SNPs did not show significant bASA associations (Chi-square test P = 1.4* 10'148, Fig. 4E), indicating an advantage of snASA in identifying cell type-specific regulatory variants. Furthermore, the present study observed strong positive correlations of allelic effect sizes both across different cell types (median Spearman’s rho = 0.99) and between snASA and bASA (Spearman’s rho = 0.90, and 13D). These correlations indicate robust biological mechanisms regulating chromatin accessibility. For instance, allele C of the variant rsl0875467, situated in an intron of the SLC45A4 gene, was significantly associated with decreased chromatin accessibility in bulk kidney samples (bASA P = 4.8* 10'13) and various cell types, including PT (snASA P = 3.5* 10’101) and LOH (snASA P = 2.6* 10’5) (Fig. 13E).

[0483] To investigate the transcription factors (TFs) mediating allele-specific chromatin accessibility in kidney cell types, the present study conducted a TF motif enrichment analysis for snASA SNPs specific to each cell type. The present study identified 29 TF motifs that were preferentially disrupted by snASA SNPs, with an enrichment score greater than 3 and a p-value < 3.7* IO'5(Bonferroni adjustment for 1,358 tests overall, across 7 cell types and 194 TFs at a 5% significance level, Fig. 4G). Among these motifs, some showed cell type-specific disruption, such as the HNF4A and HNF4G motifs in the proximal tubule and the ESRRB and ESRRA motifs in the loop of Henle. Others, like the FOSL2 and NFKB1 motifs, were enriched in injured proximal tubule cells. Additionally, the present study found motifs with shared enrichment across various cell types, such as those binding the CCCTC-binding factor (CTCF), an architectural protein involved in regulating three-dimensional genome structure (Fig. 4G). eGFRcrea GW AS signals were found within a lOkb radius of 8 genes encoding these disrupted TFs, including HNF4G, HNF4A, CTCF, NFKB1, and PPARG (Fig. 13F).

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[0486] Having identified and characterized allelic imbalance in chromatin accessibility across kidney cell types, the present study next assessed whether snASA SNPs could mediate the genotype effect on eGFRcrea. The analysis revealed that 669 snASA SNPs were significantly (P < 5* 10'8) associated with eGFRcrea across 337 GWAS loci, which included high-probability variants for eGFRcrea association at the DAB2, SHR00M3, and SLC47A1 loci (Figs. 4D and 13G). Most (79.5%, 532 / 669) of these snASA-GWAS SNPs have been validated by complementary kidney function measurements (eGFRcys and / or BUN). A substantial proportion (63.4%, 448 / 738) of these snASA-GWAS SNPs resided in transcription factor binding sites, a frequency significantly greater than the 18.8% observed in GWAS SNPs not associated with snASAs (odds ratio = 7.5, chi-square test P = 1.9* IO’206) (Figs. 4H and 41). A TF enrichment analysis further emphasized the potential involvement of CTCF, HNF4A, PAX5, and KLF5 in the pathogenesis of kidney disease (Fig. 13H). The findings suggest that allele-specific chromatin accessibility maps of human kidneys are instrumental in identifying both the cell types and regulatory variants implicated in kidney function.

[0487] Example 2-7: Gene regulatory circuits via single nuclear multiomics

[0488] While the present study observed associations between gene regulatory elements, gene expression, and kidney function, the present study aimed to understand a potential causal relationship. The present study simultaneously profiled chromatin accessibility and gene expression in nine human kidney samples using single-nucleus multiome sequencing, which combines RNA and AT AC sequencing. Following rigorous quality control procedures, the present study compiled a comprehensive atlas of joint chromatin accessibility and gene expression across 62,278 cells spanning 19 kidney cell types (Figs. 5A and 14A). To pinpoint open chromatin regions involved in gene activation, the present study devised a statistical approach named Open4Gene. This method uses the hurdle negative binomial regression model to estimate the association between chromatin accessibility and gene expression, specifically designed to handle the overabundance of zeros in single-nucleus RNA data (Figs. 5A and 14B). For validation, the present study applied Open4Gene alongside two widely-used single-cell multimodal peak-to-gene linkage methods, ArchR and Signac, to analyze a set of 903,472 peak- to-gene pairings (spanning 16,239 genes and 347,480 open chromatin peaks within a 100 kb cis- regulatory range) based on the joint profiles from the 62,278 kidney cells. By using HiC-based

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[0490] 56242423.3 Attorney Docket No. 046483-7468W01(04021) chromatin interactions as a benchmark for replication, the present study observed that the top peak-to-gene pairs identified by 0pen4Gene had higher validation rates compared to those identified by the alternative methods (Fig. 14B). These top pairs identified by 0pen4Gene exhibited significantly (Wilcoxon rank sum test P < 1 * IO'300) greater correlation scores between peak accessibility and gene expression than those by other methods. Additionally, simulation analysis indicated a low rate of false positives identified by Open4Gene (Fig. 14D). These findings suggest that Open4Gene is an effective tool for discerning functional cis-regulatory elements within single-cell multimodal datasets.

[0491] Using the Open4Gene tool, the present study delineated a definitive set of peak-to-gene associations for each human kidney cell type (FDR< 0.01). This process yielded 35,388 unique Open4Gene links, with 40.6% being distinct from those obtained when analyzing a combination of all cell types. The quantity of Open4Gene links detected within each cell type was directly proportional to the cell count recorded for that specific type (Fig. 5B). By integrating the findings from each cell type with those from the collective cell analysis, the present study altogether identified 142,452 peak-to-gene connections, encompassing 125,699 peaks, nearly 90% of which were specifically associated with a single gene (Fig. 5C). The derived Open4Gene associations indicated a median of eight linked peaks per gene, with gene PKHD1 — implicated in kidney disease — having the highest number of peaks (Figs. 14E-14F). Furthermore, an overwhelming 97% of Open4Gene associations were positively linked (effect estimate beta > 0) with the expression of their target genes (Figs. 14G and 14H). Additionally, Open4Gene beta values exhibited high correlations across different cell types (Fig. 141), reinforcing the crucial role of open chromatin in gene activation.

[0492] Furthermore, Open4Gene was instrumental in linking variants to gene expression and function by identifying 1,351 target genes for 7,137 genetic variants located within Open4Gene peaks (Fig. 5D). Genetic variants situated in these Open4Gene peaks exhibited strong associations with kidney function (Fig. 5E). The present study observed that 80.2% (5,723 / 7,137) of these variants were exclusive to a single gene (Fig. 15A). There were 253 genes targeted by 10 or more GWAS variants, which displayed significant enrichment in pathways associated with abnormal renal system physiology (FDR = 1.1* 10'7, Figs. 15B-15C). This group includes genes previously linked to kidney disease, such as LRP2, UMOD, DAB2, SLC34A1, PAX8, and KLF5 (Figs. 5F-5G and 15D). For the genes without known kidney association in the

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[0494] 56242423.3 Attorney Docket No. 046483-7468W01(04021) literature, the present study focused on ACSM2A (Acyl-CoA Synthetase Medium Chain Family Member 2A), which encodes a mitochondrial enzyme involved in fatty acid metabolism, and explored its potential function in kidneys. The expression of ACSM2A was predominantly found in proximal tubules and appeared to be correlated with open chromatin, as indicated by Open4Gene links (Fig. 15D). Leveraging RNA-sequencing data from 433 human kidneys, the present study established that ACSM2A expression was significantly positively correlated with kidney function (eGFRcrea, Spearman’s rho = 0.31, P = 7.7* 10'11) and inversely correlated with kidney fibrosis (Spearman’s rho = -0.58, P < 2.2*10’16) (Fig. 15E). Additionally, ACSM2A expression was notably reduced in chronic kidney disease (ANOVA P = 1.9* 10’5), a finding corroborated in three mouse models: unilateral ureteral obstruction (UUO, P = 3.4* 10'25), folic acid nephropathy (FAN, P = 3.7* 1011), and a cisplatin model (P < I x lO-300) (Figs. 15E-15F). These results underscore the efficacy of the Open4Gene framework in elucidating the regulatory mechanisms of disease-associated genes and resolving variant-to-function issues in GWAS.

[0495] Example 2-8: Integrated Kidney Disease Genetic Scorecard concept for combined variant and gene prioritization

[0496] The present study generated a multitude of multi-omics datasets for the annotation of regulatory variants, encompassing allele-specific expression and chromatin accessibility at both bulk and single-cell levels, Open4Gene links, complementing existing datasets of eQTLs, meQTLs, exome-wide association analyses and used complementary trait GWAS studies (eGFRcys, BUN). The present study observed important differences in prioritizing different genes and variants with no single tool or dataset enabling variant-to-function annotation. The present study, therefore, reasons that a Kidney Disease Genetic Scorecard that includes all available datasets and tools (currently 32) and uses a simple additive approach to nominate kidney disease genes and variants. Here the present study included eight datasets, including bulk allele-specific accessibility (bASA), single-nucleus allele-specific accessibility (snASA), and fine-mapping credible sets to evaluate regulatory variants. Additionally, the present study assessed the disease risk of genes using 12 annotations, such as coding sequence (CDS), exome- wide association studies (ExWAS), and phenome-wide association studies (PheWAS). The present study examined the influence of non-coding variants on target genes through 12 types of cis associations, including Open4Gene links, allele-specific expression (ASE), and colocalization

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[0498] 56242423.3 Attorney Docket No. 046483-7468W01(04021) analyses (Fig. 6A). The number of prioritized variants diminished with increasing prioritization scores; however, the proportion of variants targeting unique genes showed a marked increase, indicating the effectiveness of the prioritization strategy in pinpointing authentic regulatory variants (Figs. 6B and 16A-16B).

[0499] Focusing on 24,437 regulatory variants that target 1,060 genes, identified by prioritization scores of 10 or higher, the present study noted the top prioritized regulatory variant rs35716097 (with a prioritization score of 27) targeting the SLC34A1 gene (also known as NPT2), a known kidney disease-causing gene (Fig. 16C). 64.4% of prioritized regulatory variants were located in intronic regions, a proportion greater than expected (odds ratio = 1.76, chi-square test P = 1.9* 10'295, Fig. 16D), and nearly half (44.1%) were associated with distal genes (Fig. 16E). Moreover, 29.2% of these regulatory variants coincided with transcription factor binding sites (TFBSs), which was a significantly higher overlap than the 14.5% observed in non-regulatory GWAS variants (odds ratio = 2.42, chi-square test P < 1 * IO'300) (Fig. 16F), underscoring the regulatory impact of non-coding variants on gene regulation.

[0500] Example 2-9: The convergence of regulatory and coding variants for kidney disease

[0501] Both coding and regulatory variants contribute to disease risk, yet their collective presence at GWAS loci remains largely unexplored. To address this gap, the present study integrated multi-omics datasets to prioritize genetic variants linked to kidney function and disease (Fig. 6A). Initially, the present study annotated eGFRcrea GWAS variants according to their proximity to gene regions and discovered significant (P < 1 *1O'70) enrichment in proteincoding sequences (CDS), five prime untranslated regions (5’UTR), three prime untranslated regions (3’UTR), and introns (Figs. 6C and 17A). Furthermore, exonic variants showed significant enrichment within the fine mapping credible set (odds ratio = 1.53, chi-square test P = 1.4x io-16, Fig. 17B).

[0502] When the present study annotated GWAS variants based on chromatin states — defined by histone modifications in human kidneys — the present study noted significant enrichment of these variants in genic enhancers (odds ratio = 3.2, chi-square test P < 1 * 1 O’300), active promoters (odds ratio = 2.3, chi-square test P < 1 * 1O'300), enhancers (odds ratio = 2.1, chi-square test P < lx IO'300), and other regulatory elements (Fig. 17C). To determine whether this enrichment was unique to the kidney, the present study conducted stratified LD score regression

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[0504] 56242423.3 Attorney Docket No. 046483-7468W01(04021) using eGFRcrea GWAS summary statistics alongside expression and chromatin data from the Roadmap Epigenomics project. This analysis confirmed a consistent enrichment of eGFRcrea GWAS variants in kidney-specific active genes, chromatin marks, and enhancers (Fig. 17D). These findings suggest a convergence of coding and regulatory variants at GWAS loci, highlighting their collective contribution to the genetic landscape of kidney disease.

[0505] The present study then narrowed the focus to coding variants. Comprehensive GWAS mapping facilitated the identification of 1,363 coding variants linked to kidney function, with over 90% being previously undetected by ExWAS studies based on whole exome sequencing in about 450,000 UK Biobank participants (Fig. 18A). The common coding variants concurrently identified by both GWAS and ExWAS exhibited highly correlated effect sizes with respect to kidney function (Fig. 18B). Using the Variant Effect Predictor, the present study pinpointed 83 loss-of-function variants (such as those resulting in a gain of stop codon, splice region variation, and frameshift mutations), 776 missense variants, and 505 synonymous variants (Fig. 6D). Among 782 genes hosting these coding variants, over 95% had not been identified by either ExWAS or phenome-wide association studies (PheWAS) which primarily focused on rare variants with MAF < 10% (58) (Figs. 18C-18D). Within these genes, GWAS, ExWAS, and PheWAS collectively identified 21 kidney disease-related genes, including solute carrier genes (such as SLC47A1 and SLC6A19), multiligand receptors (LRP2 and CUBN), and genes implicated in polycystic kidney disease (PKD1, PKD2, and PKHD1) (Fig. 18E). Among these, 289 genes (37.0% of the 782 total) possessed multiple coding variants, with ALMS1 (Centrosome and Basal Body Associated Protein) — a gene whose malfunction can lead to a progressive decline in kidney filtration function — harboring the highest number (16) of coding variants (Fig. 18F). As expected, the analysis revealed that while most common coding variants exhibited small effect sizes, rare coding variants tended to have larger effect sizes (Fig. 18G).

[0506] In the concluding analysis, the present study concentrated on 601 genes identified by both coding and regulatory variants across 316 GWAS loci (Figs. 6E and 19A). Most (93.8%, 563 / 600) of these genes were prioritized by at least one variant validated by complementary kidney function measurements (Figs. 6F and 19B). Functional enrichment analysis of 601 genes indicated their roles in proximal tubule transport (P = 9.9* 10'10) and kidney-specific phenotypes such as abnormal renal system physiology (P = 4.0* 10'9, Fig. 19C). Notably, 74 of these genes are documented nephropathy genes, including 10 genes (PKD1, PKD2, PKHD1, CUBN, GATM,

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[0509] LRP2, SLC34A1, SLC34A3, SLC6A19, and SLC7A9) validated by both ExWAS and PheWAS (Fig. 19D).

[0510] For each of these genes, the present study performed conditional analysis on the top variant, resulting in 161 genes with the convergence of coding and regulatory variants, including 29 genes that have already been published to cause renal abnormalities in knockout mice (Figs. 6F-6G and 19E). Compared with non-converged coding variants, converged coding variants showed significantly lower minor allele frequency (P = 1.9><10’13), higher effect size (P = 1.5x10"15), and higher significance (P = 1 ,4x 10"5) in eGFRcrea GWAS (Fig. 19F).

[0511] These genes also demonstrated pronounced cell type-specific expression and chromatin accessibility at their regulatory variants (Fig. 20A). To delineate cell types contributing to kidney disease etiology, the present study assessed the cell type-specific expression of these genes. The present study found 316 genes with significant cell type-specific expression (adjusted P < 0.05, accounting for all tested genes), with an average of 16 specific genes per cell type and the highest number, 94, in proximal tubule cells (Fig. 20B). Among these cell type-specific genes, 63.3% (200 out of 316) exhibited significant associations (Open4Gene FDR < 0.01) with open chromatin at their top regulatory variants, and 54.1% (171 out of 316) showed concordant expression and open chromatin profiles within the same cell type. For instance, the SLC34A1 gene displayed specifically high expression and open chromatin in proximal tubule cells (Fig. 16C), while the KNG1 gene showed these features in the loop of Henle and distal convoluted tubule cells (Fig. 20C).

[0512] Furthermore, in exploring therapeutic implications, the present study identified 124 genes amenable to targeting by FDA-approved drugs, offering potential prospects for drug repurposing and the development of therapeutic approaches (Fig. 20D). In conclusion, the integrative maps of coding and regulatory variants facilitate the identification of causal genes, implicated cell types, and potential druggable targets.

[0513] Example 2-10:

[0514] By conducting a multi-ancestry GWAS in 2.2 million individuals, the present study provides insights into the genetic architectures of human kidney function, with a primary focus on common genetic variation. The present study generated genetic maps for eGFRcrea GWAS (n=2.2 million), allele-specific gene expression in tubule and glomerulus compartments, allele-

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[0516] 56242423.3 Attorney Docket No. 046483-7468W01(04021) specific chromatin in both bulk kidney and single-cell level, and regulatory circuits based on single-nucleus multiome information. By constructing the Kidney Disease Genetic Scorecard, the present study developed a new prioritization strategy and identified 601 kidney disease genes targeted by both coding variants and regulatory variants, including 161 genes with converged coding and 10 regulatory variants. In these analyses, the present study also developed several new strategies, including snASA and Open4Gene, to integrate single-cell omics and GWAS studies. Using these tools, the present study found critical cell types (including proximal tubules), transcriptional regulators (including HNF4A), and potential drug targets for kidney disease, providing an overall foundation to understand kidney disease.

[0517] The present study created what is likely a complete GWAS map of loci associated with kidney function within the European population based on a sample size exceeding 1.7 million individuals. This extensive GWAS resource has led to the discovery of 97 loci related to kidney function. The identification of specific GWAS signals in underrepresented populations, such as BICC1 in the East Asian population and APOL1 in the African population, underscores the importance of increasing sample sizes in these groups. Expanding the GWAS efforts to include diverse populations is crucial for uncovering genetic insights and enhancing the understanding of disease mechanisms in the future.

[0518] By capitalizing on allelic differences in the transcriptome, the present study identified a greater number of disease-related genes. For instance, the genetic associations of HNF1A were only detected through allele-specific expression (ASE) analysis within the tubule compartment. Further investigations into allelic imbalance have illuminated the epigenetic alterations attributable to heterozygosity that contribute to allele-specific expression.

[0519] The present study found a pronounced enrichment of cell type-specific regulatory elements, including open chromatin peaks and genic enhancers, as well as transcription factors such as HNF4G and HNF4A. The presence of eGFRcrea GWAS signals in proximity to genes encoding these transcription factors provides compelling evidence for their involvement in kidney function.

[0520] Coding variants, particularly those that lead to a loss of function in proteins, are the major cause of mortality and morbidity at an early age. However, coding variant mutations are extremely rare due to the selective pressure acting to eliminate them in the general population. Most prior exome sequencing studies indicated that coding mutations are not major contributors

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[0522] 56242423.3 Attorney Docket No. 046483-7468W01(04021) to common disease heritability due to their rarity. In the large GWAS, the present study have been able to identify a large number of coding variants (n = 1,363) associated with kidney function. These coding variants influence 782 genes implicated in disease, including 601 genes also affected by non-coding variants in cis-regulatory regions. The observations underscore the convergence of coding and non-coding variants in hundreds of genes and enable the identification of key disease-causing genes and pathways. Unraveling the complex interplay between these variant types holds great promise for informing the development of innovative therapeutic strategies.

[0523] In summary, the present study presents a large-scale analysis of the genetic architecture of human kidney function, a multitude of omics datasets, and information to highlight biological insights, including 601 prioritized disease genes. This study emphasizes the convergence of coding and regulatory variants on key disease genes and presents the concept of a Kidney Disease Genetic Scorecard for disease diagnostics and therapeutics development.

[0524] Example 2-11: Materials and methods

[0525] The collection of human kidney samples was approved by the institutional review board of the University of Pennsylvania, and the data from population-based cohorts were approved by relevant ethics committees. The present study first performed de novo mapping of genome-wide associations for eGFRcrea in each of 9 population-based cohorts, such as MVP, TWB, All of Us, MGB, GHS, PMBB, BioMe, eMERGE-III, and CCPM, Additionally, the present study obtained ten more GWAS datasets from published studies, including CKDGen, Pan-UK Biobank (https: / / pan.ukbb.broadinstitute.org), HUNT, BioVU, MGI, TOPMed, UKHLS, PAGE, SUMMIT, and BBJ). After quality control, the present study conducted a meta-analysis of eGFRcrea GWAS in multi-ancestry populations with a total sample size of 2,287,877, using METAL (version 2011-03-25). Similarly, the present study performed ancestry-group-specific GWAS meta-analyses for 1,785,582 European individuals from 15 studies, 282,852 East Asian individuals from five studies, and 67,943 African individuals from seven studies, respectively. Variants associated with eGFRcrea were defined by the genome-wide significance threshold p < 5* 10'8, with validation using two complementary kidney function markers. The present study used a clumping method to define independent loci and identified new loci by comparing them with previous studies. Down-sampled GWAS analyses were performed to evaluate the saturation

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[0527] 56242423.3 Attorney Docket No. 046483-7468W01(04021) of GWAS discovery, and fine mapping analysis was conducted in both European-ancestry GWAS and multi-ancestry GWAS using the Bayesian model CARMA (version 1.0). Pleiotropy maps between eGFRcrea and other traits were assessed using HyPrColoc (version 20 1.0) and bidirectional GSMR (version 1.1.0) based on GWAS summary statistics of European-ancestry individuals.

[0528] To explore the genetic effect of eGFRcrea variants on gene expression and chromatin accessibility, the present study conducted multi omic profiling in over 1000 kidney samples, including genotyping 729 human samples using Axiom arrays (n = 641) and whole genome sequencing (n = 88), transcriptome analysis of 613 tubule samples and 522 glomerulus samples by RNA sequencing, single-nucleus multi ome sequencing (joint RNA and AT AC) in nine kidneys and snATAC sequencing in eight kidneys. After data processing and quality control, the present study explored the genetic effect on gene expression via ASE mapping using RASQUAL and typical eQTL mapping using MatrixeQTL. Significant associations were determined after multiple testing corrections based on eigenMT and used to prioritize target genes of eGFRcrea variants. To investigate the effect of genetic variants on chromatin accessibility, the present study created comprehensive maps of kidney open chromatin regions by integrating bulk and single-nucleus ATAC-seq datasets and mapped bASA associations using RASQUAL. Validated associations were used to prioritize chromatin accessibility affected by eGFRcrea variants. Next, the present study constructed open chromatin maps of 237,274 high-quality cells in 30 human kidneys and explored the genetic effect on chromatin accessibility at the cell type level by developing a snATAC -based allele-specific accessibility analysis strategy, snASA, based on WASP (version 0.3.4) and two-tailed Binomial test. Further, the present study developed a new statistical method (Open4Gene) based on the hurdle negative binomial regression model for mapping peak-to-gene links in multiome data. Using Open4Gene, the present study mapped the regulatory circuits in different kidney cell types and explored the genetic effect on open chromatin and gene expression. By integrating these multiomic datasets, the present study proposed a Kidney Disease Genetic Scorecard and prioritized coding variants and regulatory variants associated with eGFRcrea. Finally, the present study explored the convergence of coding and regulatory variants using GCTA-COJO (version 1.93), and identified potential drugs targeting these genes using DGIdb (v4.2.0) and DrugBank.

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[0531] Study-level GF AS mapping

[0532] The present study first performed de novo mapping of genome-wide associations for eGFRcrea in each of 9 population-based cohorts, such as MVP, TWB, All of Us, MGB, GHS, PMBB, BioMe, eMERGE-III, and CCPM, which were approved by relevant ethics committees. In the BioMe dataset, GWAS mapping was performed after excluding 9,838 samples that were included in CKDGen. The eGFRcrea was calculated using the CKD-EPI Creatinine Equation. Self-identified Race / Ethnicity was used to define the ancestries (European ancestry, African ancestry, East Asian ancestry, South Asian ancestry, Admixed American ancestry, Hispanic / Latino ancestry) referencing the 1000 Genome Project. Samples with outlying genetic ancestry were excluded. After quality control, the imputed genotype data was used for eGFRcrea GWAS mapping with covariates including sex, age, and the top 10 genetic principal components, in each study. Moreover, the present study obtained ten additional GWAS datasets from published studies, such as CKDGen, Pan-UK Biobank (https: / / pan.ukbb.broadinstitute.org), HUNT, BioVU, MGI, TOPMed, UKHLS, PAGE, SUMMIT and BBJ). All study files were checked for quality control. The bcftools package was used to annotate rsID for each variant based on dbSNP annotation (build 151) if rsID was unavailable in the original data. For each study, only variants with rsID and MAF > 0.1% were used for further analysis.

[0533] GJVAS meta-analysis

[0534] The present study next performed meta-analysis of eGFRcrea GWAS based on the summary statistics of 17 non-overlapping multi-ancestry studies, such as MVP, TWB, All of Us, MGB, GHS, PMBB, BioMe, eMERGE-III, CCPM, CKDGen, Pan-UK Biobank, HUNT, BioVU, MGI, TOPMed, UKHLS, PAGE, and SUMMIT) with a total sample size of 2,287,877. Meta-analysis was performed using METAL (version 2011-03-25), as described before, via sample size-weighted meta-analysis of z scores, to allow for differences in eGFRcrea estimation and scaling, with genomic control correction for each input study. The between-study heterogeneity was assessed with Cochran’s Q-test and 12 statistic. After meta-analysis of 45,013,520 variants, the present study filtered out 12,032,581 variants only available in one study, 19,061,917 variants with sample size < 500,000 individuals, 1,628 variants with MAF < 0.1%, and 217,003 unplaced and non-autosomal variants subsequently, resulting in the most comprehensive eGFRcrea GWAS map of 13,700,391 variants in 2,287,877 multi-ancestry

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[0536] 56242423.3 Attorney Docket No. 046483-7468W01(04021) individuals (78.8% were of European ancestry). To make sure the effect was always reported to the alternate allele, z scores were harmonized based on the annotation of dbSNP annotation (build 151), and then converted to effect sizes following a method proposed by Zhu et al. (Nat Genet 48, 481-487 (2016)). Similarly, the present study further performed ancestry -groupspecific GWAS meta-analyses for 1,785,582 European individuals from 14 studies, 282,852 East Asian individuals from five studies, and 67,943 African individuals from seven studies, respectively.

[0537] To estimate the amount of population stratification in these GWAS meta-analyses, the linkage-disequilibrium score regression was performed using the LDSC package for GWAS meta-analyses, each study and 28 UK Biobank traits. The attenuation ratio between the LDSC intercept and mean x2statistic, defined as (intercept - 1) / (mean x2- 1), was used to estimate the relative balance of confounding and genetic effects in each study. The attenuation ratio is close to zero if most of the inflation in the test statistics is due to polygenic effects, while a high ratio indicates a high proportion of other sources of inflation, such as population stratification.

[0538] Definition of genomic risk variants and loci

[0539] The present study defined variants associated with eGFRcrea by the genome-wide significance threshold p < 5x 10"8. Specifically, variants with between-study heterogeneity (Cochran’s Q-test HetlSq > 50 or 12 statistic HetPVal < 0.05 estimated in the meta-analysis) were considered significant only if they met genome-wide significance level (p < 5 * 1 O'8) in both the meta-analysis and at least one original study. The variants at the major histocompatibility complex (MHC) region were filtered out, and the remaining variants were used for further analysis. The relevance of significant variants to kidney function was validated using GWAS data for eGFR based on cystatin C (eGFRcys) of 421,714 individuals from Pan-UKBB (https: / / pan.ukbb.broadinstitute.org) and blood urea nitrogen (BUN) of 852,678 individuals from CKDGen Consortium. For each eGFRcrea-associated variant, its relevance to kidney function was treated as ‘validated’ if it showed significant (P < 0.05) association with eGFRcys in the same effect direction or significant (P < 0.05) association with BUN in the opposite effect direction. Further independent loci were defined. In brief, the significant variants were clumped using PLINK with parameters clump-r2 0.1 — clump-kb 10000” and then lead variants within O. lcM of each other were merged, resulting 1,026 independent loci in multi-ancestry GWAS.

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[0542] For each locus, the sentinel variant was determined as the variant with the lowest GWAS p- value. Novel independent loci were defined if their sentinel variants are 1) not significant (p 5* 10'8) in previous studies, 2) 500Kb away from sentinel variants previously reported, and 3) with LD r2 < 0.001 to sentinel variants previously reported. Functions of new loci were evaluated using annotation of mouse phenotypes provided in GREAT (version 4).

[0543] Down-sampled GWAS analyses

[0544] To evaluate the saturation of GWAS discovery, the present study re-analyzed 39 down- sampled GWAS datasets (22 multi -ancestry GWASs and 16 European-ancestry GWASs). These down-sampled GWAS datasets include various iterations of previous efforts of GWAS studies with sample sizes ranging from 67,093 to 2,230,452. For each GWAS, the significant variants were determined using genome-wide significance threshold p < 5* 10'8, and then independent loci were defined using different window sizes (35kb, 50kb, and lOOkb). The genome coverage of identified loci in each GWAS was calculated for comparison.

[0545] Fine mapping analysis

[0546] To identify potentially causal variants, the present study performed fine mapping analysis for European-ancestry GWAS and multi-ancestry GWAS, using a new Bayesian model CARMA (version 1.0) which enables accounting for discrepancies between summary statistics and external LD reference in meta-analyses. The present study used the UKBB LD of 420,531 European individuals obtained from the Pan-UK Biobank (https: / / pan.ukbb.broadinstitute.org). For each GWAS, the independent loci within lOOkb were merged, and fine mapping analysis was performed for each locus by including 187 functional annotations from the baseline-LF 2.2.UKB model and the prior causal probability estimated for given GWAS using PolyFun (version 1.0.0). The credible set was determined by a threshold p > 0.99.

[0547] Assessing pleiotropy maps

[0548] The present study first examined shared genetic variation with GWAS traits obtained from the GWAS catalog (version 1.0.2, last update: July 20, 2023). Only traits with sample sizes > 50,000 were considered. In cases where there were multiple GWAS studies for the same trait, the present study used studies with the largest sample size. The genetic variants associated

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[0550] 56242423.3 Attorney Docket No. 046483-7468W01(04021) with eGFRcrea GWAS of European-ancestry were queried against significant variants (p < 5* 10'8). Fisher’s test was performed to estimate the odds ratio and significance of the enrichment of shared genetic variants between eGFRcrea and each of the GWAS catalog traits.

[0551] To identify the GWAS loci with pleiotropy, the present study performed a genome-wide multi -trait colocalization analysis of European-ancestry eGFRcrea and related traits identified by enrichment analysis above. To this end, the present study collected full summary statistics of 23 European-ancestry GWAS traits. Multi-trait colocalization analysis was implemented using HyPrColoc (version 1.0) for each locus from eGFRcrea GWAS of European-ancestry. HyPrColoc regional probability > 0.8 was used to determine the colocalization between eGFRcrea and at least one related trait.

[0552] Further, the present study defined the causal associations between European-ancestry eGFRcrea and 23 related European-ancestry GWAS traits by performing Mendelian randomization analysis using bi-directional GSMR (version 1.1.0), which is multi-SNP Mendelian randomization method using summary-level data. For each trait, the present study selected variants at the genome-wide significance level (p < 5* 10'8) using the PLINK clumping algorithm with parameters clump-r2 0.1 --clump-kb 10000” and reference panel of the 1000 Genomes Phase 3 (European ancestry, n = 503). These variants were used as instrumental variables for the bi-directional GSMR analysis, with an adjustment for mediation effects, including potential sample overlap, to test for a putative causal effect between eGFRcrea and a given trait. Significant causal associations were defined using p value < 1.1 * 10‘3, Bonferroni’s threshold accounting for 46 bi-directional GSMR tests between eGFRcrea and 23 related traits).

[0553] Kidney sample procurement

[0554] The collection of human kidney samples was approved by the institutional review board of the University of Pennsylvania. Deidentified kidney samples were obtained from the non- neoplastic portion of surgical nephrectomies via the Cooperative Human Tissue Network. The present study also collected demographic and clinical information, including age, sex, selfreported ethnicity, diabetes, and hypertension status, from medical records by an honest broker. eGFRcrea values were calculated using the CKD Epidemiology Collaboration equation. DNA was isolated by the Qiagen DNAeasy or MagAttract High Molecular Weight DNA Kits (Qiagen

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[0557] No. 67563) and quantified by the Tnvitrogen Quant-iT PicoGreen dsDNA Assay Kit (Invitrogen No. Pl 1496), according to the manufacturer’s instructions.

[0558] Generation of genotype data

[0559] Genotype data by array. Genotypes of 641 kidney samples were profiled using Axiom Tx SNP GWAS array or Affymetrix Axiom Biobank array and processed. In brief, quality control was performed using PLINK (vl.9), genotypes were phased with SHAPEIT2 (v2.17), and imputed by IMPUTE2 (v2.3.2) using the panel reference from the 1,000 Genomes Project Phase 3, for each platform. After imputation, genotyping data from two array platforms were merged, and low-quality variants were filtered out for samples for tubule and glomerulus, respectively, resulting in 5,802,576 SNPs in 613 tubule samples and 6,010,272 SNPs in 522 glomerulus samples. For each compartment, genotype-based principal component analysis (PCA) was conducted using EIGENSTRAT (v7.2.1) with an additional 2,504 samples from the 1,000 Genomes Project Phase 3. These genotype datasets were used for ASE mapping.

[0560] Genotype data by whole genome sequencing. Genotypes of 88 kidney samples were profiled using whole genome sequencing. For each sample, pre-processing of lane-specific alignment files was performed in accordance with the Genome Analysis Toolkit (GATK) best practice workflow, with duplicate read removal using Picard, insertion-deletion realignment, and base recalibration using GATK. Run-specific alignments were merged for each sample and then subjected to a second round of indel realignment and base recalibration with GATK. Preliminary sample-level variants were called using HaplotypeCaller with base pair resolution in gVCF mode in GATK, and known variants were identified from the dbSNP 138 hg!9 database. Sample-level variant call sets were combined and joint-genotyped with GATK, resulting in 22,133,038 variants. Then, variant-level quality control was performed using SNPTEST (v2.2.0) and PLINK (vl.9), and 6,272,592 SNPs remained for bASA analysis.

[0561] RNA sequencing

[0562] The transcriptome of 613 tubule samples and 522 glomerulus samples were profiled by RNA sequencing. RNA-Seq libraries were generated and sequenced using Illumina TruSeq protocol. After trimming low-quality bases, RNA-seq reads were aligned to the human genome (GRCh37 / hgl9) using STAR (v2.4.1 d)( 112) with twopassMode Basic” based on GENCODE

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[0564] 56242423.3 Attorney Docket No. 046483-7468WOI(04021) v!9 annotations. Reads with mapping biases were identified using WASP (version 0.3.4) and were realigned to the human genome using the same mapping arguments used above. Only reads mapped correctly were remained for ASE mapping.

[0565] Bulk ATAC sequencing

[0566] Open chromatin of 96 kidney samples was profiled using transposase-accessible chromatin with sequencing (ATAC-seq). ATAC-seq libraries were generated. In brief, kidneys were minced and lysed in lysis buffer, and the centrifuged nuclei were tagmented with Tagment DNA TDE1 Enzyme and Buffer Kit (Illumina, 20034198). Isolated DNA was purified by MinElute Reaction Cleanup Kit (Qiagen, 28204) following the manufacturer’s manual. After amplification and quality control, libraries were submitted to 150 bp PE sequencing with the Illumina HiSeq 3000 system. The raw reads were aligned to the human genome (hgl9) using Bowtie2 (version 2.4.5) after trimming adaptors by TrimGalore (version 0.5.0). The present study used WASP (version 0.3.4) to identify reads with mapping biases and then realigned them to the human genome using the same mapping arguments used above. Reads mapped correctly remained for bASA mapping.

[0567] Single-nucleus multiome sequencing (joint RNA and ATAC)

[0568] Nine human kidneys were collected after surgical nephrectomies. Nuclei were isolated, and lOx barcoded libraries were generated using the Chromium Single Cell Multiome ATAC + Gene Expression Reagent Kits (10X Genomics, PN- 1000283, PN- 1000282) according to the manufacturer’s manual and further sequenced on an Illumina Novaseq-6000 system. For each sample, RNA reads were aligned to the human genome (hgl9) using Cell Ranger (version 6.1.2). Ambient RNA contamination was detected and removed using SoupX (version 1.5.2). Seurat (4.1.0) was used to fdter out low-quality cells (RNA feature < 200, RNA feature > 3,000, or mitochondrial counts > 15%) and low-quality clusters (median RNA feature < 200 or median mitochondrial counts > 5%). Then, doublets were predicted and filtered out using DoubletFinder (version 2.0.3). RNA datasets were merged using Seurat and integrated using Harmony (version 0.1.0). ATAC reads were aligned to the human genome (hgl9) using Cell Ranger ATAC (version 2.1.0), and Signac (version 1.5.0) was used for quality control by filtering out low-

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[0570] 56242423.3 Attorney Docket No. 046483-7468W01(04021) quality cells (AT AC count < 500, AT AC count > 100,000, nucleosome signal > 4, or TSS enrichment < 1).

[0571] In total, 62,278 common cells passed quality control in both RNA and ATAC. Clusters were identified by Seurat’s FindClusters function. And cell types were annotated using cell-type marker genes (Fig. 14A), resulting in 19 main cell types (PT, Proximal tubule; Injured PT, Injured proximal tubule; PEC, parietal epithelial cells; LOH, Loop of Henle; Macula Densa; DCT, distal convoluted tubule; CNT, connecting tubule cells; PC, principal cells of collecting duct; IC-A, type alpha intercalated cells; IC-B, type beta intercalated cells; Podo, podocyte; Endo peritubular, endothelial cells of peritubular vessels; Endo GC, endothelial cells of glomerular capillary tuft; Endo lympho, endothelial cells of lymphatic vessels; Stroma / VSMC, Stroma cells / vascular smooth muscle cells; Fibro, fibroblasts; T Lympho, T lymphocytes; B Lympho, B lymphocytes; and Mac, macrophage. Open chromatin peaks were identified using Signac’s CallPeaks function based on MACS2 (version 2.2.7.1) with the parameter “combine.peaks = TRUE, extsize = 200, shift = -100”, resulting in 328,829 cell-type peaks. These data were used for further analysis, including bASA, snASA, and Open4Gene.

[0572] Single-nucleus ATAC sequencing

[0573] Eight human kidneys were collected after surgical nephrectomies and processed for single-nucleus ATAC-seq (snATAC-seq) as described before(8). In brief, diluted Nuclei Buffer (10X GEM) was used for resuspension, and Countess AuoCounter (Invitrogen, C10227) was used to measure nuclei quality and concentration. After incubation in the Chromium single cell ATAC library & gel bead kit’s transposition mix (10X Genomics, PN-1000110), the present study generated single cell gel beads in the emulsion (GEM) using Chromium Chip E (10X Genomics, PN-1000082) according to the manufacturer’s protocol. Then, snATAC-seq libraries were generated using the Chromium Single Cell ATAC Library & Gel Bead Kit and Chromium i7 Multiplex Kit N Set A (1 OX Genomics, PN- 1000084) according to the manufacturer’s manual. After quality control using the Agilent Bioanalyzer High Sensitivity DNA kit, libraries were demultiplexed and further sequenced using two 50-paired-end kits on an Illumina Novaseq-6000 system. To enhance the power of analysis, the present study obtained 13 publicly available kidney snATAC-seq datasets. For each sample, reads were aligned to the human genome (hgl 9) using Cell Ranger ATAC (version 2.1.0). Signac (version 1.5.0) was used for quality control by

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[0575] 56242423.3 Attorney Docket No. 046483-7468WOI(04021) filtering out low-quality cells (ATAC count < 500, ATAC count > 100,000, nucleosome signal > 4, or TSS enrichment < 1). scATAC-seq cells were annotated via label transfer using Seurat’s FindTransfer Anchors function based on multi ome annotation above, classifying 174,996 cells with prediction scores >0.6 using both multiome snATAC-seq and snRNA-seq. Integration anchors were identified in multiome snATAC-seq by reciprocal latent semantic indexing projection and multiome snRNA-seq by canonical correlation analysis, respectively. Finally, these snATAC-seq datasets were merged with multiome snATAC-seq datasets using Seurat, resulting in 237,274 high-quality cells from 30 human kidneys for snASA analysis.

[0576] Allele-specific expression analysis

[0577] For each sample, allele-level read count quantifications were calculated using GATK’s ASEReadCounter function, and gene-level read count quantifications were estimated using RSEM (vl.3.1). To remove the effects of unobserved confounding variables, probabilistic estimation of expression residuals (PEER) was performed on gene-level expression with technical and clinical covariates such as age, gender, collected site, sequencing batch, RNA integrity number (RIN), library size, and fibrosis percentage (for tubule samples) or sclerosis percentage (for glomerulus samples). For each compartment, RASQUAL was implemented to test all SNPs within 100 kb of each gene for association with expression levels, with covariates of technical and clinical variables and 60 PEER factors, referring to the Genotype-Tissue Expression (GTEx) project. Then, the RASQUAL script “rasqualToEigenMT.py” was used to convert RASQUAL output to a format suitable for eigenMT, which is a computationally efficient multiple testing correction method. Accounting for the number of independent tests estimated by eigenMT, significant variants were determined by Bonferroni corrected p-value < 0.05 for each gene. To evaluate the performance of ASE analysis, typical eQTL mapping was performed in the same dataset using a linear regression model implemented by MatrixeQTL(38), with the same covariates and window size used in the RASQUAL ASE analysis in each compartment. Then, multiple testing correction was performed based on eigenMT, and significant eQTL variants were determined by Bonferroni corrected p-value < 0.05 for each gene, accounting for the number of independent tests estimated by eigenMT. The ASE gene list was obtained from AlleleDB, an allele-specific annotation for the 1000 Genomes variant catalogue, and used to validate the ASE genes identified in this study. To prioritize the target genes of eGFRcrea

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[0580] GWAS variants, the present study identified the significant ASE variants that were also associated with eGFRcrea.

[0581] Comprehensive maps of kidney open chromatin

[0582] Kidney open chromatin maps were defined by integrating bulk and single-nucleus ATAC-seq datasets. To enhance the power of peak calling, 96 bulk ATAC-seq bam files were merged, and 375,037 peaks were called using MACS2 —callpeak (with parameters: —nomodel, — extsize 200, and —shift 100). Then, 429,333 subpeak summit positions were identified using PeakSplitter (version 1.0) and resized to 500bp. The present study merged 500bp subpeaks and 328,829 cell-type peaks identified above, resulting in 524,324 kidney open chromatin peaks, which were used for further analysis, including bASA, snASA, and Open4Gene.

[0583] Allele-specific accessibility analysis using bulk ATAC-seq

[0584] For each 524,324 kidney open chromatin peaks, the read count was calculated in each of 96 bulk ATAC-seq samples using featureCount (version 2.0.3). The present study selected 459,296 peaks with read count > 10 in at least 5 samples and then normalized them using TMM and mean-variance modeling-based transformation (voom), which were implemented using edgeR (version 3.24.3). Open chromatin level was defined as log transformed read count per million reads. Then, six outlier samples were detected based on Mahalanobis distance. Further, 82 samples with whole genome sequencing and bulk ATAC-seq data were used for allelespecific accessibility analysis. Allele-level read count quantifications were calculated using GATK’s ASEReadCounter function. RASQUAL was implemented to test all SNPs within 100 kb of each peak for association with open chromatin levels, with covariates of technical and clinical variables and PEER factors.

[0585] PEER factors were estimated using peak open chromatin data with technical and clinical covariates such as age, gender, collected site, sequencing batch, fibrosis percentage, and top 5 genetic PCs, to remove the effects of unobserved confounding variables. The present study optimized the number of used PEER factors to identify the most SNP-peak pairs on chromosome 1.

[0586] Finally, four PEER factors, together with general variables, were used as covariates in RASQUAL to perform genome-wide bASA mapping for 2* 108SNP-peak pairs between

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[0589] 6,272,592 SNPs and 446,385 peaks. For each peak, eigenMT was used to estimate the number of independent tests for Bonferroni correction. Significant bASA variants were defined using Bonferroni corrected p-value < 0.05. To further remove potential false positive associations, the present study performed two different models for typical caQTL mapping using MatrixeQTL and allele-specific analyses using stratAS, on the same dataset used for bASA mapping. 650,237 (89.8%) bASAs were validated by at least one model at FDR < 0.05, while 73,554 bASAs were not validated by either model. These 73,554 potential false positive associations were filled out for further analysis.

[0590] The enrichment of bASA peaks in regulatory elements was examined based on the chromatin state annotations estimated using various histone modifications in human kidneys. The associations between open chromatin, DNA methylation, and gene expression were explored using bASA variants with kidney meQTL and tubule ASE, respectively. Moreover, shared significant variants between bASAs and eGFRcrea GWAS were extracted to prioritize the regulatory potential of variants associated with kidney function.

[0591] Allele-specific accessibility in kidney cell types

[0592] To explore cell type-specific ASA, the present study developed a snAT AC -based allelespecific accessibility analysis strategy, snASA, which enables ASA analysis even without available genotype data for snATAC samples. In brief, 1) genotype detection was performed for each sample using QuASAR (version 0.1) after filtering low-quality reads and duplicates from bam files. 2) Genotype Imputation was performed for each sample using the TOPMed Imputation Server, and variants with low imputation quality R2 < 0.7 were filtered out. 3) Reads with mapping biases were identified using WASP and remapped to the human genome using Cell Ranger ATAC (version 2.1.0). 4) Correctly mapped reads were extracted for each cell type in each sample using subset-bam (version 1.1.0), and allele-level read counts were counted for each variant using WASP’s bam2h5.py function. 5) Read count imbalance between two alleles for each variant was tested by a two-tailed Binomial test using R binom.test for each cell type in each sample. 6) For each cell type, meta-analysis was performed to combine the Binomial tests across samples for each variant using Stouffer's Z-score method. 7) For each cell type, p values were adjusted for multiple comparisons, and FDR < 0.05 was used to define the variants with significant allele-specific accessibility.

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[0595] Regulatory circuits by Open4Gene

[0596] To map regulatory circuits single-nucleus multiome, the present study developed a new statistical method, Open4Gene, based on the hurdle negative binomial regression model(48). To account for excess zeros in single-nucleus RNA data, the present study used a two-component mixture model consisting of a zero mass and the positive observations component following a truncated count negative binomial distribution. The first part of the model is a binary logistic regression model in which the gene expression takes a positive count or not. The second part of the model is a truncated negative binomial model only fitting positive expression counts. This two-component mixture model is fitted using the hurdle function of the pscl package with the formula where RNA is the observed expression count of a gene, ATAC is the observed read count of a peak, and Xi were the covariates. By including covariates, this model enables accounting for batch effects and technical factors such as mitochondrial reads.

[0597] The present study applied Open4Gene to analyze 1,155,118 peak-to-gene pairs (16,164 genes and 425,429 open chromatin peaks in cis with distance <100kb) using the joint profiles in 62,278 kidney cells, with covariates including log-transformed total RNA read count and percent of mitochondrial reads in each cell. For comparison, the present study also analyzed the same data using two popular single-cell multimodal peak-to-gene methods (ArchR and Signac) with default parameters. To evaluate the performance, the present study obtained chromatin interactions and compared them with the peak-to-gene pairs top-ranked by each method, using pairtopair function of bedtools (version 2.29.2). To examine the risk of false discovery, the present study obtained 154 potential ground-truth positive peak-to-gene pairs by overlapping chromatin interactions profiled by HiC and peak-to-gene pairs top-ranked (1%) by both ArchR and Signac in kidney cells. For each pair, a false association was simulated by shuffling its ATAC data, and its significance was estimated by Open4Gene. FDR was calculated as the prediction score, and the Receiver Operating Characteristic (ROC) curve was plotted to display the true positive rate versus the false positive rate using the function roc. curve in the ROSE package (version 0.0-4).

[0598] For each cell type, Open4Gene was applied to identify the peak-to-gene pairs, and significant pairs were determined by FDR < 0.01 in either the zero model or the count model.

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[0601] The identified peak-to-gene pairs were further used to prioritize the eGFRcrea GWAS if variants were in the 0pen4Gene peaks. The number of GWAS variants prioritized by 0pen4Gene links was counted for each gene. The functions of 253 genes with 10 Open4Gene GWAS variants were analyzed using modPhEA. RNA-seq data from 433 human kidneys was used to explore the difference in ACSM2A expression and its associations with eGFRcrea and fibrosis. RNA-seq data from three mouse models were used to analyze the expression changes of Acsm2 in kidney disease.

[0602] Bayesian colocalization analysis

[0603] The present study performed Bayesian colocalization analysis to identify the variants where the genotype effect on kidney function, gene expression, or open chromatin was shared. In brief, variants in the MHC region were excluded first. Significant eGFRcrea GWAS variants identified above were defined as leading variants. To estimate the posterior probability that a leading variant is associated with any trait (tubule ASE, glomerulus ASE, or kidney bASA), the present study extracted available variants within a lOOkb search window for each leading variant. To avoid violation of the assumption that there is one causal variant per signal, the search window was narrowed (lOOkb / number of independent signals) for GWAS loci with multiple independent signals according to fine mapping. Bayesian colocalization analysis was implemented using R package coloc (v5.1 ,0)(l 32) with default parameters (p 1=1 * 10'4, p2=l * 10'4, and pl2 =1 * 10'5). For ASE and bASA data, the beta and standard error were estimated using RASQUAL outputs Chi-square statistic and Pi using the following formula, beta = Pi - 0.5. Posterior probability > 0.8 was considered evidence of colocalization between GWAS and each trait. Function enrichment analysis of genes with ASE-GWAS colocalization was performed using the overrepresentation test of PANTHER (Protein ANalysis THrough Evolutionary Relationships) Classification System (vl9.0).

[0604] Integrated Kidney Disease Genetic Scorecard

[0605] To prioritize GWAS variants, the present study first explored their distribution in the human genome by overlapping GWAS variants with gene features (CDS, 5’UTR, 3’UTR, and intron) and chromatin states. LDSC enrichment analysis was performed to estimate the enrichment of heritability explained by GWAS variants in different genome regulatory elements,

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[0607] 56242423.3 Attorney Docket No. 046483-7468W01(04021) including histone modification peaks, open chromatin peaks, enhancers, and tissue-specific highly expressed genes.

[0608] Coding variants were identified as GWAS variants located in the CDS regions. For comparison, variants identified by ExWAS for creatinine and eGFRcrea were obtained from recently published studies. The association of effect sizes between GWAS and ExWAS was estimated by the Speaman correlation test. Data of gene-based PheWAS burden test of creatinine in 376,624 UK Biobank individuals was downloaded from genebass. Genes prioritized by GWAS, ExWAS, and PheWAS were compared. Further, the effect of coding variants on protein products was predicted using annotations based on the Ensembl Variant Effect Predictor and UCSC Variant Annotation Integrator, and loss of function variants was defined as variants causing gain / loss of stop codon, loss of start codon, inframe insertion / deletion, frameshift, NMD transcript or in splice region.

[0609] Regulatory variants were identified as non-coding variants targeting potential disease- related genes. To this end, the present study proposed a prioritization strategy to score the function of GWAS variants, gene risk, and regulatory potential from variant to gene. The function of GWAS variants was evaluated using regulatory elements, such as bASA, snASA, ATAC peak, TSS, HMM state, eGFRcys, BUN, and fine-mapping credible sets. The disease risk of genes was defined based on coding variants and other gene-level studies, such as pLoF, missense variants, CDS, ExWAS, PheWAS, MAGMA, Nephropathy, DEPICT, and kidney phenotypes. For each pair of a variant and gene, the regulatory potential was determined by the association links, such as 0pen4Gene, tubule ASE, glomerulus ASE, kidney eQTL, meQTL, coaccessibility, colocalization, cS2G, and ABC. The sum of these scores was defined as the prioritization score. To determine the cutoff of the prioritization score, the present study used a list of 17 nephropathy genes that have been validated by all coding variant evidence (GWAS CDS, ExWAS, and PheWAS) or knockout mice studies. The highest cutoff of prioritization score that covered all these validated nephropathy genes was used to define the regulatory variants and their target genes.

[0610] Finally, 601 genes prioritized by both coding variants and regulatory variants were identified. The cell type-specificity of these genes was examined in the single-nucleus mutiome dataset using the Wilcoxon Rank Sum test implemented by the function Find AllMarkers in the Seurat package (4.1.0). Cell type-specific expressed genes were defined by log2 -transformed

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[0612] 56242423.3 Attorney Docket No. 046483-7468W01(04021) fold change (avg_log2FC) > 0.25 and FDR < 0.05. The functions of 601 genes were estimated by enrichment analysis on Wiki pathways using Enrichr and mouse phenotypes using modPhEA. The FDA-approved drugs targeting these genes were extracted using two databases, DGIdb (v4.2.0) and DrugBank. In particular, the prioritization evidence was visualized for SLC34A1 and KNG1 using the UCSC genome browser. The expression of these two genes was plotted using Seurat’s VlnPlot function.

[0613] The convergence of coding and non-coding regulatory variants

[0614] The evolution of coding and non-coding variants in the genome is shaped by different selective pressures due to their distinct effects on protein function and transcription. The present study hypothesized that functional coding and non-coding variants should not tag each other in genotype if they converge on targeting the same gene by affecting its protein and transcription, respectively. To explore the convergence of coding and non-coding regulatory variants, the present study performed conditional analysis on the most significant GWAS variants for each gene using GCTA-COJO (version 1.93), with a reference panel from the 1000 Genomes Phase 3 (European ancestry, n = 503). For each significant variant (P < 5* 10'8) after conditional analysis, the present study further explored its independence with the given conditioned variant using LD metrics from Pan-UKBB (European ancestry, n = 420,531), and LD R2 < 0.05 defining the independence of coding and regulatory variants. These independent coding-regulatory pairs passing conditional tests were defined as convergent. The features of coding variants with convergence were explored by examining their MAF, effect size and significance in eGFRcrea GWAS, compared to coding variants without convergence.

[0615] Example 3: Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1) increases kidney disease risk by modulating ferroptosis

[0616] Genome-wide association studies (GWASs) have identified more than 1000 loci where genetic variants correlate with kidney function.

[0617] Here, the present study identified glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1) on chromosome 15 as affected by GWAS variants by analyzing human kidney gene expression and methylation information. Both CHAC1 RNA and protein were expressed in the

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[0619] 56242423.3 Attorney Docket No. 046483-7468W01(04021) loop of Henle region in mouse and human kidneys, and CHAC1 expression was higher in patients carrying disease risk variants.

[0620] Using CRISPR technology, the present study created mice with a single functional copy of the Chad gene (Chacl+ / “) that displayed no baseline phenotypic alterations in kidney structure or function. These mice demonstrated resilience to kidney disease in multiple models, including folic acid-induced nephropathy, adenine-induced chronic kidney disease, and uninephrectomy-streptozotocin-induced diabetic nephropathy.

[0621] The present study further showed that CHAC1 plays a critical role in degrading the cellular antioxidant glutathione. Tubule cells isolated from Chacl+ / " mice showed increased glutathione, decreased lipid peroxidation, improved cell viability, and protection against ferroptosis. Expression of ferroptosis-associated genes was also lower in mice with only one copy of Chad. Higher CHAC1 protein also correlated with ferroptosis-related protein abundance in kidney biopsies from patients with kidney disease.

[0622] As such, the present study positions CHAC1 as an important mediator of kidney disease that influences glutathione concentrations and ferroptosis, suggesting potential avenues to explore for the treatment of kidney diseases.

[0623] The article titled “Glutathione-specific gamma-glutamyl cyclotransferase 1 (CHAC1) increases kidney disease risk by modulating ferroptosis” (Sci Trail si Med. 2025 Apr 23;17(795):eadn3079) is hereby incorporated in its entirety by reference.

[0624] Genetic, epigenetic, and regulatory integration

[0625] Locus plots at rs4924525 show GWAS association colocalized with kidney eQTL, ASE, and meQTL, and overlapping an snATAC peak in the loop of Henle. Risk alleles associate with increased CHAC1 expression.

[0626] As such, multi-omic colocalization assigns a causal regulatory mechanism to the CHAC1 locus in tubular lineages, consistent with KDGS mapping.

[0627] Animal protection across models

[0628] Phenotypic comparisons of Chacl+ / " versus wild-type mice in folic acid nephropathy, adenine CKD, and diabetic (Unx-STZ) models show improved creatinine, BUN, UACR, and reduced fibrosis markers and histology in Chacl+ / " animals.

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[0631] As such, partial genetic reduction of CHAC1 is sufficient to protect against kidney injury, establishing in vivo causality.

[0632] Ferroptosis markers

[0633] Western blots and IHC for ACSL4, GPX4, and 4-HNE demonstrate ferroptosis induction in wild-type injury and protection in Chacl+ / " kidneys.

[0634] As such, CHAC1 abundance tracks ferroptosis severity, linking mechanism to phenotype.

[0635] Cellular siRNA rescue

[0636] Human HKC8 and RPTEC cells transfected with CHAC1 siRNAs (and primary mouse tubules) were challenged with stressors; viability, lipid peroxidation, and fibrosis readouts showed protection with CHAC1 knockdown.

[0637] As such, post-transcriptional silencing of CHAC1 rescues tubular cells from ferroptotic injury, supporting RNAi -based therapeutic strategies.

[0638] Epigenetic editing

[0639] Although targeted CpG editing was not performed at the CHAC1 locus, in one embodiment such editing is contemplated.

[0640] Functional proof-of-principle was demonstrated at the TNF locus in diabetic kidney disease, where dCas9-TETl demethylation increased TNF expression and worsened injury, while higher methylation was protective. By analogy, KDGS-prioritized CpGs at CHAC1 (e.g., cg05124934) are suitable for modulation using dCas9-TETl or dCas9-DNMT3A constructs. These results demonstrate the feasibility of applying epigenome editing to KDGS genes, including but not limited to CHAC1.

[0641] Chronic Kidney Disease (CKD) represents a significant and escalating global health burden. Over 850 million people are affected by CKD, which carries a high risk of mortality. When CKD progresses to end-stage renal failure, patients require dialysis or transplantation. Gaining insights into the molecular pathways that drive kidney dysfunction can foster the development of novel therapies.

[0642] The heritability of kidney function is well-established. Genome-wide association studies (GWAS) have been employed to map regions of the genome where genetic variants are linked

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[0644] 56242423.3 Attorney Docket No. 046483-7468W01(04021) with disease development. These studies have analyzed various kidney disease-related traits, including kidney function as indicated by eGFR (estimated glomerular filtration rate), albuminuria, blood pressure, and blood metabolite levels 10. While these studies have proficiently identified nucleotide variants in the genome linked with specific traits, interpreting GWAS findings remains a challenge. Firstly, the pinpointed single nucleotide polymorphisms (SNPs) frequently co-segregate with numerous other variants, complicating the determination of which are causally related to disease. This phenomenon is referred to as linkage disequilibrium! 1. Another hurdle is that over 90% of the significant variants identified by GWAS are located in the non-coding regions of the genome, posing questions about which genes they influence.

[0645] Disease-causal variants are enriched in cell-type-specific gene regulatory regions and affect target gene expression by altering transcription factor binding. Recently, epigenetic annotations like Assay for Transposable Accessible Chromatin (ATAC-seq) and histone chromatin immunoprecipitation have emerged as innovative tools for prioritizing causal variants. Expression Quantitative Trait Loci (eQTL) analysis elucidates the influence of genetic variants on gene expression by examining the correlation between genotype and tissue-specific gene expression. The present study developed one of the first tissue compartment-specific eQTL at lases for the human kidney. The most recent GWAS highlighted nearly 800 genetic loci linked with eGFR creatinine. However, validation of these many genes is challenging, but studying at the individual gene level may eventually offer druggable candidates to better treat kidney disease. One gene the present study spotlighted in relation to kidney dysfunction was the Glutathione-specific gamma-glutamylcyclotransferase 1, colloquially known as CHAC1.

[0646] CHAC1 belongs to an enzyme family conserved across all phyla, embodying a cytosolic pathway that modulates glutathione reserves in living cells. Glutathione, a pivotal cellular antioxidant tripeptide, primarily serves to counteract reactive oxygen species. Elevated CHAC1 expression has been linked to glutathione exhaustion and cellular demise. The exact molecular function of CHAC1 remains to be elucidated. Furthermore, CHAC1 expression has been found to be triggered by the integrated stress response, and its role in Notch signaling has also been suggested.

[0647] The GWAS and computational examination of chromosome 15 pinpoint CHAC1 as a gene causally associated with kidney disease risk. Mice with genetic deletion of CHAC1 exhibit

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[0649] 56242423.3 Attorney Docket No. 046483-7468W01(04021) mitigated kidney disease progression. The in vitro experiments herein underscore the central role of CHAC1 in modulating glutathione concentrations and subsequent ferroptosis in kidney tubule cells.

[0650] Example 3-1: Prioritization of CHAC1 as a kidney disease gene

[0651] The present study turned the focus to the chromosome 15 eGFRcrea GWAS locus. A large number of SNPs reached genome-wide significance at this locus (p<10-8), encompassing few genes along with CHAC1. Fine mapping of this locus underscored two credible sets lead by variants: rs4924525 (PIP=0.97) and rs2412608 (PIP=0.65), respectively (Figs. 30A-30B). These SNPs were located within the CHAC1 and EXD1 genes respectively. To discern the likely target gene of the GWAS variants, the present study analyzed expression and methylation QTL data from human kidney samples. In two large human kidney eQTL datasets, comprising 359 microdissected tubule samples and 303 glomerulus samples, the rs4924525 genotype (with a GWAS p = 1.9 x 10’45) was significantly linked to CHAC1 expression in both tubules (eQTL p = 2.0 x 10'8) and glomeruli (eQTL p = 3.6 x 10'8) (Figs. 21A-21D). Methylation QTL analysis revealed strong correlation between rsl 1070317 (in perfect LD with rs4924525, R2=0.86) and methylation of CpG site (cg05124934) at this locus in human kidney tissue samples (meQTL p = 4.9 x IO’50) (Figs. 21A-21D).

[0652] Subsequently, the present study employed Bayesian colocation (Coloc) studies to identify genes whose expression is influenced by the GWAS-associated SNPs. Coloc analysis yielded a posterior probability value (PP4) of 0.94, suggesting shared genetic variants for kidney function and kidney CHAC1 expression at this locus. CHAC1 expression was elevated in human kidney tissue samples from individuals with the C allele (associated with reduced eGFRcrea) at rs4924525. Summary mendelian randomization (SMR) analysis posited that CHAC1 is instrumental in mediating the genotype's effect on kidney function. The eQTL effect sizes were inversely related to eGFR GWAS effect sizes, suggesting that enhanced CHAC1 expression correlated with diminished eGFR levels.

[0653] While numerous variants demonstrated association with eGFR and CHAC1 expression, SNPs situated in regulatory domains, such as enhancers, are more probable to modulate gene expression and thus are likelier to be disease causal. The present study harnessed human kidney single-nuclear assay data for transposase-accessible chromatin (snATAC) to refine the mapping

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[0655] 56242423.3 Attorney Docket No. 046483-7468W01(04021) of the region. Variants intersecting with human kidney open chromatin domains were favored. The rs4924525 variant earned further emphasis as it was positioned at an open chromatin region in the Loop of Henle- and distal convoluted tubules (Fig. 2 IE).

[0656] To conclude, the thorough gene and variant prioritization highlighted CHAC1 as a probable kidney disease risk gene, elucidating the relationship between genetic variants on chromosome 15 and kidney function.

[0657] Example 3-2: Mice with reduced CHAC1 expression experienced less renal injury across various disease models

[0658] The present study generated mice with a genetic deletion of Chad using the Cas9- mediated genetic manipulation. Gene and protein expression analysis indicated an approximate 50% reduction in CHAC1 levels in kidneys of Chad heterozygous (CHAC1+ / -) mice compared to wild type (WT) animals (Figs. 22A and 22B). At baseline, no differences were observed in body weight (Fig. 3 IB), or kidney function parameters, including blood urea nitrogen (BUN) levels (Fig. 3 IB). Similarly, expression of kidney injury markers (KIMI and NGAL) (Fig. 31 A), and fibrosis markers were not different between WT and CHACU7- mice (Fig. 31C). At baseline, no differences were identified in markers of loop of henle and proximal tubule cells (Figs. 31D & 31E).

[0659] The present study then examined CHAC1 expression under various disease conditions. Kidney CHAC1 gene expression was elevated in adenine-induced kidney injury, folic acid nephropathy (FAN), and unilateral ureteral obstruction (UUO) models in bulk RNA sequencing (Fig. 32A). The present study also verified its expression in various kidney injury models by qRT-PCR (Fig. 32B). The present study aimed to determine whether reducing CHAC1 levels would protect mice from kidney injury and disease development. The present study selected the folic acid (FA) nephropathy model, as it represents an acute on chronic injury model linked to fibrosis development27 (Fig. 22C). CHACU7- mice treated with FA exhibited lower creatinine and BUN levels (Figs. 33A & 33B). FA-injected CHAC1+ / - mice also demonstrated less fibrosis and morphological changes when compared to WT animals by PAS, H&E and Sirius red staining (Fig. 22D). Moreover, the expression of fibrosis markers such as fibronectin (Fn), collagenl (Collal), and collagen 3 (Col3al) was reduced in FA-injected CHACU7- mice compared to

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[0661] 56242423.3 Attorney Docket No. 046483-7468W01(04021) their WT counterparts (Fig. 22E). The protein levels of fibronectin and SMA were similarly decreased in FA-injected CHAC1+ / - mice in comparison to FA-injected WT mice (Fig. 22F).

[0662] Diabetic kidney disease is the leading cause of CKD and ESRD in the US. The present study used uninephrectomized (UNx) mice injected with streptozotocin (STZ) as a diabetic nephropathy model (Fig. 23 A), since the removal of one kidney accelerates diabetic injury in mice. Diabetic mice with lower Chad expression exhibited lower albuminuria than WT diabetic mice (Fig. 23B). Blood glucose levels were higher in STZ-injected mice, but no difference was noted between CHACU7- and WT diabetic animals (Fig. 23C). The CHACU7- diabetic mice showed less injury analyzed by morphological changes using H&E, PAS and Sirius red staining (Fig. 23D). Diabetic CHAC1+ / - mice also had reduced expression of fibrosis-related genes (Collal, Col3al, and Fnl) compared to WT diabetic mice (Fig. 23E). The protein level of fibronectin and SMA was also lower in diabetic CHAC1+ / - mice compared to WT diabetic mice (Fig. 23F).

[0663] Subsequently, the present study investigated the impact of CHAC1 reduction on chronic kidney disease development (Fig. 24A). After feeding mice a 0.2% adenine diet (ad libitum) for 30 days, mice with decreased CHAC1 expression demonstrated reduced levels of creatinine, blood urea nitrogen, and cystatin C compared to the WT group (Fig. 24B). CHACU7- mice on the adenine diet also exhibited less fibrosis than the WT mice on adenine diet (Fig. 24C). The present study evaluated the expression of fibrosis markers such as Collal, Col3a, Fnl, and SMA. The expression of fibrosis associated markers was lower in adenine-treated CHAC1+ / - mice compared to WT mice (Fig. 24D). Similarly, the protein levels of fibrosis associated genes, such as SMA and FN were lower in CHACU7- mice on adenine diet compared to WT mice (Fig. 24E).

[0664] In conclusion, consistent with the human genetic studies CHAC1+ / - mice were protected from kidney injuries in the FA, diabetic nephropathy, and adenine models.

[0665] Example 3-3: CHAC1 is expressed in Loop of Henle and distal convoluted tubules

[0666] To identify cells expressing CHAC1 in human kidneys, the present study first turned to single nuclei gene expression datasets obtained human kidney samples from publicly available KPMP dataset29. The present study found Chacl to be expressed in the loop of Henle cells (Fig. 36A). Next, the present study conducted in situ hybridization. In situ hybridization analysis of

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[0668] 56242423.3 Attorney Docket No. 046483-7468W01(04021) healthy human kidney samples showed a similar expression pattern in the UMOD-positive Loop of Henle segment (Fig. 25A). In healthy mice, CHAC1 expression was found in the uromodulin- positive segment of the Loop of Henle (Fig. 25B). CHAC1 immunohistochemistry performed for healthy and diseased mouse and human kidney samples indicated increased CHAC1 expression in the Loop of Henle and a few distal convoluted tubules in both diseased mouse and human kidneys (Fig. 25A & 25B). In summary, single-cell analysis and in situ and immunohistochemistry staining indicated that CHAC1 is expressed in the loop of Henle segments both in the mouse and human kidneys.

[0669] Example 3-4: CHAC1 is regulated by various stress conditions in tubular cells

[0670] In several cancer cell lines CHAC1 has been found to be induced by endoplasmic reticulum stress (ER stress) and is downstream of the EIF2a kinase-ATF4 pathway. The present study next cultured the human renal tubule epithelial cells (RPTECs) and examined CHAC1 expression following tunicamycin treatment, a known inducer of ER stress. CHAC1 expression (both RNA and protein) showed time dependent increase following tunicamycin treatment (Figs. 25C & 25D) RPTECs. The present study next cultured primary kidney tubule cells from mice and examined CHAC1 expression under various stimuli. TGF-P is a recognized primary mediator of kidney fibrosis. TGF-P stimulation can induce ferroptosis in tubule cells. The present study found that expression of CHAC1 was higher in tubule cell treated with TGF-P (Fig. 25E). Erastin and cysteine, methionine deprivation (CMD) are known inducers of ferroptosis. Ferroptosis was also evident in tubule cells by elevated ferroptosis associated genes in erastin treated tubule cells or CMD (Figs. 25F, 25G and 34A). In summary, the present study found CHAC1 to be regulated by ER stress TGF-P and ferroptosis.

[0671] Example 3-5: Ectopic Expression of Human CHAC1 induces ferroptosis

[0672] To better understand CHACl’s function the present study expressed human CHAC1 in HEK293T cells. Overexpression of CHAC1 in HEK cells resulted in increased cell death, as detected by increased LDH release (Fig. 26A). To understand the mechanism of CHAC1- induced cell death the present study performed gene expression analysis. Overexpression of CHAC1 resulted in the increased expression of ACSL4 and FTH1 gene expression (Fig. 26B). Protein levels of ferroptosis markers like GPX4, SLC7A11 were lower and FTH1 was higher

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[0674] 56242423.3 Attorney Docket No. 046483-7468W01(04021) following CHAC1 overexpression (Fig. 26C). At the same time, the present study did not observe changes in other mediators of cell death, such as cleaved caspase3 (apoptosis) and NLRP3 / gasdermin (pyroptosis) (Fig. 26D). Moreover, cellular glutathione levels decreased in cells overexpressing CHAC1 (Fig. 26E). Lower glutathione levels could be a reason for an increased cell death in ectopically expressed CHAC1 cells. Collectively, these findings suggest that overexpression of CHAC1 acts as a ferroptosis inducer and CHAC1 expression is sufficient to induce ferroptosis. In summary, the observed cell death mostly via ferroptosis.

[0675] Example 3-6: Reduced Chad level limits ferroptosis in kidney cells

[0676] The present study found that ectopic expression of human CHAC1 is sufficient to induce ferroptosis, therefore the present study tested whether CHAC1 is necessary for ferroptosis in kidney tubule cells. Cysteine methionine deprivation has been shown to be a potent inducer of ferroptosis in glioblastoma cells. Therefore, the present study exposed primary tubule cells to CMD for 24h. The present study observed that CMD increased tubule cell death confirming that tubule cells are susceptible to cysteine and methionine restriction induced ferroptosis (Fig. 27A). To understand other cell death mechanisms, play role in CMD-induced tubule cell death, the present study treated tubule cells with various cell death inhibitors, including apoptosis (caspase 9) inhibitor; Z-VAD-FMK, necroptosis inhibitor; Nec-1, pyroptosis inhibitor; Vx765, and ferroptosis inhibitors; Ferrostain-1 (Fer-1) and Liproxstatin (Lipro). Cells treated with Fer-1, and Lipro showed markedly lower cell death under CMD conditions compared to those only exposed to CMD (Fig. 27B), indicating that ferroptosis is the major cell death pathway induced by CMD in tubule cells. Ferroptosis markers including GPX4 and ACSL4 were increased in cells cultured in CMD, which was sensitive to Feri treatment (Fig. 27C). These indicate that CMD is a potent inducer of tubule ferroptosis.

[0677] As the present study identified conditions associated with increased tubule cell ferroptosis, the present study compared WT and CHACH7- primary tubule cells in CMD. CHAC1+ / - cells showed lower LDH release, indicating lower cell death when compared to WT cells (Fig. 27D). B0DIPY-C511 staining indicating lipid peroxidation, was higher in WT cells cultured in CMD (Fig. 27E). Whereas CHAC1+ / - deficient cells exhibited lower lipid peroxidation (Fig. 27E). Furthermore, while GSH levels were lower in CMD condition, but it was almost normalized in CHAC1+ / - cells, reinforcing the notion that CHAC1 plays a

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[0679] 56242423.3 Attorney Docket No. 046483-7468W01(04021) significant role in maintaining cellular GSH levels (Fig. 27F). Expression of ferroptosis markers, especially FTH1 and PTGS2 (Fig. 27G) were lower in CHAC1 heterozygous cells.

[0680] To further confirm the role of CHAC1 in ferroptosis, the present study analyzed the effect of erastin, a widely used inducer of ferroptosis. Treatment of wild type cells with erastin resulted in increased expression of CHAC1 and ferroptosis markers including FTH1 and PTGS2 (Fig. 34A). Cell death and ferroptosis markers were lower in CHACU7- cells when compared to WT cells treated with erastin (Fig. 34B).

[0681] In addition, the present study also tested the role of CHAC1 in TGF-P induced ferroptosis. The present study next exposed WT and CHAC1+ / - tubule cells to TGF-P for 24h. While TGF-P increased cell death in WT primary tubule cells, cell death was lower in CHAC1+ / - cells (Fig. 35A). B0DIPY-C511 staining was lower in CHAC1 silencing cells when compared to WT cells with TGF-P treatment (Fig. 35B). Fer-1 inhibited TGF-P induced lipid peroxidation and restored GSH levels (Figs. 35C and 35D). Next, the present study treated cells with TGF-P and examined fibrosis markers in wild type tubule cells and cells treated with CHAC1 siRNA. TGF-P-induced fibrosis markers protein expression was reduced in cells with CHAC1 silencing compared to WT cells (Figs. 35E). Furthermore, levels of fibrosis associated markers gene expression was higher with TGF-P treatment in wild type cells, but not in CHAC1 silencing cells (Figs. 35F).

[0682] In summary, CHAC1 were elevated in tubule cells cultured in CMD, erastin or TGF-p. The enhanced CHAC1 expression lowered GSH levels and contributed ferroptosis and cell death under these conditions.

[0683] Example 3-7: Reduced Ferroptosis in CHAC1+ / - Mice In Vivo

[0684] Having observed the role of CHAC1 in ferroptosis in vitro using cultured tubule cells, the present study proceeded to analyze indicators of ferroptosis in mouse models of kidney disease. The present study found the expression of ferroptosis-associated gene, acyl-CoA synthetase long chain family member 4 (Acsl4), to be elevated in kidneys of FA-injected and STZ UNx WT mice in comparison to FA-injected and STZ UNx CHACU7- mice (Figs. 28A and 28B). Moreover, the expression of acyl-CoA synthetase long chain family member 3 (Acsl3) was also elevated in diabetic and FA-injected CHACU7- mice than in WT mice. Additionally, GPX4 protein levels were found to be lower in kidneys of STZ UNx diabetic and FA-injected mice, and

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[0686] 56242423.3 Attorney Docket No. 046483-7468W01(04021) this reduction was ameliorated in CHAC1+ / - mice. The ACSL4 protein levels followed the pattern of Acsl4 RNA in CHAC1+ / - diabetic and FAN models compared to WT mice (Figs. 28C and 28D). In summary, CHAC1+ / - mice showed less ferroptosis when compared to WT mice with the injury.

[0687] Example 3-8: Elevated CHAC1 and diminished GPX4 in kidneys of CKD patients

[0688] The in situ hybridization studies indicated that CHAC1 is expressed in the Loop of Henle- and distal convoluted tubules segments. Therefore, the present study reanalyzed publicly available human kidney single nuclear expression atlas for CHAC1 and other ferroptosis signature genes. The present study observed CHAC1 expression in the thick ascending Loop of Henle in healthy samples and its expression was higher in patients with CKD. The ferroptosis markers such as FTH1, NC0A4, HSPB1 are also found to be higher in the TAL cell cluster. SLC7A11 and ACSL3 was lower in CKD patients in the TAL cluster. This data suggests that there appears to be a surmised role playing by TAL in CKD patients by regulating ferroptosis (Figs. 36A-36F).

[0689] Subsequently, the present study examined the protein levels of CHAC1 in both healthy and kidneys affected by diabetes or hypertension attributed CKD. Through the immunostaining studies, the present study observed that CHAC1 protein was predominantly expressed by the loop of Henle and distal tubule cells. An elevated expression of CHAC1 in kidneys of patients with CKD was noted (Fig. 29A).

[0690] Turning the attention to GPX4 expression, a recognized marker of ferroptosis, the present study observed its expression in kidney tubules. GPX4 levels, as determined through immunohistochemistry (Fig. 29A) and immunoblot analysis (Fig. 29B), were diminished in CKD kidneys relative to healthy samples.

[0691] Further investigations revealed that other markers of ferroptosis, such as ACSL4 and FTH1, were more also higher in human CKD samples (Fig. 29A). Conversely, the expression of SLC7A11 was lower in human CKD samples as evidenced by immunostaining (Fig. 29A). Consistent with the immunostaining findings, immunoblotting analysis validated the increase in CHAC1 and ACSL4 expression and the decrease in GPX4 expression in kidneys from CKD patients compared to healthy controls (Fig. 29B).

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[0694] In conclusion, the analysis revealed higher CHAC1 and lower GPX4 levels in human CKD kidneys, aligning with the presumed role of CHAC1 and ferroptosis in CKD patients.

[0695] Example 3-9:

[0696] The goal of the study herein was to investigate the mechanism of how genetic variants on chromosome 15 contribute to changes in kidney function. Here the present study show that nucleotide variants at this region alter CHAC1 expression in the kidney. Chad is an enzyme responsible for degrading glutathione, was expressed in the LOH and distal convoluted tubules. Mice with lower Chad level showed improved kidney function in three different mouse kidney disease models. In vitro and in vivo studies indicated the role of CHAC1 in glutathione metabolism and ferroptosis. Chad regulates cellular glutathione levels and ferroptosis severity in tubule cells. The data indicates that CHAC1 is a kidney disease risk gene via influencing tubule cell ferroptosis.

[0697] Mice with global heterozygous knockouts for CHAC1 experience a reduced availability of CHAC1 protein but it isn't entirely eliminated. These mice did not show any baseline abnormalities. CHAC1 global homozygous knockouts result in embryonic lethality, which aligns with the observations. It's notable that increased CHAC1 expression in diseased mice could have detrimental effects. This isn't unexpected, given that diseases often exhibit elevated ROS and a buildup of peroxidized lipids. In such conditions, the deletion of CHAC 1 might be protective, as maintaining glutathione levels could be instrumental for detoxification processes. Further supporting the potentially harmful nature of CHAC1, cells with CHAC1+ / - treated with TGF-P, a known stimulator of fibrosis, exhibited comparable outcomes.

[0698] In summation, the findings suggest that CHAC1 plays a significant role as a kidney disease risk gene, which may elucidate the association between genetic variations on chromosome 15 and kidney function. Mice with decreased Chad expression were shielded from kidney disease. Moreover, CHAC1+ / - cells are more resilient to lipid peroxidation and ferroptosis, likely due to the associated increase in glutathione levels with the loss of Chad. This information sets the stage for potential exploration into how pharmacological modulation of CHAC1 could serve as a therapeutic avenue for kidney disease treatment.

[0699] Example 3-10: Materials and Methods

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[0702] Kidney samples, GWAS, kidney eQTL and meQTL and snATACseq data

[0703] Human kidney expression QTL (n=356 tubule, n=303 glomerular and 686 kidney samples) and methylation QTL (n=443 kidney samples) were used. To estimate the posterior probabilities of sharing of genetic variants between kidney function GWAS and gene expression in human kidney tubuli and glomeruli, the present study performed colocalization analysis using coloc. A 100-kilobase region around the index SNP was used to calculate posterior probability with a threshold of PP H4 > 0.8. Summary mendelian randomization (SMR) was used to test potential causal effects of a gene expression on phenotype development. Human kidney single- nuclear ATAC sequencing (snATAC-seq) data was used.

[0704] Generation of mouse models

[0705] CRISPR Cas 9 technology was used to generate a frameshift deletion in exon 1 of the CHAC1 gene. Guide RNAs of 20bp length were designed against mouse Chad gene using CRISPOR database. Two guide RNAs were generated, one targetingd the promoter region of Chad and the second targeting the intronic region after exonl. Guide RNAs were prepared for microinjection using Guide-it™ sgRNA In Vitro Transcription Kit (Takara #632635). Microinjection of Chad sgRNAs and Cas9 mRNA (lOO ng / pl; ThermoFisher, A29378), was performed with in CRISPR Cas9 Mouse Targeting Core at the University of Pennsylvania.

[0706] Mice

[0707] Eight- to ten-week-old male mice were used in this study. All mice were maintained under pathogen free conditions with ambient temperature 20-22 Celsius, humidity 50-70%, and a 12 / 12 h light / dark cycle. All animal experiments were reviewed and approved by the Institutional Animal Care and Use Committee of the University of Pennsylvania and were performed in accordance with the institutional guidelines.

[0708] Three main renal injury models were used, folic acid (FA) adenine diet and a diabetic nephropathy model. In the folic acid model, male mice, aged eight- to-ten weeks were injected intraperitoneally with FA (#10752485 ACROS Organics, 250 mg / kg, prepared in 300 mM sodium bicarbonate). The control mice received similar volume of sodium bicarbonate (#S6014, Sigma-Aldrich). All the mice were euthanized on day 7 for further analysis.

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[0711] In the diabetic nephropathy model, four-week-old male mice were subjected to uninephrectomy. At six weeks of age, these mice were injected with streptozotocin at 50 mg / kg, via intraperitoneal, (Santa Cruz Biotechnology, #U-9889) for five consecutive days. Control mice received a similar volume of PBS for five consecutive days. Diabetes was defined as a blood glucose >300mg / dl by glucometer. Urine was collected in metabolic cages. Albuminuria was analyzed using ELISA (Bethyl Bioscience). Urinary creatinine was measured with liquid creatinine assay reagent (Diazyme DZ072B).

[0712] For adenine-induced CKD model, eight-week-old male mice were fed ad libitum 0.2% adenine containing diet supplemented with casein (TD.160020; Envigo) for 4-weeks. Control mice were fed ad libitum casein-base rodent diet (0.9% phosphate and 0.6% calcium, TD.150303 Envigo) for 4-weeks. At the end of the treatment mice were euthanized and examined for the further studies.

[0713] Kidneys and blood were collected for functional biochemical and histological analysis. For histological analysis kidneys were fixed in 10% formalin in Phosphate Buffered Saline.

[0714] Renal Functional assays

[0715] Serum Blood Urea Nitrogen (BUN) was measured using iSTAT Portable Clinical Analyzer (Abbott) using CHEM8+ cartridge (Abaxis, #10023291). Additionally, BUN (Medtest #B7552-150), serum creatnine (Diazyme #DZ072B) and serum cyastatin c (Crystal Chem #80738) levels were measured using commercially available kits as per the manuals supplied.

[0716] Quantitative reverse transcription polymerase chain reaction

[0717] RNA was isolated from kidney tissue or cells using TRIzol (Invitrogen, #15596018). RNA was reverse-transcribed using the High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems, #4368813), and qRT-PCR was run in the QuantStudio 5 (Applied Biosystmes) instrument using SYBR Green Master Mix (Applied Biosystems, #4367659). The gene expression was determined by normalizing the CT values of test gene to endogenous control gene. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as a control gene and the AACt method was used to derive relative expression of the test gene.

[0718] Western blot

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[0721] Kidney tissue was homogenized in SDS lysis buffer [Cell Signaling Technology (CST), #7722] and transferred onto polyvinylidene difluoride membranes. After blocking in 5% milk in tris-buffered saline and 0.1% Tween 20, the membranes were incubated overnight with the following primary antibodies at 4°C : CHAC1 (Proteintech #15207-l-AP 1 : 1000), Fibronectin (Abeam #ab2413 1 : 1000), GPX4 (Abeam #abl25066 1 : 1000), ACSL4 (Abeam #abl55282 1 : 1000), SLC7A11 (Proteintech #26864-l-AP 1 : 1000), SMA (Sigma #A5228 1 : 1000), Caspase3 (CST #9664 1 : 1000), NLRP3 (Adipogen #20B-0014-C100 1 : 1000), Gasdermin (Abacm, #219800 1 : 1000), FTH1 (Novus #60920 1: 1000), GAPDH (CST(14C 10) #2118 1 : 1000), Antirabbit IgG (H + L) (DyLight™ 8004X PEG Conjugate) (CST #5151 1 : 10000) and anti -mouse IgG (H + L) (DyLight™ 680 Conjugate 1 : 10000) (CST #5470) was used as a secondary antibody. Signal was detected by enhanced chemiluminescence (SuperSignal West Femto Maximum Sensitivity Substrate, #34094; Thermo Fisher Scientific). Western blots were quantified in Fiji software.

[0722] Cell culture

[0723] Primary tubule cells were cultured from mice aged 3-4 weeks. Kidneys were minced in RPMI and incubated for 30 min with collagenase I (lOOug / ml) at 37°C (Worthington Biochemical Product, #CLS-1). Digested kidney was filtered through 100-, 70-, and 40-pm mesh to generate single cell suspension. Cell suspensions were cultured in RPMI 1640 (Corning, #10- 040-CM) supplement with 10% fetal bovine serum (Atlanta Biologicals, #S11950), EGF (20 ng / ml; PeproTech #AF-100-15), insulin-transferrin-selenium (ITS) (Gibco, #51500-056), and 1% penicillin-streptomycin (Corning, #30-002-CI) at 5% CO2 and 37°C. Approximately 1 x 106cells were seeded per well in six-well plates and allowed to adhere overnight.

[0724] Culturing human renal proximal tubule epithelial cells

[0725] Immortalized human proximal tubule epithelial cells (pLXSN-hTERT) were obtained from ATCC (#CRL-4031, ATCC). The cells were cultured in base medium DMEM F12 (#30- 2006, ATCC) supplemented with hTERT RPTEC Growth kit (#ACS-4007, ATCC), and 0.2% FBS at 37°C with 95% Air and 5% CO2 in incubator. The cells were subjected to subculturing once they reached -90% confluence. The subculture process involved treating them with 2ml of Trypsin-EDTA (#PCS-999-003, ATCC) for 5-8min at 37°C and neutralized with trypsin-

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[0727] 56242423.3 Attorney Docket No. 046483-7468W01(04021) neutralizing solution (Soyabean trypsin inhibitor). Human RPTECs were used for tunicamycin treatment only.

[0728] In vitro cell death measurements

[0729] Primary cells were cultured overnight in 96-well plates. The next day, cells were treated with CMD and TGF-pi (20ng / mL) for 24 hrs. At the same time cells were assayed for cell death in the presence of various cell death inhibitors including Z-VAD(OMe)-FMK (20pM) (#11658, Cayman), Vx-765 (lOpM) (#28825, Cayman), and Nec-1 (20pM) (#ab221984, abeam). Ferrostain (#S7243, selleckchem) and Liproxastatin (#17730-10, Cayman) in the presence of CMD. Cell death an LDH-release based assay comparing with to maximal cell lysis (#G1780, Promega). For some of the experiments, cells were treated with 5 pM erastin (Cayman #17754).

[0730] Live cell BODYPI C 11 staining

[0731] Primary tubule cells were cultured on cover glass overnight. To assess the lipid peroxidation, cells were treated with CMD and TGF-P for 24hrs and then incubated with 1.5 pM BODIPY™ 581 / 591 Cl 1 (#D3861, Thermo Fisher) for 30 min at 37 °C in 5% CO2 incubator. Cells were washed in PBS and then incubated with Hoechst 33342 (#62249, Thermo Fisher) at a final concentration of 1 pg / mL in PBS for 20min. Finally, cells were washed in PBS two times and then imaged with an Olympus DP73 microscope.

[0732] For BODIPY™ 581 / 591 Cl 1 quantification, cells were cultured in 96-well plates and the treated with CMD and TGF-P for 24hrs. Following BODIPY™ 581 / 591 Cl 1 staining, the plates were measured for fluorescence at 581 / 591 and 488 / 510 in spectrophotometer (BioTek). The data was normalized to the mean fluorescence of the Hoechst 33342 dye from each well.

[0733] Ectopic CHAC1 expression

[0734] The human CHAC1 ORF was cloned in the pcDNA3.1eGFP vector. The overexpressed CHAC1 was transfected into HEK293T cells using lipofectamine 3000 according to the manufacture instructions. The efficiency of transfection was checked by the GFP. After 2 days of transfection the overexpressed cells were examined for protein levels of CHAC1 for further confirmation.

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[0737] CHAC1 knockdown

[0738] CHAC1 specific siRNA designed for exclusively target mice CHAC1 gene without any anticipated off-target effects, was purchased from Dharmacon (L-063606-01-0005). The CHAC1 siRNA transfection was performed using RNAiMAX according to the guidelines provided by the manufacture. After 2 days of transfection cells were further examined. The control cells were transfected with the scrambled siRNA (D-001810-10-05). RNA extracted and gene expression analysis performed as above described.

[0739] Cystine methionine deprivation

[0740] Cysteine and methionine deprived medium was prepared from the base medium lacking the cysteine, methionine and glutamine (#R7513 Sigma) to which L-glutamine ( 59202C, Sigma) (final concentration 4mM), 10% FBS, and 10% Penicillin-Streptomycin was added mine. The base RPMI (#MT10-040-CM) media is the control media for this condition.

[0741] In situ hybridization

[0742] The RNAscope 2.5 HD Duplex Detection kit (#322435, ACD Bio) was employed and followed the manufacturer’s protocol. For the RNAscope insitu assay, the present study utilized the Mm CHAC1, Mm UMOD, Hs CHAC1 probes.

[0743] Immunostaining

[0744] Formalin fixed; paraffin embedded 5-pm-thick sections were cut in microtome. Sections were deparaffinized, followed by antigen retrieval in citrate buffer at 95°C for 10 min. Sections were allowed to cool slowly, washed in distilled water, and incubated in 3% H2O2 for 10 min. Sections were incubated in 5% goat serum (blocking buffer) at room temperature for 1 hour. Avidin / biotin blocking was performed using the avidin / biotin blocking kit (Vector Laboratories, #004303). Sections then were incubated overnight at 4°C with CHAC1 primary antibody (1 : 100; abeam, #279365). After washing, sections were incubated with goat anti-rabbit secondary antibody for 1 hour at room temperature. ABC ready-to-use reagent (Vector Laboratories, #PK- 6101) and ImmPACT DAB Peroxidase (HRP) Substrate (Vector Laboratories, #SK-4105) were used for visualization.

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[0747] Glutathione measurements

[0748] Glutathione was measured using a Glutathione calorimetric detection kit (EIAGSHC) following manufacturer’s protocol.

[0749] Statistics

[0750] Data are expressed as mean ± Standard Error of the Mean (SEM). Statistical significance was assessed by a 2-tailed Student’s t test for 2-group comparison or 1-way ANOVA for multigroup comparisons followed by Tukey’s post hoc test for subgroup comparisons. P<0.05 was considered significant.

[0751] Example 4: CHAC1 siRNAs

[0752] In one embodiment, the invention provides small interfering RNAs (siRNAs) targeting CHAC1 (ChaC Glutathione-Specific y-Glutamylcyclotransferase 1), a KDGS-prioritized effector gene implicated in ferroptotic tubular injury.

[0753] These siRNAs were screened in human proximal tubule cell lines (HKC8 and RPTECs) and in primary mouse proximal tubule cells. Cells were plated at 40,000-120,000 cells / well and transfected with 1.5 pM siRNA in Opti-MEM containing 3% FBS. Both 36-hour and 66-hour

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[0755] 56242423.3 Attorney Docket No. 046483-7468W01(04021) time points were assessed. Negative controls (non-targeting siRNA, NTC) and medium-only controls were included; a positive control siRNA (HTT) was used to confirm assay performance.

[0756] Referring to Fig. 37, knockdown of CHAC1 was confirmed by quantitative PCR, with GAPDH and HPRT used as normalization controls. Across multiple runs, CHAC1 siRNAs reduced CHAC1 mRNA abundance compared to controls, with 316, 355, and 356 showing the strongest knockdown effects. Functional assays in mouse cells demonstrated that CHAC1 knockdown reduced lipid peroxidation (BODIPY 581 / 591 -C 11 signal), normalized ferroptosis markers (GPX4 up-regulation, ACSL4 down-regulation), and decreased LDH release under ferroptotic stressors such as cysteine / methionine deprivation and erastin treatment.

[0757] Accordingly, these siRNAs serve as enabling species for RNA interference-based modulation of CHAC1. The invention encompasses the disclosed sequences as well as conservative variants and chemically modified derivatives (e.g., 2'-O-methyl, 2'-fluoro, locked nucleic acid (LNA), and phosphorothioate linkages), formulated in delivery vehicles such as lipid nanoparticles (LNPs), GalNAc conjugates, or megalin-targeted conjugates for kidneyspecific uptake

[0758] Example 5 (Prophetic): In vivo CHAC1 siRNA delivery in murine kidney injury

[0759] Objective

[0760] Evaluate knockdown of CHAC1 in proximal tubules and protection from ferroptotic injury using LNP- or megalin-targeted siRNA.

[0761] Agents and formulation siRNA targeting CHAC1 (e.g., siRNA 316 or 355 of Example 4) with 2 ' -O-Me / 2 ' -F and PS linkages. Two delivery formats:

[0762] (i) LNP (ionizable lipid:cholesterol:helper:PEG-lipid) in citrate buffer, and

[0763] (ii) megalin (LRP2)-targeted conjugate (megalin-binding peptide or antibody fragmentsiRNA conjugate; alternatively GalNAc-lipid dual conjugate).

[0764] Animals and dosing

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[0767] Male C57BL / 6J mice (10-12 wks). Randomize to: vehicle, scrambled siRNA, CHAC1 siRNA (LNP), CHAC1 siRNA (megalin-conjugate). Dose 0.3-3 mg / kg IV (tail vein) or 3-10 mg / kg SC (LNP), q7d x 2. Collect PK plasma / urine at defined timepoints.

[0768] Injury models

[0769] (a) Folic acid nephropathy (250 mg / kg IP folic acid),

[0770] (b) Adenine CKD (0.2% adenine diet x 4 wks),

[0771] (c) Unx-STZ (uninephrectomy + streptozotocin 50 mg / kg x 5 days).

[0772] Endpoints

[0773] (i) Target engagement: CHAC1 mRNA / protein in microdissected PTs (qPCR / WB / IHC),

[0774] (ii) Ferroptosis markers: GPX4 / ACSL4 WB; 4-HNE IHC; BODIPY 581 / 591-C11 lipid ROS,

[0775] (iii) Renal function: BUN, creatinine; UACR (Unx-STZ),

[0776] (iv) Histology: H&E, PAS, Sirius red; a-SMA / fibronectin IHC,

[0777] (v) Biodistribution / safety: tissue levels; ALT / AST; cytokines.

[0778] Analysis

[0779] ANOVA / mixed models with Tukey correction.

[0780] Expected outcome

[0781] CHAC1 siRNA reduces CHAC1 expression in PTs, normalizes ferroptosis markers, and improves renal function and histology vs. controls.

[0782] Example 6 (Prophetic): DPEP1 siRNA in ischemia-reperfusion (I / R) AKI

[0783] Rationale

[0784] KDGS prioritizes DPEP1; ferroptotic and inflammatory phenotypes suggest benefit from DPEP1 knockdown.

[0785] Agent

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[0788] DPEP1 siRNA (choose 2-3 sequences from SEQ ID NO: 2001-2010) with 2 ' -O-Me / 2 -F / PS; LNP or lipid-tail conjugate (cholesterol or DHA) to enhance renal uptake.

[0789] Model

[0790] Bilateral renal pedicle clamping 30 min followed by reperfusion; treat with siRNA 24 h prior (prophylaxis) and / or 2 h post-I / R (treatment). Dose 1-3 mg / kg IV x 1-2.

[0791] Endpoints

[0792] BUN / creatinine; KIM-l / NGAL; ferroptosis markers (ACSL4 / GPX4, 4-HNE); DPEP1 mRNA / protein in PTs; histology (tubular necrosis scores).

[0793] Expected outcome

[0794] DPEP1 knockdown reduces tubular injury and ferroptosis signatures vs. scrambled siRNA.

[0795] Example 7 (Prophetic): Correction of an ACSS2 risk SNP by base or prime editing

[0796] Rationale

[0797] KDGS maps a chromosome 20 locus to ACSS2. Edit the fine-mapped risk SNP to the protective allele and assess lipogenesis / pyroptosis readouts.

[0798] Editor and delivery

[0799] ABE / CBE or Prime Editor RNPs (SpCas9-HFl nickase + pegRNA) with kidney -tropic AAV or LNP-RNP delivery. gRNAs designed to the KDGS fine-mapped SNP in ACSS2 regulatory region / coding exon.

[0800] Model and dosing

[0801] Mouse tubule primary cells (in vitro) and / or in vivo AAV dosing 10Al 2- 10Al 3 vg by tail vein; assess after 2-4 weeks.

[0802] Endpoints

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[0805] On-target editing rate (NGS); ACSS2 mRNA / protein; lipogenesis readouts (FASN, SREBP1, lipid droplets); NLRP3 inflammasome activation markers; kidney function / histology if in vivo.

[0806] Expected outcome

[0807] Editing converts risk to protective genotype, reduces ACSS2 over-activity, attenuates lipogenesis and pyroptosis markers.

[0808] Example 8 (Prophetic): Epigenome editing at a KDGS inflammatory locus (TNF)

[0809] Rationale

[0810] KDGS identifies a TNF promoter DMR; targeted demethylation increases TNF expression and worsens DKD phenotypes. Demonstrate editability and phenotypic impact.

[0811] Constructs dCas9-TETl (demethylation) and dCas9-DNMT3A (methylation). sgRNAs tiled across the promoter DMR.

[0812] Systems

[0813] Human RPTEC / HKC8 cells and optional kidney organoids. Transduce MOI 1-5, assay at 7-14 days.

[0814] Readouts

[0815] Targeted bisulfite sequencing (% 5mC); TNF mRNA / protein; pro-inflammatory signaling; cell stress assays.

[0816] Expected outcome dCas9-TETl lowers methylation and raises TNF; dCas9-DNMT3A does the converse — establishing causal epigenetic control. By analogy, CHACl-linked CpGs identified by KDGS (e.g., cg05124934) are contemplated for similar modulation.

[0817] Enumerated Embodiments:

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[0820] In some aspects, the present invention is directed to the following non-limiting embodiments:

[0821] Embodiment 1: A method of treating, ameliorating and / or preventing a kidney disease in a subject in need thereof, the method comprising: administering to the subject an effective amount of a compound down-regulating CHAC1 in the subject.

[0822] Embodiment 2: The method of Embodiment 1, wherein at least one of the following applies:

[0823] (a) the kidney disease causes a reduction in a filtration capacity of the kidney in the subject as compared to a healthy control subject, or

[0824] (b) the kidney disease is chronic kidney disease, diabetic kidney disease, or acute kidney injury.

[0825] Embodiment 3: The method of any one of Embodiments 1-2, wherein the compound comprises a nucleic acid that downregulates CHAC1 by RNA interference, and / or an expression vector expressing the nucleic acid that downregulates CHAC1 by RNA interference.

[0826] Embodiment 4: The method of any one of Embodiments 1-3, wherein the compound comprises an siRNA molecule comprising the sequences set forth in SEQ ID NOs:8-14.

[0827] Embodiment 5: The method of Embodiment 4, wherein the nucleic acid is enriched in the kidney of the subject.

[0828] Embodiment 6: The method of any one of Embodiment 4-5, wherein at least one of the following applies:

[0829] (a) the siRNA is conjugated to a megalin (LRP2)-binding ligand that promotes receptor- mediated endocytosis into proximal tubular cells,

[0830] (b) the siRNA is lipid-conjugated (cholesterol or polyunsaturated fatty acid) to enhance renal uptake and plasma protein binding, and

[0831] (c) the siRNA comprises dual conjugation (GalNAc + lipid tail) to increase renal tubule accumulation.

[0832] Embodiment 7: The method of any one of Embodiments 1-6, wherein the subject is a human.

[0833] Embodiment 8: A method of treating, ameliorating and / or preventing a kidney disease in a subject in need thereof, the method comprising:

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[0836] (a) performing a genomic editing in a cell of the subject to replace a risk allele of a single nucleotide polymorphism (SNP) associated with the kidney disease with a reference allele associated with an absence of the kidney disease;

[0837] (b) down-regulating a gene associated with the kidney disease, wherein the up-regulation of the gene in the subject as compared to a healthy subject causes or is associated with the kidney disease; and / or

[0838] (c) up-regulating a gene associated with the kidney disease, wherein the down-regulation of the gene in the subject as compared to a healthy subject causes or is associated with the kidney disease, optionally, the kidney disease is chronic kidney disease, diabetic kidney disease, or acute kidney injury.

[0839] Embodiment 9: The method of Embodiment 8, which comprises performing the genomic editing, wherein the SNP associated with the kidney disease is at least one selected from the group consisting of rs4924525, and those exemplified in Table 2.

[0840] Embodiment 10: The method of any one of Embodiments 8-9, wherein the genomic editing is performed in a kidney cell of the subject.

[0841] Embodiment 11 : The method of any one of Embodiments 8-10, wherein the genomic editing is performed with a base editing method or a prime editing method, or a CRISPR-Cas9 based method.

[0842] Embodiment 12: The method of Embodiment 8, which comprises down-regulating or up- regulating the gene associated with the kidney disease, and wherein the gene associated with the kidney disease comprises at least one selected from the group consisting of CHAC1, SLC34A1, SLC22A7, SLC6A19, ABCC2, SLC26A6, MIOX, CUBN, PCK1, BHMT, GOLGB1, SLC6A13, STRA6, ACSM2B, AGMAT, SLC7A9, GSTA2, DPEP1, HNF1A, SLC25A10, ACSM2A, SLC34A3, PBLD, GSTA1, SERPINF2, SLC47A1, LRP2, SLC22A5, SYN2, ITIH4, CYP24A1, NPLOC4, ACOT6, SLC2A9, POR, SH3YL1, CAPN12, TPCN2, ACSS2, TM6SF2, KMT2B, ATXN1L, TTBK1, GLIS1, GATM, SLC25A47, KLHDC7A, ALDH1L1, NAT8, CUX1, ACSM5, ULK3, KNL1, SLC2A4RG, SNX30, XPC, GCC1, PEMT, SMLR1, THUMPD1, AP5B1, STK36, F12, C9, PGC, GCDH, WIPI1, FAM177A1, ZGPAT, SLC22A18, CERS2, SALL1, SLC3A1, WDR25, SPEN, SLC22A2, DMGDH, GIPC2, CCDC158, SLC22A4, NFE2L1, MARVELD3, GSS, ESCO1, ATP5IF1, IGF2R, THBS3, MAST2, BBS1, ANXA9,

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[0845] RTEL1, RNF123, ATP5P0, APEH, CFAP74, ZC3HC1, SNUPN, CA3, NUSAP1, IPP, CHD9, SLC28A2, STYXL1, RBM12, H0XA13, DNAJC16, WDR73, DCDC1, KY, SLC39A8, PKHD1, CDK7, RASSF6, 0RC4, CELSR2, SPATA7, ABCG2, N0S3, RASIP1, LKAAEAR1, IZUM01, IHO1, MAP3K11, SPTBN1, LUZP1, WDR87, ACP2, EBPL, SPG7, EEF1AKMT2, TRIP10, TSPAN9, ZNF142, SHROOM1, BMP4, DUSP11, EXOC6, CST6, IFITM2, TNFRSF6B, CD34, EFNA3, TPRKB, PIK3R3, ATRAID, GATA5, ADAM15, MTX1, TMBIM1, HLX, PITX3, C15orfi9, CHGA, RP1L1, SEMA7A, FAAP24, SWAP70, C2orfl6, STAT5A, SNX32, APOL3, ERI2, PHETA2, BIN3, CCDC51, NDUFAF1, USP35, MDH2, PTPN12, TBC1D8, PNPT1, IBA57, ARL16, TMEM60, FAAP100, GPN1, TRIM49B, DNAJC17, PKD1L3, LAMC1, IDI2, ART4, DNMBP, NXPH4, ZNF468, ADAMTS7, PRKAR1B, MXD3, GUSB, GNAS, FKBP4, NFATC1, JMJD1C, FRMD8, STARD3, EDEM3, ADAMTSL4, SLC5A6, FDPS, PDLIM4, RPL3L, STRN3, ALPK3, LAMB2, APH1B, BSN, SLC39A13, NR1H3, ABO, DPM2, PMF1, ZNF260, UMOD, PDILT, CLDN14, RNF212, NEB, CFAP70, MARVELD2, MST1, SLC9A3, CGNL1, CLCNKA, PPARGC1A, SLC22A1, ILDR1, RMDN1, SLC25A17, VPS9D1, CCDC125, CBR1, AGBL2, MYH7B, ZNF585B, ZNF573, GAL3ST1, IFT172, ZNF585A, EXOC3, ZNF568, USP24, FBXW12, HOXD8, KNG1, MITF, KIAA1614, TBX4, ZNF607, TPPP, ZNF778, CYP2D6, PTPN3, NISCH, ERI1, CPNE7, TH, NR0B2, ELF3, CASP9, TJP3, FUT2, GRB7, CELA2B, CCDC17, IP6K2, TSPAN10, NOXO1, GGT7, PAPP A, SLC25A29, BNIPL, BANP, ZNF571, FGF21, SLC45A4, TBX2, ATXN7, ATP12A, GSTA5, NASP, CWH43, DUSP6, RAPH1, DOCK7, GCKR, TMEM51, PRRG2, ERBB2, CR1L, SRARP, TMEM116, SHROOM3, NCOA6, FAM83F, DCAF4, WDR1, PTPRJ, FRK, APOE, RERE, MC1R, DDX1, ZNF875, NDUFS4, SPATA2L, B4GALNT2, WDR72, PSEN2, TFCP2L1, MINDY1, CYP26C1, PCMTD2, ATP6V1B1, MY019, TOMM40, GIGYF2, CYP1A2, PTPN21, CHCHD10, KCNJ13, ABCD3, HEATR4, DYDC2, NDUFA6, ZDHHC5, CA2, DPP3, OGDHL, UBE2H, SCRIB, ZNF687, RALGPS1, QARS1, PLA2R1, NPHS1, ACOT4, ARHGEF26, CACNA1S, DAG1, TRIM51GP, CAND2, ACTN4, CELSR3, COL7A1, EPB41L5, FGFRL1, SORT1, RERG, CAND1, CBLB, METTL21A, ZNF461, ZNF436, FGFR4, MAMSTR, FAM47E, HOXA9, CASZ1, SCYL1, PGAP3, CCAR2, C2orf73, IMP3, SLC4A11, CDH15, C10orf53, ZNF713, DCDC2, C19orf73, TPM1, JPH2, EVC, SHARPIN, CFAP36, MAPK15, MISP3, EXD1, LOXL4, CEP89, PLEKHH2, ZNF148, SEMA4A, ZNF608, IQCN, MEP1A, ARMC9, PLXNB1, NMB, RAH, OBSCN, WBP2NL, LMNA, LAMA5, FAM149B1,

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[0848] SENP2, ALMS1, USP19, TMEM239, DGKH, TUBB3, PLEKHA1 , MUC1, CPS1, PKD2, MFHAS1, VCL, ANXA11, IQANK1, Cl lorf49, METTL15, SPEG, AN01, GNRH2, ISLR, TNFAIP6, FILIP1L, NEXN, GPR88, PKD1, FOXO3, MGP, COL18A1, PDLIM5, IL1RL1, CLDN23, NBEAL1, AMT, BEGAIN, MPRIP, ITIH3, DDI2, SVIL, CYP20A1, PCGF6, GABPB2, ADCY6, RUFY2, SPI1, STAB1, NAGA, SH2B3, MANBA, USP4, RIN3, GAB2, NINJ1, AHR, CTSS, TEN, LRP1, OPRL1, WDR81, SDCCAG8, MYBPC3, LACTB, CENPE, TET2, DAB2, PHF20, SIRT1, EHBP1L1, RBM47, WBP1L, PLEKHM2, ZNF641, RREB1, MADD, MSL1, SIPA1, PPM1J, SREBF1, FNIP1, TDRD12, NUDT19, TRAFD1, MYPN, SHISA8, TNFRSF13C, ZPBP2, CENPM, CTCFL, ARHGEF18, DENND5B, PRAG1, IKZF3, HSPA4, MMP11, SH2B2, SND1, TFEB, SLC22A31, RBM6, NT5C3A, CHRNB4, PDCD11, RSBN1L, UVRAG, MUTYH, EDEM2, RAD17, ATF1, INHBC, ACSF3, NARS2, SLC15A2, EML5, CCDC77, HINFP, RAPSN, QRICH1, NUP160, GABI, SREBF2, ABRAXAS2, UQCC1, SPATA5L1, FANCA, NSD1, STAG1, MPI, SCAPER, RBL2, IL12RB1, LIME1, RASA2, ZFP36L2, SIGIRR, ZNF276, PSD4, PDE7A, PCNX3, GATAD2A, RPL13, PHTF2, RPS2, SLC25A45, HERC4, PRR12, ANO9, R3HCC1L, IRF3, GSDMB, R3HDM2, ITPKB, PRRC2C, CPNE1, RPRD2, ANKRD27, SEC24C, ANKRD11, THAD A, FAM102A, CCDC137, MTMR9, TCF20, WHAMM, ZBTB42, MMP24OS, GGNBP2, ARFRP1, HGS, ACPI, LASPI, PRMT7, XPO7, TBL3, PIGU, TNKS, SART1, RPAP1, UBE2D3, FOXA1, RSC1A1, LRWD1, SHF, C3orf84, USP38, FBXO42, ABCC10, ZNF598, ZNF816, C3orf62, GIPR, ACVR2A, TRIM65, XPO5, RTEL1-TNFRSF6B, AL691442.2, OR4B1, OR4C3, WDR78, TREX1, C20orfl94, PMF1-BGLAP, OR4X1, OR4S1, AC092143.1, AC093227.2, HOXD12, NPBWR2, FAM47E-STBD1 and PAX4, optionally, the gene associated with the kidney disease comprises at least one selected from the group consisting of DPEP1, CHMP1A, ACSS2, WHAMM, TET2, DACH1, TNF, and CHACl, optionally, the gene associated with the kidney disease comprises CHAC1.

[0849] Embodiment 13: The method of Embodiment 8 or Embodiment 12, which comprises administering to the subject a compound that down-regulates the gene associated with the kidney disease, and wherein the compound comprises: a small molecule inhibitor of the gene, a protein inhibitor of the gene,

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[0851] 56242423.3 Attorney Docket No. 046483-7468W01(04021) a nucleic acid that downregulates the gene by RNA interference, and / or an expression vector expressing the nucleic acid that downregulates gene by RNA interference, a compound for forming epigenome editing, optionally a catalytically inactive Cas protein fused to TET1, DNMT3A, a DNA methylase, histone acetyltransferases, or histone deacetylases, or a nucleotide expressing the same, a ribozyme that downregulates the gene, and / or an expression vector expressing the ribozyme, an expression vector comprising an expression cassette, wherein the expression cassette expresses CRISPR components that downregulate gene by CRISPR knockout or CRISPR knockdown, and a trans-dominant negative mutant protein of the gene, and / or an expression vector that expresses the trans-dominant negative mutant protein of the gene, optionally, the compound comprises a compound for epigenome editing at cg05124934, or a RNA interference molecule down-regulating CHAC 1.

[0852] Embodiment 14: The method of Embodiment 13, wherein the method comprises administering to the subject the nucleic acid that downregulates the gene by RNA interference, and wherein the nucleic acid is enriched in the kidney of the subject.

[0853] Embodiment 15: The method of Embodiment 8 or Embodiment 12, wherein the method comprises administering to the subject a compound that up-regulates the gene associated with the kidney disease, wherein the compound comprises the gene, the protein or mRNA product of the gene, a functional equivalence thereof, an expression vector expressing the same, or a compound for forming epigenome editing, optionally wherein the compound for forming epigenome editing comprises a catalytically inactive Cas protein fused to TET1, DNMT3A, a DNA methylase, histone acetyltransferases, or histone deacetylases, or a nucleotide expressing the same.

[0854] Embodiment 16: The method of any one of Embodiments 13-15, wherein the compound that down-regulates or up-regulates the gene associated with the kidney disease is delivered using a lipid nanoparticle, a GalNAc conjugate, a polymeric nanoparticle, an adeno-associated virus (AAV), or an exosome.

[0855] Embodiment 17: The method of any one of Embodiments 13-16, wherein the compound that down-regulates the gene associated with the kidney disease is an siRNA molecule, and wherein at least one of the following applies:

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[0858] (a) the siRNA is conjugated to a megalin (LRP2)-binding ligand that promotes receptor- mediated endocytosis into proximal tubular cells,

[0859] (b) the siRNA is lipid-conjugated (cholesterol or polyunsaturated fatty acid) to enhance renal uptake and plasma protein binding, and

[0860] (c) the siRNA comprises dual conjugation (GalNAc + lipid tail) to increase renal tubule accumulation.

[0861] Embodiment 18: The method of any one of Embodiments 8-17, wherein the kidney disease causes a reduction in a filtration capacity of the kidney in the subject as compared to a healthy control subject.

[0862] Embodiment 19: The method of any one of Embodiments 8-18, further comprises administering to the subject an effective amount of a compound selected from a SGLT2 inhibitor, an ACE inhibitor, an angiotensin receptor blocker, a mineralocorticoid receptor antagonist, an endothelin receptor antagonist, or a GLP1 receptor agonist.

[0863] Embodiment 20: The method of any one of Embodiments 8-19, wherein the subject is a human.

[0864] Embodiment 21 : A method of predicting a risk of kidney disease in a subject, stratifying the a subject based on a risk of kidney disease, and / or selecting a therapy for a subject with kidney disease, the method comprising

[0865] (a) detecting the presence or absence of a risk allele in a single nucleotide polymorphism (SNP) associated with kidney disease in a sample of the subject, wherein a presence of the risk allele in the SNP indicates a heightened risk of kidney disease, or

[0866] (b) detecting a CpG meQTL sites linked (LD r2 0.2) to a SNP associated with kidney disease, optionally wherein the detection is performed using PCR, sequencing, digital droplet PCR, or methylation-specific arrays.

[0867] Embodiment 22: The method of Embodiment 21, further comprising collecting the sample from the subject.

[0868] Embodiment 23: The method of any one of Embodiments 21-22, wherein the SNP is at least one selected from the group consisting of rs4924525, and those listed in Table 2.

[0869] Embodiment 24: The method of any one of Embodiments 21-23, which comprises detecting a risk allele at rs4924525 at the CHAC1 locus, and / or CpG cg05124934.

[0870] 114

[0871] 56242423.3 Attorney Docket No. 046483-7468W01(04021)

[0872] Embodiment 25: The method of any one of Embodiments 21-24, wherein the kidney disease causes a reduction in a fdtration capacity of the kidney in the subject as compared to a healthy control subject.

[0873] Embodiment 26: The method of any one of Embodiments 21-25, wherein the subject is a human.

[0874] Embodiment 27: A method of identifying a causal kidney disease gene, the method comprising: performing a genome-wide association study (GWAS) of kidney function in a population; performing a fine-mapping credible sets of variants from the GWAS; integrating the fine-mapped variants with kidney-specific molecular data selected from the group consisting of expression quantitative trait loci (eQTL), allele-specific expression (ASE), bulk allele-specific chromatin accessibility (bASA), single-nucleus allele-specific chromatin accessibility (snASA), methylation quantitative trait loci (meQTL), and single-cell multiome peak-to-gene mapping (Open4Gene); and prioritizing one or more causal variants, genes, or regulatory elements associated with kidney disease.

[0875] The foregoing outlines features of several embodiments so that those skilled in the art may better understand the aspects of the present disclosure. Those skilled in the art should appreciate that they may readily use the present disclosure as a basis for designing or modifying other processes and structures for carrying out the same purposes and / or achieving the same advantages of the embodiments introduced herein. Those skilled in the art should also realize that such equivalent constructions do not depart from the spirit and scope of the present disclosure, and that they may make various changes, substitutions, and alterations herein without departing from the spirit and scope of the present disclosure.

[0876] 115

[0877] 56242423.3

[0878]

[0879]

[0880]

[0881]

[0882]

[0883]

[0884]

Claims

1. Attorney Docket No. 046483-7468W01(04021)CLAIMSWhat is claimed is:

1. A method of treating, ameliorating and / or preventing a kidney disease in a subject in need thereof, the method comprising: administering to the subject an effective amount of a compound down-regulating CHAC1 in the subject.

2. The method of claim 1, wherein at least one of the following applies:(a) the kidney disease causes a reduction in a filtration capacity of the kidney in the subject as compared to a healthy control subject, or(b) the kidney disease is chronic kidney disease, diabetic kidney disease, or acute kidney injury.

3. The method of any one of claims 1-2, wherein the compound comprises a nucleic acid that downregulates CHAC1 by RNA interference, and / or an expression vector expressing the nucleic acid that downregulates CHAC1 by RNA interference.

4. The method of any one of claims 1-3, wherein the compound comprises an siRNA molecule comprising the sequences set forth in SEQ ID NOs:8-14.

5. The method of claim 4, wherein the nucleic acid is enriched in the kidney of the subject.

6. The method of any one of claims 4-5, wherein at least one of the following applies:(a) the siRNA is conjugated to a megalin (LRP2)-binding ligand that promotes receptor- mediated endocytosis into proximal tubular cells,(b) the siRNA is lipid-conjugated (cholesterol or polyunsaturated fatty acid) to enhance renal uptake and plasma protein binding, and(c) the siRNA comprises dual conjugation (GalNAc + lipid tail) to increase renal tubule accumulation.

7. The method of any one of claims 1-6, wherein the subject is a human.11656242423.3Attorney Docket No. 046483-7468W01(04021)8. A method of treating, ameliorating and / or preventing a kidney disease in a subject in need thereof, the method comprising:(a) performing a genomic editing in a cell of the subject to replace a risk allele of a single nucleotide polymorphism (SNP) associated with the kidney disease with a reference allele associated with an absence of the kidney disease;(b) down-regulating a gene associated with the kidney disease, wherein the up-regulation of the gene in the subject as compared to a healthy subject causes or is associated with the kidney disease; and / or(c) up-regulating a gene associated with the kidney disease, wherein the down-regulation of the gene in the subject as compared to a healthy subject causes or is associated with the kidney disease, optionally, the kidney disease is chronic kidney disease, diabetic kidney disease, or acute kidney injury.

9. The method of claim 8, which comprises performing the genomic editing, wherein the SNP associated with the kidney disease is at least one selected from the group consisting of rs4924525, rsl2767621, rs4148384, rs56050010, rs55804858, rsl 12344408, rsl7216177, rs34456559, rs72838129, rs7920448, rsl 137968, rs72838134, rs72838141, rsl 11866537, rsl 13513789, rs72838143, rs72838146, rs72838149, rs72838150, rs56333232, rs8187707, rsl7216212, rs8187710, rsl 13741841, rsl 11281941, rsl l816708, rs56080571, rs55725645, rsl46860861, rs7899966, rsl0883432, rs6584337, rsl 1190351, rsl0786579, rs7900025, rsl0128320, rsl986519, rs7917150, rs7915731, rs7902856, rs7088596, rsl2267374, rs4919412, rs72845694, rsl 1597439, rs7072014, rs284859, rs61869825, rs72846198, rs7076463, rs7831, rs!45384631, rs!90722793, rsl 1198455, rsl 1198458, rs2278202, rs3850765, rs7902176, rs8181474, rs4751890, rsl0901812, rs3824765, rs4962697, rs55668701, rsl39067922, rsl39217986, rs78593499, rs7078652, rsl2761149, rs2936540, rs3012069, rsl008982, rs7905095, rsl 133400, rs6602818, rs7094565, rs74962910, rsl 1254232, rsl 17035284, rs2669153, rsl41640975, rsl707275, rsl707277, rsl707278, rsl707280, rsl337311, rsl337310, rsl 1013566, rsl0828481, rs7081567, rsl2773508, rs7078949, rs7090769, rsl0828490, rs7093761, rs71493333, rs71493334, rs35241775, rsl 1592534, rsl0828509, rs7915768,11756242423.3Attorney Docket No. 046483-7468W01(04021) rs2886851, rsl 1006779, rs3824590, rs3802517, rs34717952, rs933065, rs2368268, rs4494226, rs4600119, rsl 1596317, rsl 1596400, rs7907415, rsl2778429, rs7907935, rsl2778301, rsl2767652, rs4489649, rs2790450, rs2807731, rs813694, rs28585535, rs2768665, rs6481598, rs34163498, rsl0827415, rs7923244, rsl 1009923, rsl2413778, rsl0827420, rs61840961, rsl6935716, rsl6935717, rs61840962, rs9418121, rsl0827439, rsl2249828, rsl 1253465, rs80282103, rsl 1253467, rsl 1812523, rs2050944, rsl 1253485, rsl0904577, rsl 1253488, rsl 1815185, rsl2254002, rsl2778891, rs35825568, rs61830965, rs36172393, rsl 1239536, rs72796498, rs61848597, rs35647145, rs2377942, rs7894727, rs6537530, rsl258179, rsl258182, rsl 1101238, rsl438928, rs3849145, rs4012536, rsl 1592181, rsl43788922, rsl0994860, rsl0821905, rs3808919, rs7077633, rs2393426, rsl013474, rsl427207, rsl2262629, rsl0821939, rsl0821944, rs725529, rs7090871, rsl2773075, rs3740353, rs9633556, rs9633557, rs3740352, rs2393729, rs2393728, rs7083045, rs7924036, rs4746729, rsl45701607, rsl0998000, rs7095603, rs7095607, rsl2415105, rsl2416503, rs7079974, rsl2241767, rsl2262121, rs7075996, rs3812637, rsl0824036, rs7087290, rsl0762586, rs816850, rsl l002181, rs74410628, rs7078632, rs3127449, rs3127450, rsl439787, rsl866594, rs79037708, rs72809508, rs74577679, rsl 1002194, rs78740294, rs7907504, rs61096875, rs2673433, rs2673434, rs2448394, rs2719978, rs2448395, rs2673477, rs73291804, rsl 12728740, rs372893521, rs58640785, rsl 13797354, rs2619634, rs2673463, rsl877993, rs79221966, rs60674751, rsl2218866, rs7083734, rs!0824743, rsl l002931, rsl !002932, rsl l002933, rsl2414178, rsl2411493, rs7077812, rsl317617, rsl892501, rsl892500, rs2186235, rsl2769165, rs6480936, rs7900144, rsl 1002957, rsl0824749, rsl0824750, rs7898802, rs2279337, rsl 1598614, rs9943407, rs2819940, rsl43396142, rs59028692, rsl 1202957, rs9421581, rs9421590, rs376416910, rs368285394, rs376737866, rsl750274, rs72820049, rsl7343157, rs2477956, rsl7343533, rs72820074, rs2297312, rs7896106, rs7101264, rsl 1185825, rsl 12289686, rs61854360, rs61854426, rs61869183, rsl7127289, rsl7127307, rsl92403351, rs72823192, rsl0882018, rs66526527, rs2068888, rsl2260218, rs55744367, rsl0882171, rs7919934, rs7894625, rs7070948, rs7070947, rsl2769915, rsl 1187539, rsl0882272, rsl 17061060, rsl0786213, rsl0748632, rs4328157, rs9663482, rs4918943, rs2125060, rsl 1599170, rsl 1188622, rsl 1595809, rsl0882723, rsl 1593049, rs60450792, rsl 1188631, rsl 1188632, rs7896077, rsl 1598546, rsl2761705, rsl0509701, rs34999669, rsl0491070, rsl 1189526, rsl042752, rs!2417556, rs605923, rs3737445,11856242423.3Attorney Docket No. 046483-7468W01(04021) rs61899413, rs3829258, rs665731, rs75919952, rs!2721043, rs!7120152, rs555639, rs2510897, rs555649, rs2105782, rsl784300, rsl 12119822, rs4938626, rs77751615, rs7945293, rs4938654, rs4938659, rsl0790452, rsl893841, rs4935802, rsl2785310, rsl2808150, rsl2808357, rsl 1218783, rs75564112, rsl44399213, rsl42471120, rsl0790795, rsl0893488, rsl 12771035, rs59822672, rs876071, rs8705, rs61909096, rs500090, rs2510121, rs686486, rs670516, rs3763950, rs4756786, rsl 1369, rsl 1238, rsl043237, rsl 1023168, rsl 1605531, rs61883858, rsl l023170, rsl l023172, rsl431374, rsl0832240, rs7934671, rsl l023178, rsl l606558, rsl0832242, rsl2291662, rs34171876, rsl2795545, rs4757250, rsl0832246, rsl 1023198, rsl6930126, rs2060076, rsl 1023203, rsl0832248, rsl2806025, rs2882128, rsl0832525, rsl 1023747, rs2351958, rsl77546, rs59828007, rsl77551, rs59258722, rs4757483, rsl0734250, rs7481960, rs60835408, rs62650851, rsl 1564725, rsl 1564722, rs3842761, rs7481129, rs7395734, rs6578999, rs6579001, rs7123180, rs6579003, rsl 1043133, rsl 1043135, rs7121452, rsl058873, rsl058935, rs74045276, rsl 1748, rsl 134578, rs7945319, rs7947, rsl 17739035, rs9667408, rs4930004, rs6578283, rs9888189, rsl2287110, rs55763223, rsl971929, rs231890, rsl 1023996, rs6578296, rs463535, rs231873, rs233438, rs81205, rsl048046, rs72850026, rsl2277177, rs3764895, rs3764896, rsl056819, rsl2223953, rsl2361922, rsl2363207, rs61871197, rsl0832936, rs4758492, rsl 1024672, rs4758561, rs4758562, rsl 1024687, rsl2286120, rs2071117, rs3213614, rs4758576, rsl 1602817, rsl 1024746, rs4758590, rs7940694, rs737872, rs60898246, rs60026059, rs3825063, rs7127443, rs4758501, rs7946134, rs74869735, rsl6928966, rs4758504, rs6578306, rs6578307, rs7113131, rs6578308, rs4758622, rsl 16848871, rs7935248, rs3741343, rs6578312, rs4758458, rs7950766, rsl7309986, rs72874485, rs72874488, rs34667360, rs34357760, rs7937778, rsl6917735, rsl384903, rs34337978, rsl7310076, rs7931847, rs7128045, rsl351787, rsl l603799, rsl l605717, rsl 1601602, rsl7244387, rsl2786351, rsl2797155, rsl2797712, rs34351528, rsl 1030269, rs!2787721, rs61889048, rs!2802830, rsl 1826837, rs35357280, rs34827038, rs7934085, rs7110074, rs34857148, rsl7652117, rs34906813, rs2582905, rs35031414, rsl39841307, rsl83380256, rsl 1030598, rs55937300, rs7938219, rs7933990, rs74528749, rsl7402305, rsl46685651, rsl41851059, rs4922556, rs7930738, rs294348, rs538000, rs294394, rsl88395, rs3925584, rsl 1602582, rs72906988, rs72908928, rsl45678014, rs55707359, rs55683589, rsl40914801, rs72908033, rs72908034, rsl0501318, rs72908050, rs72908052, rs72908056, rs72908057, rs72908060, rs72908065, rs79052740, rsl43391621, rsl 51258518, rs72908086,11956242423.3Attorney Docket No. 046483-7468W01(04021) rs72908091, rs72908092, rs72908098, rsl 12976598, rs!48157878, rs72908102, rsl 11771311, rs7926726, rsl984777, rs2306353, rsl0838702, rslO839315, rsl2416837, rsl 1040455, rsl2364577, rs4881721, rs28490238, rsl0902013, rsl 1245609, rsl 1245616, rs4066591, rsl0902022, rsl 1246496, rs80282099, rs7929989, rs71484844, rs4533026, rsl2795686, rsl0902380, rsl 1246655, rs7479178, rs528112218, rs7107218, rs4243961, rsl975200, rs!2271333, rsl2272771, rs4567498, rsl2292448, rs4309185, rs56895655, rs7105587, rsl912014, rs3862669, rs7120357, rsl783980, rsl785498, rs563888682, rs2524299, rsl74475, rsl74478, rsl2366107, rsl 1231284, rsl0897307, rsl 11438108, rsl 1231285, rsl0792364, rsl0897309, rsl0750977, rsl0897310, rsl944044, rs58077467, rs34400381, rs78829599, rs79280212, rsl47500819, rsl42601087, rsl0896005, rs35292734, rsl 12253806, rs4102217, rs3200401, rsl0896012, rsl783541, rsl787663, rsl 143756, rsl 144928, rs947791, rs56076708, rsl 1227217, rs2846139, rs58621819, rsl2789028, rsl346, rsl 17952737, rsl39847315, rsl 1227299, rs948494, rs948493, rs4930319, rsl786171, rsl 1227378, rsl 131544, rs632640, rs7933510, rs685334, rs684546, rs548435, rsl785639, rsl785633, rs947978, rs2236679, rsl0750784, rsl892940, rsl0896111, rsl0896112, rsl0791869, rs7110944, rs3016767, rs4930177, rsl 1601396, rsl2794121, rs73489638, rs56123976, rs4930178, rs4244813, rsl047029, rsl039594, rsl2577196, rsl2576299, rs7126018, rs2279861, rs2279862, rsl2416747, rsl0791872, rs7107191, rs4930360, rsl0896115, rsl0791874, rs67780191, rs7948058, rs74863039, rsl0896116, rs61891449, rs55998145, rs7931458, rs4930362, rs7117630, rs6591213, rs7104253, rs905770, rs4930179, rs34043951, rs7104570, rs7105015, rs7105401, rs66810040, rs56321771, rs4930181, rs7125752, rs4630308, rsl0896118, rsl2418706, rsl2420203, rsl 1227474, rs7938676, rs7939111, rsl0791876, rs4930363, rs6591215, rs7115577, rs7940980, rs6591217, rsl546358, rs2282530, rs77754842, rsl2785321, rs79798028, rs2279865, rsl 18011533, rs7104378, rsl2099041, rs57691879, rs3892818, rs2277302, rs4930377, rs57634456, rsl 1550299, rs4930378, rs7943327, rsl7147644, rs7950407, rs7950790, rsl l824771, rsl l227495, rs7123176, rsl 11511881, rsl l227497, rsl 1227498, rs56144989, rs2305535, rsl 1227499, rsl0501397, rsl 1227500, rsl 1227501, rsl 1227502, rsl 1822099, rs61561111, rsl 1227509, rsl 1227510, rsl 1227511, rsl 1227512, rs2298806, rsl0896124, rsl l227514, rsl l227515, rsl l822028, rsl0896125, rs28414721, rsl2223478, rsl2223479, rs3819247, rs74869459, rs3816492, rs2305532, rs2305533, rs3741360, rsl2221821, rs755761, rsl0792015, rsl0750838, rsl0792016, rs!0896406,12056242423.3Attorney Docket No. 046483-7468W01(04021) rsl 0896408, rs76603088, rs3750966, rsl 0896416, rsl 2363597, rsl 1228482, rs7945151 , rsl 1228485, rs896973, rsl005858, rsl2280942, rsl0896437, rsl2798031, rs7929203, rs3019748, rsl2418948, rsl2418451, rs66592032, rs!2420758, rs9651718, rsl 1228551, rsl2809032, rsl2800787, rsl 1228553, rsl2223972, rs55814684, rs7113988, rs4980598, rsl 1602223, rs7946918, rs647451, rs602652, rsl789167, rsl789164, rs4411303, rsl 1232979, rs7104619, rs2186797, rs!48865428, rsl 1822234, rsl 1236214, rs7102580, rs61389091, rsl 1236476, rsl 1823410, rs609799, rs575976, rsl0899104, rs72997616, rsl0899457, rs4944195, rsl0899458, rs4627115, rs4944196, rsl0793297, rsl0899460, rsl 1601866, rs4417308, rsl0899465, rsl0899466, rsl0899467, rs6592772, rsl0899468, rsl0793298, rsl0899469, rsl0793299, rsl0793300, rsl0899470, rsl0793301, rs4945265, rs4945266, rs7116611, rs4944198, rs!2574042, rsl2574044, rs55808581, rs7113042, rs72931639, rs58565853, rs72931642, rs4945267, rs4945268, rsl 1237456, rsl0793302, rsl0899472, rsl0899473, rsl 1601196, rsl0899474, rs7115850, rsl2281104, rs4945269, rsl 1237458, rsl0899475, rsl0899476, rsl0899477, rsl0899478, rsl0899479, rs2292573, rsl0899480, rsl2277648, rsl 1237460, rsl0501426, rsl0899481, rsl 1237462, rsl0899482, rsl 1237463, rsl0793303, rsl0899483, rsl 1237464, rsl0793304, rs4245459, rs4945270, rsl0899485, rsl0899486, rsl0751287, rsl0751288, rsl 1237469, rs72931690, rsl 1601161, rsl 1601195, rsl 1237471, rsl0899487, rsl0793308, rsl2291726, rsl0899488, rsl0793309, rs4945273, rsl0793310, rsl567890, rsl567891, rs7128666, rs7112234, rsl2284390, rsl0793311, rsl0899491, rs4945274, rsl0899492, rsl 1237480, rs7939646, rs7941639, rsl0899493, rs7110387, rs4945275, rsl0431155, rs4944199, rsl0899495, rsl0899496, rsl0899497, rsl0899499, rsl0899500, rsl 1237485, rsl 1237487, rsl0899501, rs2063724, rsl 1237490, rs990706, rs79338137, rsl49013553, rs7928772, rsl0902235, rsl0902239, rsl0902243, rs7395402, rsl0902248, rs7396677, rsl0794356, rs7123912, rs7394958, rs7394912, rs7394436, rs7933889, rsl0902257, rs4072741, rs4075990, rs6597960, rs415895, rs75248620, rs7948688, rs7930281, rs7938316, rsl7039076, rs74735986, rs79589059, rs76727811, rs79685573, rs79872044, rs78768625, rs76722883, rsl7039089, rs79144950, rs74459373, rs78463444, rsl 17012212, rsl 18079645, rsl 17980587, rs76972589, rs2374686, rsl46120104, rsl 17616994, rs79264325, rsl7039104, rsl 17170723, rs80187574, rsl 17399660, rs3742003, rsl0849948, rs7976462, rs79209359, rsl2369009, rsl 1065961, rsl 1065967, rsl0849966, rs601663, rs608814, rs847900, rs57454118, rs7295396, rs737280, rs375329393, rs9706432, rsl0849979,12156242423.3Attorney Docket No. 046483-7468W01(04021) rs7309970, rsl 6941724, rsl 2580246, rs4767284, rs60998439, rsl 2319718, rsl 1066127, rs7952986, rsl 1066128, rs79761579, rs58368428, rs74778442, rs7314282, rs7298532, rs2339973, rs4767364, rs60690688, rsl0850001, rs60549974, rs3519, rs!2423572, rs74187049, rs3741993, rsl6941909, rsl2423268, rs7295628, rsl005902, rs58249241, rsl2424641, rs7977534, rsl0161290, rsl0850024, rs77468840, rsl468252, rs60728177, rsl 1066308, rs!2423190, rs7953150, rsl0850043, rs77779680, rs78205093, rs2216475, rs7956523, rsl0850459, rsl0850462, rs7133396, rsl 1832443, rsl 17113238, rsl 1616030, rs719450, rs2280168, rs3759402, rsl800574, rsl83144890, rsl 169076, rsl0840641, rs7312404, rsl2301673, rs75989601, rsl0846582, rs4764132, rs61922971, rsl 1056376, rsl0846157, rsl0848574, rs555044, rs7969761, rsl0848644, rs73075659, rsl0771021, rs7296821, rs2239062, rs56196860, rsl 1614061, rs28990715, rs!81112800, rsl7688567, rs7977942, rs7980759, rs34623502, rsl7695429, rs79050656, rsl2426678, rs7296615, rs73047059, rsl6930370, rs632887, rs6489451, rs6869, rs4766091, rs55979725, rs899159, rsl259389, rsl234035, rs7300560, rsl234052, rsl234054, rs7958455, rsl234002, rs7136038, rs7305763, rsl0880224, rs824688, rsl688855, rsl994284, rs824700, rs824701, rsl095048, rsl095054, rsl095055, rsl095056, rsl732350, rs6582378, rs824716, rs824717, rs824718, rs844046, rs824722, rsl688884, rs865420, rsl463613, rs2629522, rs3852592, rsl683202, rs712106, rs824734, rs712114, rs712120, rsl2309460, rs4766230, rsl2815443, rs78470967, rsl7177326, rsl 1063202, rs2909380, rsl45878042, rs2544025, rs34922454, rs2228570, rs536750977, rsl82464338, rs2634675, rs3730071, rsl 126930, rs3782357, rs75022468, rs78097831, rs7313400, rs4898530, rs4463912, rs3205718, rs7132908, rs836968, rsl 1169571, rs319943, rs319944, rs2630353, rsl 13346821, rs2554861, rs829016, rs319938, rsl48940696, rsl48043157, rs2630367, rs319930, rs55874852, rs77481269, rs2554859, rs2554858, rs2046498, rsl095998, rs829023, rs706803, rs706804, rs829021, rs2277383, rs2293093, rs3847858, rs7974773, rs61914027, rs58617820, rs61914028, rs4761839, rsl 1610143, rsl 1612312, rs813469, rs813470, rs772222, rsl0876222, rsl 1169970, rs2242106, rsl 1169971, rs34437092, rs2252526, rs7301802, rs4762039, rs2854464, rs2359997, rs7306790, rsl0747655, rsl0876470, rsl 1170630, rsl7102221, rsl 1543260, rs7302925, rs2277339, rs3741580, rs7964492, rsl0877033, rs4128707, rs6581157, rs6650219, rs3751331, rs4335583, rs9971722, rsl0783857, rs7298370, rs6581159, rsl2308413, rs2372309, rs2888288, rs4272820, rsl 1172387, rs4373979, rs4534624, rsl0783859, rs6581161, rs4760346, rs4590915, rs4509811,12256242423.3Attorney Docket No. 046483-7468W01(04021) rs3751327, rs3751326, rsl 0783860, rs7959475, rsl 0877043, rs4760352, rsl 0877044, rs4362183, rs4606520, rs7132521, rsl0783864, rs2659662, rs2659659, rs2089377, rs2720191, rs3913866, rs7135728, rsl7120179, rsl7120182, rsl2820787, rs871907, rsl0877055, rsl911260, rsl0877056, rsl506890, rs4435045, rsl 1834807, rs7308860, rs7309322, rsl605329, rsl605330, rsl605331, rsl857941, rsl0783867, rsl0783868, rs4444117, rs4465402, rs7980024, rs7979813, rs7966544, rs!2369381, rsl 1514202, rsl 1495528, rs2466160, rs6581184, rs7133552, rsl0783873, rs982492, rs982493, rs4760188, rsl580976, rsl580977, rs2720179, rsl0877063, rsl l l72456, rs2720178, rs2720176, rsl395511, rsl567130, rsl0878301, rs4257020, rs7971777, rs4237904, rsl0784472, rsl0784473, rs4556591, rs4762101, rs4254112, rs4540868, rs7308104, rsl0784477, rs7308337, rs4536280, rsl0784478, rs4301828, rsl0784480, rs4762103, rs4762104, rsl0784481, rsl 1175835, rs2468388, rs!0878305, rs2248625, rs7976914, rs61921604, rs4992846, rsl0506473, rs59806226, rs61921608, rsl 1175978, rsl 12299942, rsl 1175981, rs3115954, rs77034711, rs77548748, rsl 1064333, rs2286730, rs9478, rs775636, rsl252424, rsl252423, rs710627, rs710624, rs775624, rs710623, rs710622, rs775628, rsl252410, rsl 152901, rsl 152900, rs800167, rs775661, rsl697233, rs775308, rsl252422, rsl l52896, rs775310, rs796508, rs811820, rs2248751, rsl658780, rsl 143954, rs710630, rs710629, rsl621634, rsl 152895, rsl252402, rsl252364, rsl082700, rsl066387, rsl066388, rsl066391, rsl066395, rsl082701, rsl066399, rsl082702, rsl 161092, rsl 184743, rsl 177317, rs!082709, rsl082708, rsl092475, rsl082711, rsl 143948, rsl252414, rs710798, rs775650, rs7136124, rs61918326, rsl0878963, rsl2827594, rs7959452, rsl0784774, rsl384, rs7296920, rsl275609, rs75565148, rs74556661, rsl2316443, rsl 1109717, rs7971664, rs2403151, rsl2579095, rs2403155, rsl7011446, rs56260363, rsl2579559, rsl2580431, rs9943755, rsl 1608921, rs61927574, rs61927575, rs61927576, rs76674639, rs2279574, rsl2369904, rsl0506965, rsl 1047939, rsl 1048037, rsl 1048063, rs4883201, rsl805776, rs3026261, rs4842695, rs60343103, rs2053196, rs2072593, rsl 14697502, rsl 13918189, rsl 1107523, rsl 1107530, rsl3377736, rs7995703, rsl84548, rs77279628, rsl2427994, rs4142040, rs872589, rs872587, rs913746, rs9521717, rs9521718, rs9521720, rs9521721, rs9515196, rs9515197, rs9559780, rs7333748, rs7333596, rs9555692, rs9559781, rs4773169, rs9555694, rs4773170, rs4773171, rs9559797, rs6492273, rs7787, rs9506541, rs7326074, rs55641580, rs55840438, rs2149077, rs7994814, rs4454823, rs4771085, rs2148758, rs7318048, rs56181982, rs7995310, rs2149129, rsl l616427, rs2481951, rs61944748, rs!42386496,12356242423.3Attorney Docket No. 046483-7468W01(04021) rs461 189, rs465056, rs404234, rs457707, rs365873, rs2755233, rs2755236, rs73173150, rsl 170178, rsl2585075, rsl2876965, rs71429406, rsl2872074, rsl2585865, rsl2877052, rsl0492439, rsl7645560, rs60039389, rsl2863254, rsl3378979, rs78087039, rsl 12435975, rsl 11658977, rs9567207, rsl 13541848, rs9562802, rs9526445, rs2252544, rs58325618, rs41284816, rs770379, rs770380, rs770383, rs770384, rs770386, rs770388, rs706602, rs706601, rs770391, rs770392, rs770393, rs770394, rs770395, rs770396, rsl239707, rsl239703, rs947383, rs947382, rs947380, rsl239696, rsl239695, rsl271766, rsl239693, rsl239692, rsl239691, rsl239690, rsl239689, rsl239688, rsl239687, rsl270717, rsl239686, rsl239684, rsl239683, rsl239682, rs476990, rsl239675, rsl239674, rs677585, rs484304, rs797512, rs797517, rs797519, rs2497087, rs797472, rs797536, rs797537, rsl772872, rs2794468, rsl272436, rs7989991, rs7990306, rs750176, rs9535492, rsl570603, rs9535494, rs4312209, rsl841677, rsl 1148198, rs2061624, rs9535495, rs9535496, rs9535497, rs9316505, rs9526693, rs9568476, rs9563002, rs9568481, rs4360838, rs8002319, rsl 1616586, rsl 1617765, rs9591371, rs7992624, rs7993060, rs9526698, rs7491820, rs8000150, rs8001874, rs9535519, rs7323313, rs9535522, rs7335786, rsl041017, rs9526703, rs9526706, rs74080784, rs73525441, rs716877, rs303937, rs303933, rs9543208, rs7489384, rs7489409, rs59660046, rs9318186, rs9530201, rsl7290460, rsl7218496, rsl 13319799, rsl 12091740, rs78396746, rsl7219517, rs7991281, rsl 12800422, rsl 11914166, rsl0507822, rs7338608, rs7337594, rsl7062027, rsl7311314, rsl7219984, rs2025532, rsl 11841167, rsl46537811, rsl41110431, rs77394627, rsl7311461, rsl0507823, rs76319853, rsl7062045, rsl2870505, rs78851859, rs78062845, rs7981330, rsl957452, rsl2432201, rs78523130, rsl 13911074, rsl 1848096, rsl2587475, rs34076421, rsl0133357, rs75741145, rsl2893211, rsl 1160626, rsl537763, rs2152370, rsl537761, rsl 1160627, rsl 1621508, rsl2882087, rs4900485, rs7493865, rs2273905, rs4900538, rsl951629, rs942021, rsl 1622216, rs35785423, rs4906246, rsl 1626274, rsl 1628569, rsl 1160698, rs35696698, rs34010412, rs7143468, rs911555, rs911554, rsl l7507755, rs67110142, rs2582565, rs8008126, rs28593146, rs587653404, rs564681644, rs8021296, rs6736, rs7152493, rs7148564, rs2231806, rs875908, rs2273171, rs61976859, rs7494025, rsl0151563, rsl2889162, rsl0135213, rsl0138200, rs6571403, rs6571404, rsl041088, rs9788563, rsl0151517, rsl741177, rsl884803, rsl956438, rs2064665, rsl 1157727, rsl2586183, rs9944008, rs60692740, rs4900987, rsl955927, rsl l850798, rsl l l57729, rs74244415, rs!0483600, rsl 1157731, rsl950510, rs7160591, rs73289637, rs79866668, rs58509432, rs73291657, rs73291663, rs3783419,12456242423.3Attorney Docket No. 046483-7468W01(04021) rs2273326, rs72683923, rsl 557010, rs3783412, rs! 7563, rs2071047, rs2761884, rs2738265, rs78748659, rsl0144425, rs76936296, rs34642953, rs74555566, rs7141548, rsl 1620803, rsl0142814, rs28546344, rsl46194354, rs28707162, rs7158665, rs4901541, rsl254028, rs8016830, rs7157442, rs7153820, rs35211290, rs2882531, rs8012628, rs61995385, rs76163472, rs2093210, rs33912345, rsl7097602, rsl2889678, rsl0873205, rs7141506, rs6573781, rsl l l598706, rs3759757, rsl314911, rsl314916, rs727129, rsl7106213, rs58638884, rs56119720, rs72731550, rsl2893429, rs2293793, rsl0142359, rs61987137, rs61987138, rsl 1625677, rs61987140, rs7159760, rsl 1159028, rsl45538420, rs61988862, rs61988863, rs61988864, rs62004868, rsl 11511359, rs55910602, rsl 1621868, rs73295349, rs55746412, rs62004878, rs62004879, rsl 11424562, rs62004881, rs72719670, rs2070598, rsl860935, rsl2894709, rsl2887934, rsl45995745, rs7140952, rs56033314, rs2267872, rs8009555, rs6574551, rsl0144099, rs9972275, rs9972105, rs7145153, rs7350729, rs7145584, rs7159642, rs7160310, rs28758824, rs61989398, rs7155755, rs7156362, rs7156387, rs983228, rs983229, rs724802, rs61989399, rsl955625, rsl7110492, rs2160354, rs55884286, rs2295138, rsl80814424, rs3742553, rs3853417, rsl 1625151, rs59787626, rsl2881349, rs61981188, rs36014449, rs4904252, rsl955435, rsl0873367, rs34485385, rsl 1845293, rs35823815, rs3179969, rs60503594, rs2116445, rs7153464, rsl0142128, rsl0133955, rs4301958, rs7150111, rs60358112, rs72697283, rs2093595, rs73330136, rsl 12146012, rs73330137, rs72699835, rs8017636, rsl 12560164, rsl 1160096, rsl2588550, rs56258011, rs4905017, rsl2883201, rsl044780, rsl 1160318, rsl889371, rs881163, rsl 1160320, rsl0873469, rsl 1625405, rs56261560, rs2614489, rsl 1160508, rs7143531, rs2614453, rsl86694602, rsl 1633550, rsl 1634006, rsl2915406, rs34471260, rs28465416, rsl2911429, rsl 1070167, rsl 1630786, rs79401209, rs3900905, rs2925345, rs2412608, rs56383987, rs55973132, rs2271436, rsl47298709, rs7174075, rs59368522, rs74467424, rsl648286, rsl648285, rs!631533, rsl706837, rs28877685, rs4775822, rsl 1854234, rsl 1854294, rs28859291, rs2413783, rs7165889, rs4775832, rs4775834, rsl 1636018, rs4238377, rsl6941238, rs8033317, rs61300393, rsl46625690, rs2433611, rs2486274, rs8024550, rsl 145077, rs79876890, rsl2439429, rs28375625, rs28495639, rsl2905525, rs6416445, rs732761, rs2470176, rsl906402, rsl906403, rsl906404, rsl7730281, rsl 12744790, rs578595, rs551225, rsl664449, rsl664448, rsl706341, rs!706340, rs7177920, rsl 1854842, rs2440968, rsl664446, rs2007058, rs2591064, rs8038172, rs!706406, rsl706403, rs!664444, rs7161907, rs2668179, rs2591065,12556242423.3Attorney Docket No. 046483-7468W01(04021) rsl 1631792, rs2414502, rs878958, rsl 567620, rsl 3380261, rs7169351, rs7169074, rs7169100, rs4774939, rsl 867644, rs4774946, rsl292363, rsl 50932609, rsl 81592246, rsl994887, rsl 17047297, rs75079269, rsl 1857838, rs59066984, rs9944289, rs9944168, rs28817334, rs8031321, rs28422841, rs28392952, rs28698238, rsl868243, rs2453089, rsl 107113, rs2451184, rsl 15452326, rs58646822, rs956006, rsl2915597, rsl2904839, rsl2438162, rs4775517, rs4569205, rs4265758, rsl2437894, rsl0851714, rs4774442, rsl2913538, rs2729806, rs2652806, rs2652805, rs2652804, rs2729805, rs745338, rsl 16907180, rs74018963, rs74018964, rs74018965, rs74018967, rsl 11642201, rs55657486, rs61300710, rs74018111, rsl 13523730, rs2228513, rs74692183, rs77106746, rs79503123, rs76640183, rs33918653, rsl2439510, rsl2441199, rsl0851749, rs4776806, rs8042578, rs56385383, rs62005619, rsl 1632964, rsl 1637537, rs4601989, rs79483120, rs4776343, rsl 1638064, rs7165382, rs34708051, rsl866320, rs7166081, rsl6954772, rsl 1852677, rs28695177, rs58378691, rs62019060, rsl 15644060, rs7177798, rsl2593783, rs2472297, rs2168518, rs8026273, rs4886658, rs8028146, rs72730601, rs4886422, rs4886661, rs4243032, rs8029760, rs6495155, rs7178005, rsl2442392, rsl2442410, rsl2914536, rs8033754, rs8025412, rs56139080, rs8034430, rs57968453, rs335713, rs62027568, rs78430278, rsl910510, rsl532783, rs9672219, rs7177266, rs974718, rs74024021, rs74024022, rs74024023, rsl 15407087, rsl0468062, rs4886750, rs335695, rs335694, rs335693, rsl394122, rs335675, rs335676, rs335679, rs335724, rs335725, rs8035611, rs2648437, rs59839117, rs74024029, rs7182720, rs335728, rs74024030, rs58044283, rs61521312, rs8030469, rs74024032, rs79798377, rs74024035, rsl39211312, rs76428135, rsl37935316, rs2133409, rs75886617, rs74024040, rs74024041, rs74024047, rs75279464, rs74024048, rs74024051, rs74024052, rs74024053, rs78434972, rs58789594, rs59819402, rs7181550, rs78514161, rs78037048, rs56173902, rs8025372, rs57737646, rs59690620, rs334951, rsl45727191, rs7174365, rs74024059, rs7173697, rs55665712, rs!0851885, rs74024060, rs7177048, rs60847237, rs9745107, rs9745133, rs9745164, rs334947, rs7162085, rs8029069, rs8028990, rs8028995, rsl42931687, rs74024064, rs74024065, rs7174280, rs58170668, rs8038740, rs74024068, rs76618651, rs74024069, rs6495191, rs8031263, rs74024073, rs57971067, rs57141410, rs58717562, rs80297148, rs62027652, rs2959851, rsl498198, rsl498197, rs35743198, rsl2911337, rsl2909723, rsl2902022, rs56117933, rs79067624, rsl 12238647, rs57708073, rsl2438645, rsl 17355348, rsl 17288281, rs2135881, rsl 1852715, rs79754687, rs73507434, rsl 1072966, rs7165424, rs8039384,12656242423.3Attorney Docket No. 046483-7468W01(04021) rs8039607, rs371891811 , rs78366152, rsl 1259952, rs!7507300, rs7169629, rs6496791 , rs28521166, rsl2592350, rsl 1858729, rs7167563, rs7167604, rs6497202, rs77264130, rs62020772, rs77032376, rs78550103, rsl 1630039, rsl 1074115, rs2119011, rsl992283, rsl0775257, rsl2908494, rs7173103, rs7173429, rsl 1857807, rsl2439642, rs8038278, rs8039706, rs8038957, rsl2440648, rsl2440633, rs2130888, rs7174817, rs2130887, rs2399761, rs9673018, rs9673020, rs!2915382, rsl2905983, rsl491175, rs8024493, rsl573891, rs45557931, rsl567811, rs3743263, rs74032572, rs8037855, rsl2437561, rs45619933, rsl85005, rs246215, rs35591, rs3851711, rsl 13956264, rsl40185678, rs338781, rs338782, rs2531327, rs2754184, rs338783, rs338784, rs338787, rsl7135716, rs7203846, rsl800705, rsl85355445, rs4018130, rsl 1861948, rs78398423, rs45592239, rs7498751, rsl3334589, rsl3329952, rsl2917707, rs77924615, rsl3334633, rs7195855, rs2221448, rsl2598584, rsl63278, rsl63277, rsl63275, rsl63274, rs9926773, rs7189996, rs7190032, rsl2599015, rs34976834, rsl2925057, rs7202719, rs7202568, rs6497535, rs6497536, rs8052157, rs6497537, rs7198998, rs8058582, rs6497539, rsl2446383, rsl 1074484, rsl3330546, rsl2708641, rs7191235, rs7191654, rs7198224, rs7196889, rs7198205, rs7204599, rs2031082, rs2031083, rsl2597357, rs7184238, rs7185097, rs7193676, rs8182130, rsl2386036, rsl882708, rs2280765, rsl3338482, rsl203979, rs7189020, rsl 1647490, rs71374885, rs72768728, rs56015787, rsl469396, rs4787971, rs756950, rsl005588, rs4787974, rs4787975, rsl 1639554, rs4787979, rs233453, rs233460, rs233464, rs233469, rs233471, rs!2933850, rs28535114, rs9923875, rsl2923861, rs964002, rs9923148, rsl2930355, rsl2924688, rsl2102783, rsl2928569, rsl2924607, rs8046545, rs2071342, rs35979293, rs79684678, rs9790, rsl635404, rsl30025, rs73501791, rs8057701, rs78320503, rs495664, rs7200336, rs8058761, rsl 17986012, rsl 16971887, rsl465338, rsl965024, rs56210058, rs728538, rs2193098, rs4306507, rsl544638, rsl3336117, rs4784296, rsl2596721, rs62039768, rs62039771, rs8062173, rs57698767, rs62039772, rs62039773, rs62039775, rs8047872, rs!43024692, rs!6949932, rs74855061, rsl2927956, rs34869093, rsl 118252, rs68152003, rsl 1862746, rsl 1863789, rsl 1862845, rs7196485, rsl 1859591, rsl7303177, rsl6952242, rs72801818, rs72801825, rs7189726, rs8054299, rs8044205, rs72801853, rs60420081, rs62048543, rs7194519, rs62048544, rs3809634, rs9937521, rs28562191, rs9937053, rs9937354, rs9930333, rs9930397, rs9939973, rs9940646, rs9940128, rs!421085, rsl 1075985, rsl7817288, rsl 121980, rs7187250, rs7193144, rs62033399, rsl7817449, rs9972653, rsl 1075987, rs8050136, rs8051591, rs9935401,12756242423.3Attorney Docket No. 046483-7468W01(04021) rs9931900, rs56313538, rs9936385, rs9923233, rs9923312, rsl 1075988, rsl 1075989, rsl 1075992, rs9926289, rs9939609, rs7206629, rs7202116, rs7202296, rs66908032, rs72803697, rs62033403, rs62033404, rs7206122, rs7190396, rs7185735, rs79994966, rs62033406, rs9941349, rsl0468280, rsl7817964, rs9930501, rs9930506, rs9932754, rs72805611, rs9922619, rs7188250, rs72805612, rsl 1075993, rsl 1642841, rsl6952577, rs2388407, rsl6953241, rs7200222, rsl2596433, rsl2929759, rs2292318, rs3785100, rs2285910, rs76501820, rsl 124993, rs6499165, rs8045705, rs2287970, rs8048032, rsl 1075728, rs74697196, rsl 1642115, rsl 1641050, rs3885612, rs!6958970, rs55751101, rsl2449005, rsl2596823, rs74026882, rsl 1646884, rs39999, rs8060588, rs56316408, rs8045142, rsl0500551, rs2217950, rs60010276, rs2118220, rs60472033, rs9788837, rs76407217, rs8053080, rs8047885, rs8054096, rsl0454066, rs75815213, rsl6959035, rs9933526, rs9921045, rs3743673, rsl 12668868, rsl 13052188, rs77944668, rsl2447883, rs57565297, rsl2595869, rsl865965, rsl2232410, rsl0163235, rs57488237, rsl0048108, rsl800566, rsl437135, rs2196574, rs2361839, rs689455, rsl 13680693, rsl 1075733, rs4985523, rsl47922055, rsl47983035, rsl 1639902, rsl035543, rs61344899, rsl 1075947, rsl858800, rs8049936, rs7498798, rs6499607, rs79193369, rsl7767491, rsl7767742, rs57652769, rs62042361, rs4627365, rs7202443, rs9925586, rs9932786, rsl3334483, rsl0459870, rs7193865, rs7194288, rs62050386, rsl2446534, rsl2444518, rsl2596682, rsl2597207, rs62050388, rs7201564, rs71386289, rsl484029, rsl 1150276, rsl0514496, rs55896457, rsl6953274, rsl6953276, rs55958632, rs8043750, rsl6953280, rs62050395, rsl6953281, rs62050422, rs62050423, rs9972739, rsl2598715, rs60512064, rsl2599299, rsl2445223, rsl 1150279, rsl 1150280, rsl 1641604, rsl2051123, rsl 1150281, rsl 1642153, rsl 1647859, rs55661884, rs7204337, rs7206242, rs7190998, rs7194714, rsl 1150282, rs4410098, rs4398122, rsl2447891, rs8053017, rs4889151, rs7192257, rs4889152, rs4889153, rs62048420, rsl 1859045, rs55863307, rs56055503, rsl6953530, rs62048424, rs4635359, rsl 1649447, rs59455907, rs58780057, rsl 1860841, rs34423425, rs55772308, rs4889154, rs4586444, rs4491516, rs4359453, rs4533300, rs4522433, rs4888092, rsl l644540, rs35968504, rs9931063, rs935942, rsl 18049419, rsl2925668, rsl2928588, rsl2933677, rs77204347, rs62048202, rs3785012, rs4782583, rs8050617, rsl2923987, rsl6963074, rs56796255, rsl 1646443, rs4782652, rs4510001, rs!874013, rs4783086, rs4783087, rs4843382, rs77626209, rs67782872, rs67785750, rsl0514617, rs6540124, rs6540125, rs7186900, rs7205205, rs7205819, rs6540127,12856242423.3Attorney Docket No. 046483-7468W01(04021) rs7498866, rs7499535, rs7194478, rs6540128, rs4843282, rs7199429, rs7206461, rs!2919526, rs7202314, rsl2933782, rsl2933332, rsl2920047, rsl 1117324, rs4843751, rs8052540, rs8052276, rsl 1640695, rsl 1117332, rs8052854, rsl 1648707, rsl 1639873, rsl 1645107, rsl l645250, rsl l639761, rsl0863195, rsl2934520, rs4843768, rs7191387, rs7191581, rs7186583, rs7187459, rs4843772, rs4843773, rs7206128, rsl 1117346, rs579740, rs35643952, rs34789784, rs9939155, rs9941273, rs9929579, rs4566167, rs9926404, rs7200693, rs!2325600, rs4290474, rs9922341, rsl54656, rs7503401, rs2322286, rsl903280, rs61130577, rs35309210, rsl 1078058, rsl 1078059, rs9910495, rsl 1078060, rsl 1078061, rsl0852806, rsl6945729, rs9912833, rsl 1867186, rsl 1867213, rsl 1867266, rsl 1869842, rs60556358, rs34382539, rs62061038, rs4792246, rsl2325909, rsl2325911, rs73977843, rs7212658, rs6502181, rs7209139, rs8081668, rs28735420, rsl7626180, rsl 1652817, rs35701443, rs9893867, rs62088028, rs57937546, rs4791603, rs57437384, rs7215329, rsl 1658854, rsl0438712, rs8080011, rs4792555, rs4792557, rs4792558, rs73979047, rsl 1870422, rsl242483, rs746900, rs4646396, rsl2945144, rs35656361, rs9892560, rs9894321, rsl2941371, rs750546, rs936108, rs4646394, rs4646390, rs4646388, rs4646387, rsl 1651620, rs80097125, rs6502602, rs6502603, rs747770, rs4646385, rsl 1656215, rs4646368, rs4646359, rs4646358, rs4646356, rsl 1871667, rsl2942059, rs9894492, rs2131704, rs77017480, rs60355329, rs739830, rs2386316, rsl 1204343, rs4924992, rsl2937053, rs7207681, rsl0491097, rsl2602013, rsl2945111, rs4924994, rs8071408, rs!2939559, rs72838831, rsl 1658544, rs9910918, rs3901427, rs2453606, rs8078465, rs4531795, rsl 12323053, rs2453580, rs2018675, rsl41572615, rsl961669, rsl l l653425, rsl l5778474, rsl l5473784, rs2440158, rsl971851, rs36034566, rsl51167535, rs73275664, rs7503922, rs7502556, rs!2150665, rsl2937411, rs9889726, rsl l2901, rs525767, rs523120, rsl6968529, rs72821519, rsl l868029, rs4794813, rs4239222, rs4795384, rs2934966, rsl43517926, rsl 136201, rs34093201, rsl 104761, rsl7616543, rsl 12673090, rsl 17862245, rs573503384, rsl 13826025, rsl92858632, rsl 17374443, rsl43879261, rsl40262628, rsl90222807, rsl7678959, rs76375500, rs9909777, rsl7678990, rsl49754556, rsl7679086, rsl48396384, rsl41218028, rs77444159, rsl48449981, rs77893013, rs45612441, rsl40695349, rsl40263623, rsl46970846, rsl42550986, rs9891944, rsl41838399, rsl41464238, rsl39522626, rsl41005253, rsl90936664, rsl42892792, rsl89784411, rsl92794752, rsl 17577021, rsl92145896, rsl43250098, rsl 17293524, rsl89122060, rsl46780027, rsl38740713, rsl41810431, rsl50588974, rsl7679361, rsl41825199,12956242423.3Attorney Docket No. 046483-7468W01(04021) rsl 82939541 , rsl 88841379, rsl 7617263, rsl 86922993, rs74939509, rs4134998, rs4135005, rs4135012, rs4135019, rs4135027, rs4135030, rsl 17488810, rs8079103, rsl 16865519, rs75309102, rsl37891066, rsl47747703, rsl40987324, rsl43494424, rs77015611, rsl90676187, rs77209292, rsl40872469, rsl 17494298, rsl40235616, rsl45108176, rsl41223821, rsl45105278, rs33998939, rsl86956796, rsl82610022, rs35783632, rsl 17736199, rs41283423, rs2229773, rs 141158879, rsl90192989, rsl82057668, rsl 16430199, rsl 17989407, rsl45033369, rsl49530458, rs77924872, rsl40144680, rsl44629348, rsl7680704, rsl 1867902, rs79875164, rsl43836380, rs2306581, rs4796791, rs34638441, rs!0840, rs880690, rs8066100, rs76280636, rs2074292, rs4792846, rs62071986, rsl97907, rsl97911, rsl97913, rsl97915, rsl662594, rs4968248, rsl052504, rsl623402, rsl662597, rsl 1658276, rs2920397, rsl 1654971, rsl97916, rs7225428, rsl97920, rsl0853086, rs2072317, rs! 1655668, rsl97922, rs!97923, rsl838105, rs8065527, rsl 1079744, rs3885731, rs3890958, rs62075895, rsl6941404, rsl2600452, rs4794426, rs77694071, rsl42760320, rsl 12875011, rs56093336, rs594398, rs35513882, rs8078806, rsl463761, rsl 16440021, rsl 1870618, rsl 12123549, rs67560975, rsl533922, rsl533920, rs598905, rs2898945, rsl6949120, rs80277878, rs76022681, rsl2943759, rs7501581, rs7224610, rsl2951993, rsl7822403, rs72837328, rs55688501, rs55815590, rs72837329, rs72837330, rs62058023, rsl7833884, rs62058026, rs9894517, rs9902064, rs792405, rs792365, rs71387499, rsl2949598, rs2643126, rs304265, rsl 1653697, rs6503921, rs8076752, rs7206932, rsl 1868647, rs9915951, rs9916000, rs78224430, rsl292070, rs60167359, rs9905761, rsl 1657044, rs28559726, rs9895661, rs2240736, rsl89987386, rs7210758, rs4968645, rs7212455, rsl 13731184, rs8866, rs34685754, rsl2601759, rsl 1656743, rs62086884, rs4791295, rs28855509, rs74564337, rs62086889, rs78186330, rs62086897, rs62086898, rs62086899, rs62086903, rs62086904, rs62086906, rsl89628481, rsl92988621, rsl83763906, rs200026262, rs62086907, rs62086908, rs7405987, rs8076753, rs78794747, rs79778350, rs62084669, rs77536355, rs35229997, rs7226002, rs62084681, rs75236169, rs62084682, rsl2752, rs7214869, rs7214119, rs8075764, rs6504576, rs62084689, rs62084692, rs62084694, rs62084697, rs4638, rs62084703, rs74354868, rs75885145, rs7214557, rs7503050, rs7503056, rs7503206, rs7503810, rs62084708, rs78192857, rs35040337, rs28580652, rs74976757, rs62084740, rs74900486, rs75544834, rs9674669, rsl 84478609, rs9330556, rs62084742, rs34937122, rs78352159, rs62084744, rs76877263, rs62084752, rs28512206, rs62084755, rs75868869, rs3764855, rs3863515, rs7216182, rs883541, rsl46388015,13056242423.3Attorney Docket No. 046483-7468W01(04021) rs36068942, rs56038313, rsl2452519, rs56156468, rsl 13292722, rs746991, rsl41015869, rs6146151, rs4788885, rsl642797, rsl642802, rsl641542, rsl642803, rsl642807, rsl641536, rsl641535, rsl641534, rsl641532, rs2541011, rs2543554, rsl641528, rsl641525, rs2955610, rsl641522, rsl641521, rsl641520, rsl641519, rs2541010, rs2543556, rsl641517, rsl641516, rs7216615, rs2061387, rs7217432, rsl 1870078, rs3744008, rs9903200, rs2410859, rs9900122, rs2290771, rs2004452, rs936396, rs936393, rs936391, rs9906971, rs9894009, rs58363746, rs57287238, rsl463485, rs936394, rs9897770, rs4588035, rsl2103594, rsl 1867560, rsl 1867582, rsl 1869977, rs8082060, rsl 1870142, rs55699990, rs55992471, rs56098714, rsl 1867315, rsl 1867339, rs8081606, rs2034945, rs2034946, rs2034947, rs56901103, rs72860389, rs9674908, rs2199048, rs56040381, rs72860390, rs66584478, rs3744017, rs3744020, rs3744021, rs!055129, rs56000661, rs59623743, rs60059537, rs78866233, rs7207180, rs34974290, rs3744028, rs9902371, rs61730171, rs2748425, rs34337072, rs4490057, rs4366775, rsl2938284, rs3816263, rsl442850, rs9893434, rs2585408, rs7211681, rs7209156, rs67050149, rsl2948708, rs8081274, rs4797782, rsl 12006560, rsl 17441302, rsl 17159665, rsl 18035855, rsl41172991, rs45579846, rsl2960229, rs9957194, rsl48477096, rs973730, rsl3381941, rs2658450, rsl40148428, rsl318652, rs2850567, rs7407412, rs77637769, rs2847125, rs73427772, rsl 1661119, rs2850576, rs2959514, rs3017644, rs45613238, rsl 1665314, rs2959517, rsl 1659957, rsl 1660772, rs6508540, rsl 1660450, rsl 1659365, rsl 1083274, rs6508544, rs4625812, rsl 17385602, rsl 1877859, rs7226385, rs7234061, rsl 17723077, rs9961451, rs67945028, rs7226554, rsl2455558, rs7232531, rs527616, rsl6942751, rsl62009, rsl51245, rs875426, rs4315413, rsl46750662, rsl50233857, rsl356505, rsl518166, rsl 518167, rsl401007, rsl518171, rs7244875, rs7244636, rs35735971, rsl 1876609, rsl6977323, rs4890432, rs4407138, rs8098753, rsl518143, rsl356501, rs4890439, rs28597806, rs62092069, rsl424392, rsl424394, rs7238152, rs918817, rs918818, rs918819, rs!607338, rsl 1876807, rs!0502839, rs!2958322, rs79926430, rs62090594, rs34233878, rsl0163551, rsl0438961, rsl7740231, rs9807214, rsl0083997, rs7237237, rs56122603, rsl2457237, rsl2456693, rs9952412, rs9945126, rs3736242, rs357897, rsl288797, rsl 12311990, rs72934723, rsl 1659764, rs72936874, rsl84332798, rsl785418, rsl87882656, rs66922415, rsl0871777, rs476828, rsl 1152213, rs8097210, rs8089364, rsl2969709, rs921971, rsl2958167, rsl2954782, rsl942872, rsl2955983, rs2045439, rsl2970134, rsl 1660069, rs35476226, rs67713315, rs56804022, rs8083289, rs!2956871, rsl2960928, rs590215,13156242423.3Attorney Docket No. 046483-7468W01(04021) rs34893777, rs2168708, rsl 2966550, rs56069042, rsl 119497, rs76632317, rs74781 103, rs79078733, rs77505623, rs76149329, rs79601081, rsl 16886631, rs8089191, rs59277369, rs34212978, rs4987719, rsl 1151938, rs6566789, rsl 17334014, rs470335, rs470933, rsl 1876196, rs470907, rs8096658, rs62096864, rs562952, rs4799053, rs549752, rsl 17011420, rs304933, rsl0438902, rs4799117, rs4799118, rs4799120, rs4807624, rs34188292, rs4804592, rsl 16886975, rs59431306, rs77279095, rsl60838, rs!67479, rsl0419627, rs2974751, rsl0410950, rs73507341, rs2305780, rs6511912, rs74183052, rsl42096538, rs74183053, rs3760702, rs2241358, rs4809184, rs4809185, rs4808301, rs6512029, rs8109755, rsl0411669, rs7247749, rsl2972998, rsl0414131, rs7253443, rs4808302, rs4809189, rs6512030, rs35663425, rs34239025, rs62123690, rs393540, rs845371, rs411130, rs379494, rsl 1667505, rsl 1575926, rs845328, rs433821, rs845332, rs399343, rs55881864, rsl469024, rs!075403, rsl0416600, rs8110070, rs8113367, rs4531856, rsl2608504, rs7247222, rs7256111, rsl2973608, rsl2980403, rsl2610373, rsl 1086102, rsl 1670056, rs60570301, rsl 1086119, rs4808154, rsl2610715, rs74736618, rsl 1878358, rs2240012, rsl50611747, rsl 17843432, rsl87429064, rs56255430, rs2905426, rs2905427, rs2965185, rs886449, rsl003531, rs2301800, rsl2981430, rsl 17415941, rsl46982937, rsl0413027, rs718202, rsl 1085020, rsl0417797, rsl 11590167, rsl2976336, rs79645906, rs8104077, rs3786900, rs73927890, rsl269214, rs3814995, rs28608841, rs28555503, rs3816390, rsl0404069, rs4806414, rsl0407224, rsl0417545, rsl0405372, rsl0425441, rs4805207, rs28701616, rsl0411176, rsl2975869, rsl529957, rs7246657, rs6508710, rsl2972195, rs558072242, rs573082306, rsl2982333, rsl2709812, rsl823061, rs67293224, rs7408563, rs7259968, rs6508711, rs6508713, rs6508714, rs6508715, rs6508716, rs!3345148, rs7257672, rs7257495, rsl0404602, rs200494406, rsl0412043, rsl2104381, rsl2104380, rsl0415937, rsl0414904, rs28402338, rsl0417844, rsl373991, rsl0405407, rsl2709813, rsl3345116, rs4803347, rs7247259, rs35085437, rs3745765, rs4803229, rs!559229, rs6508719, rs4452075, rs4803460, rs!035479, rs3803895, rs28623164, rs7252346, rsl2979470, rs2891699, rs9676967, rs8112610, rs8109632, rs7255407, rs7256130, rs2112923, rs3760825, rs2112922, rsl0420754, rs59224125, rs2081096, rs7253091, rs28605784, rs28373708, rsl382357, rs2045908, rs7253114, rs2126977, rs7248733, rs2291004, rs6508732, rs6508733, rs4803195, rs4803210, rs4803215, rs9797618, rs2291002, rsl0425795, rsl0404031, rsl0406379, rsl0412786, rsl564206, rs!564208, rs954504, rs4803231, rsl0420552, rsl0420268, rs8110865, rs4803233, rs4802024, rsl975939, rs9304568, rs4802029,13256242423.3Attorney Docket No. 046483-7468W01(04021) rs28512414, rs6508736, rs9941475, rs4803262, rs4803263, rsl0408619, rs4802051, rs4803276, rsl0412510, rs3829688, rsl3744, rsl0403173, rs4803287, rsl2461113, rsl2459015, rsl531549, rsl975937, rs8103647, rs8100646, rs35863684, rsl0402671, rsl0417576, rsl0407568, rsl0409605, rsl6958861, rsl6958863, rs2972447, rs2972446, rs2927742, rs2927740, rs3101747, rs2927739, rs9749368, rs2972452, rs2927746, rs2927747, rs2909105, rs2972448, rs3112433, rs2909085, rs2909088, rsl2979640, rsl 1083432, rs62108337, rs2287229, rs958305, rs968073, rs56317671, rs7246461, rs2972434, rs3112434, rs2909093, rsl974714, rs3095724, rs2972439, rs2909100, rs2972445, rsl291, rs241933, rs241932, rs8112706, rsl0048511, rsl71376, rs8111875, rs241950, rsl0420746, rs6508742, rs9304569, rsl0409402, rsl0409487, rs4803509, rs7257125, rsl0401968, rs3848626, rs8101752, rsl 12553171, rsl 1878269, rs8104076, rs4803524, rs!0420891, rsl2975057, rsl 1879180, rs8182498, rs8104454, rs4482405, rs4802135, rs201066921, rs8101858, rs7250868, rsl0401637, rs4803541, rs4803543, rs4239516, rsl 1083441, rs3786869, rs4802144, rs8113273, rs8108434, rs8109053, rs4802147, rsl2608883, rs28460297, rs4802151, rsl0404159, rs8113521, rs8109835, rs4803573, rsl0415548, rs705495, rsl725499, rs833927, rs705493, rs705491, rs353411, rs353410, rs353407, rs56300335, rs353404, rs353402, rsl725494, rs60450113, rs353428, rs353427, rs353426, rs353424, rs353421, rs353419, rs353418, rs353417, rs353416, rsl643469, rs377606551, rsl725485, rsl725482, rsl725481, rsl643463, rsl725480, rsl643461, rs833895, rsl643460, rs833914, rs28517878, rs61355521, rs34943246, rs8104873, rsl046268, rsl046278, rsl 1670591, rsl 1670641, rs78907076, rsl 11760718, rs737204, rs2379622, rs3760903, rsl 11211909, rs62131485, rs62131486, rs34150601, rs8102677, rs35747067, rs2084109, rs34966575, rsl867696, rs2379623, rs34853245, rs35364374, rsl47213895, rs28377909, rsl41727248, rs34716810, rs9304588, rs541195759, rs268679, rs34033973, rs268691, rsl74865, rs7255928, rsl0421779, rsl0425814, rs62106981, rs268696, rs3901215, rs2246095, rs!0425765, rs2262082, rs200729649, rs201777248, rs56113850, rsl0411377, rs2965142, rs419010, rs429358, rs7412, rsl800437, rs4802274, rsl6980013, rs915915, rs281380, rs60068692, rs606400, rs7251671, rs35430308, rs3810186, rs73046788, rsl87500064, rsl44782308, rsl2461216, rs73058052, rsl273636, rsl290751, rsl0407646, rsl062967, rs7256559, rs7256855, rs7256165, rs4801939, rs4803007, rs4801940, rs4801941, rs4803008, rs4803009, rs4801942, rs3960272, rs7257653, rsl 11951394, rs7259073, rs35231921, rs35901334, rs55759769, rs75406521, rsl 1666550, rsl 1670858, rsl 1670922, rs9304741,13356242423.3Attorney Docket No. 046483-7468W01(04021) rsl 044467, rsl 808106, rs8111196, rs8111514, rs81 12137, rs2115090, rsl 123975, rsl 049230, rsl049232, rs75383787, rs8108787, rs4804395, rs3745546, rsl2986062, rsl864009, rs72992633, rs3865461, rsl0420976, rs6603079, rsl 1166440, rs2128416, rs72858515, rs72858521, rs3790638, rs284324, rsl2073762, rs36083532, rs6660242, rs811855, rsl 1121627, rs7528419, rsl2740374, rs72646553, rsl 149168, rsl765756, rsl 144595, rs201433929, rs556883943, rsl2129649, rs41283072, rs78366259, rsl2724682, rsl2722725, rs9429742, rs7516386, rsl7602729, rs57445665, rsl801133, rs34710782, rsl 1205303, rs6587723, rsl2048493, rs6693697, rs7554686, rsl 1811885, rs2762860, rs509345, rs471738, rsl776276, rsl 1580960, rs267738, rsl969442, rs2902811, rs2091219, rs6703620, rs6657593, rs6694158, rs7366148, rs6587552, rs6587553, rs2902810, rs2864700, rs3806387, rs3806386, rsl0749659, rsl524773, rs2140709, rs3738481, rsl5740, rs4970993, rs4970936, rs4970939, rs!2134957, rs4970940, rs6668894, rsl 1204769, rsl 1810447, rsl2039334, rsl2049116, rsl2039542, rsl2040729, rs6704195, rsl84026197, rs7514185, rs7536234, rsl 1204771, rsl0788798, rs7522608, rsl 1810510, rsl2093562, rsl 16222163, rsl2117163, rs4970941, rs6697617, rsl 1204777, rsl0788799, rsl 1204778, rs7523731, rsl 1204779, rsl 1204780, rs6676190, rs61819219, rsl 13869543, rs7522302, rs4970997, rs6656450, rs4970998, rs6702344, rs4970999, rs4971000, rs4360524, rs56033976, rs4357530, rs4971002, rs4971003, rs4971005, rs4971006, rs4971007, rs4971008, rs5023311, rs7546304, rsl2569193, rs56299877, rs4512652, rs56090305, rsl 1807526, rs6674970, rsl 1204782, rs!2087892, rsl 1807847, rsl 12627384, rs2067606, rs41305062, rs4522000, rsl0888411, rsl92154135, rs4971032, rs4970948, rs5022636, rs2800946, rs2800947, rs2769273, rs2025900, rs2769269, rs2769268, rs2769267, rsl752385, rs72640764, rs72640780, rsl079314, rsl 1588775, rs6690852, rs45619934, rs2862161, rs4661653, rs872222, rs6696951, rs6427184, rs9426886, rs4971100, rs2070803, rs423144, rs72704117, rs760077, rsl80921974, rsl40959946, rsl 14760481, rsl0908480, rsl 1264409, rs708611, rs72706174, rsl 13544820, rs822494, rs!40953793, rs74404550, rs2736609, rs2758607, rs2251636, rs2758608, rs2758609, rs2072929, rs2295363, rs2254669, rs2803312, rs2459988, rs2803310, rs2459989, rs2459990, rsl 108262, rs6693908, rs6701689, rs6694101, rs6684574, rs6684579, rs925905, rs2503713, rs698696, rsl2731820, rs36043745, rs2843156, rs2843155, rs903903, rs903911, rs7530619, rsl 13689711, rs6673221, rs76082781, rs74572798, rs78397470, rs77903064, rs74638219, rs557190940, rsl 13767154, rsl853395, rsl329964, rsl745611, rs!0917833, rs200802410, rs80263076, rsl41257545, rs3845534,13456242423.3Attorney Docket No. 046483-7468W01(04021)rs4442348, rs662871, rs520131, rsl 0800544, rs6665349, rsl 0912848, rs2421841, rs4916394, rs7536695, rs72717888, rsl2024335, rsl0489250, rs6665614, rsl 1584244, rsl 1584664, rsl39031539, rsl 1805471, rsl0911278, rsl7277295, rsl0797996, rs9425591, rs!0752946, rs9425316, rsl0752957, rs3213563, rs2301455, rsl 1576862, rs6680309, rs74127154, rs61820953, rs61820965, rs6678628, rs6678812, rs7553759, rs7522843, rs7514517, rsl0913143, rsl0913923, rs4256775, rs72723045, rs72707408, rsl2048020, rsl 1800333, rsl 1812056, rs3795503, rs61808068, rsl2138049, rs4350171, rs6673768, rs9425634, rs78444298, rs41264582, rs6674490, rs4651259, rs4650681, rsl0911748, rs7533879, rsl407277, rs4651264, rs4651267, rs6424989, rsl0732977, rs7522964, rs7556158, rs6658346, rs4233121, rs4142137, rs6703061, rs4518850, rs4506426, rsl2046623, rsl2039585, rsl2032711, rs7539353, rs7542383, rs7554402, rsl2406189, rs2891253, rs3955272, rs78539703, rsl89822718, rs7535459, rs2179189, rsl569479, rs4651336, rs2891258, rs7512414, rs34109355, rsl 1261022, rs322906, rs322901, rs322898, rs322895, rs427790, rs322877, rs322876, rs322875, rs322874, rs322873, rs2624882, rs2648772, rs7524630, rs7547363, rsl2727107, rsl536095, rsl0919656, rsl7632055, rsl 1583806, rsl2062849, rs2164524, rsl2037054, rs3850625, rsl42356235, rs35383942, rs72744832, rs3806357, rs9427716, rs6656372, rs4073666, rs3923212, rsl2125605, rsl2033840, rs4951254, rs2153904, rs2808454, rs7536934, rs56166793, rs79965342, rsl0779335, rs41318015, rs41303061, rsl 14278335, rsl 15633767, rsl 13552928, rs76408327, rsl 14558185, rsl 15799666, rs76432854, rsl 15939077, rsl 16277419, rs79344540, rsl 16694119, rs79638354, rs76403726, rs75306383, rsl 15066447, rs78915104, rsl 14130945, rs74630957, rs75660657, rsl 16746400, rsl 14577368, rs78521412, rs76267745, rs79121421, rsl 16778462, rs3120789, rsl 1581934, rs34008349, rs4951588, rs3767863, rs340882, rsl7022700, rsl7022807, rs4275425, rs6540832, rs6540833, rs6540834, rsl 1120328, rs4072973, rs3902966, rsl2757404, rsl2736454, rs7535253, rs!2132412, rs829391, rs829392, rs!7045771, rs2810778, rs2810779, rsl 1118448, rs59789715, rsl694593, rsl694594, rs2642438, rs867772, rs7514450, rs61830291, rs6694031, rs2150871, rsl2407545, rs76440733, rs73089725, rs74483800, rsl 1803959, rs41303115, rsl6846855, rsl2401963, rsl2405686, rsl2405707, rsl2405723, rsl2403195, rsl 1801443, rs55685166, rsl 1802395, rsl 1808186, rs73089760, rs73089765, rsl6846872, rsl6846874, rs73089770, rsl7851754, rs73091738, rs55865118, rs73091740, rs73091742, rs2150873, rs2183837, rs73091761, rs78002062, rsl6846908, rsl6846910, rs60979561, rs74140276, rs!0495263,13556242423.3Attorney Docket No. 046483-7468W01(04021) rsl 888831, rsl 6846972, rsl 6846985, rs73093463, rsl 2401556, rsl2410460, rsl 12787790, rsl44473177, rs73093495, rs6701743, rsl513600, rs78335667, rsl2403391, rsl2407061, rsl 1806820, rs73099023, rs73099026, rsl6847098, rsl 12620261, rsl2404416, rs73100804, rs73100814, rsl7605533, rsl0495258, rs80318211, rsl83801039, rsl89924669, rsl2134624, rs6682260, rs4653919, rs6673893, rs9728020, rs9727721, rs589359, rsl765787, rsl765786, rs!765785, rsl765780, rs!765795, rs2808579, rs!615409, rs766288, rs7523139, rsl765781, rsl 1122311, rs3120734, rsl655305, rsl765791, rs2806558, rsl757048, rs9792839, rs57746659, rsl 15418738, rs754984, rs2749153, rsl0926978, rsl2079656, rs3943093, rs2451668, rsl0926991, rs201734360, rs6665809, rsl 173642, rsl 173643, rsl 173645, rs544984, rs592594, rs592961, rs593881, rs594672, rsl 148919, rs538165, rsl093918, rs499096, rs530150, rs677289, rs480394, rs969228, rsl093915, rs563114, rs475555, rs482041, rs507037, rs2282719, rs9438876, rsl 12750178, rsl 14165349, rs75460349, rs79598313, rs61551751, rs57778433, rs74061781, rs74061784, rsl 11257457, rs7543544, rsl 13035001, rs2474294, rs74061800, rs77997265, rs9438563, rs7417012, rs9438522, rs9438524, rs2486674, rs9508, rs6688791, rs534121, rs555530875, rsl84110320, rsl0914324, rs55657710, rsl2406196, rsl2409630, rs35509903, rs55657908, rs79825075, rs6697017, rsl2122125, rs499600, rsl2090153, rs7517146, rs513464, rs688540, rsl92336534, rs72692227, rs3820201, rsl 183394, rs4927209, rsl2239399, rs2802861, rsl230005, rsl7113967, rs77049555, rs75384410, rs4912285, rs76423990, rsl7113998, rs7525717, rs75490687, rsl 1206818, rs334739, rs6587912, rs334734, rs334733, rs72664856, rs332823, rs333147, rs333145, rs333142, rs333140, rs333136, rs333162, rsl67987, rs333166, rsl44397465, rsl 1207719, rsl977653, rsl 12992163, rsl 12389260, rs636497, rs634341, rsl 168036, rsl 168027, rsl627591, rsl2062275, rsl2403207, rsl 168018, rsl 1207981, rsl2074528, rsl 1207986, rs2131925, rs2131926, rsl0889343, rsl629122, rsl748195, rs6690733, rsl0889347, rsl0157265, rs2366638, rsl 168097, rsl 168099, rs72683129, rs4655729, rs6658330, rs6700896, rs7542446, rs!2034502, rsl7127849, rsl2127475, rs57274629, rsl 1809906, rs4655761, rs2376015, rsl2042779, rsl2042807, rsl938500, rsl2043644, rsl 1208711, rsl 1208712, rs4655583, rs4655584, rs4655585, rs2375805, rs2889195, rsl 1208717, rsl 1208718, rsl 1208719, rs4655792, rs4655793, rs4655795, rs72480644, rs6588156, rs6588158, rs6698842, rsl 118392, rs2815374, rs4655726, rs4655727, rsl 166698, rs7514180, rs72723588, rsl7108214, rsl 1587424, rsl 1163481, rsl l4520032, rs4040605, rs2880024, rsl3303065, rs4970392, rs3121554, rs3121555,13656242423.3Attorney Docket No. 046483-7468W01(04021) rs3128126, rs3121560, rs9442364, rsl 1584036, rs!2142465, rs2289731, rsl 889854, rs! 889853, rs2289732, rs3765972, rs2636314, rs2708628, rs2784738, rs2748456, rs2661868, rs301799, rsl 1121182, rsl 1589090, rs751790, rs55858268, rsl2403339, rs6678982, rs!2401496, rsl2122737, rs79769442, rs55830087, rsl 1121207, rsl 1578142, rs4908770, rs56305243, rsl 1121213, rsl 1121214, rsl 1121221, rsl 1121222, rs4908774, rs7553298, rs4908508, rs821397, rsl094360, rsl2037294, rsl094353, rs2970548, rs821400, rs821388, rs821387, rs821385, rs821383, rs849158, rs9701898, rs9661608, rs9661951, rsl775992, rsl764295, rsl775985, rsl775986, rsl764287, rsl775987, rsl775989, rs9651138, rs7528385, rsl2756841, rsl0873718, rsl0747324, rs432254, rs420515, rs369999, rs401657, rs383558, rs430956, rs2785083, rs2764470, rs580828, rs488345, rs519319, rs539544, rs7514579, rs7516400, rs6692801, rs236329, rs56041528, rs41353346, rs72725120, rsl 191238, rs3917615, rs654320, rs632424, rs675365, rs677673, rs646075, rs640645, rs635689, rs651877, rs646407, rs865643, rs640336, rs621634, rs3817996, rsl051412, rs6040076, rs6040079, rs6104644, rs2206815, rs2423510, rs6074170, rs6077884, rs6040095, rs6032919, rs8183037, rs6134000, rs2057055, rs2057054, rs2057053, rs73083362, rs6040098, rs2423512, rs2179688, rs2143621, rs6108676, rs910116, rs75668019, rs2327295, rsl883800, rs6032923, rs6032924, rs6032925, rs6032926, rs6032927, rs973542, rs6077888, rs2423514, rs6040102, rslO33517, rs6074174, rs6104651, rs62187537, rs62187539, rs62187541, rs62187544, rs7274616, rs55977660, rs6131468, rs4814229, rs6042066, rs6042071, rs6033697, rs6033698, rs6042088, rs6033709, rs6033710, rs8124053, rs36018423, rs6042117, rs6042118, rsl 1087052, rs6109893, rs6109894, rs6033715, rs6042131, rs4814237, rs6042158, rs6042160, rs6033726, rs6033728, rs6033729, rs6109912, rs6033732, rs6042170, rs6042172, rs6042175, rs5019244, rs750424, rs6033744, rs4814240, rs6042207, rs6042208, rs6134916, rs6042238, rsl028508, rs2317651, rs2317652, rs6042270, rs6079133, rs6079138, rsl 1699735, rs6033807, rs3088080, rs6891, rs9575, rs6105165, rs6105308, rs6035270, rs!2625157, rs67676850, rs6050602, rs73077077, rs2422859, rs6037526, rs2236089, rs6141766, rs6141767, rs6141328, rs75744141, rs291671, rs291675, rs291695, rs291688, rs2050209, rs2050210, rs4911371, rs6057936, rs6088342, rs4911373, rs2378026, rs6059552, rsl883708, rs6059555, rs8119076, rs6142050, rs6059577, rs6142051, rs4911379, rs6141431, rs9753690, rs9753679, rs7263727, rs7264201, rs7264204, rs6142058, rs2050208, rs6142060, rs4911380, rsl 1697074, rs6142062, rs6141432, rs6141433, rs4911381,rs6141434, rs6141435, rs4911139, rsl883707, rs!883706, rsl883705, rs4012234, rs6141436,13756242423.3Attorney Docket No. 046483-7468W01(04021) rs491 1384, rs6142067, rs6142068, rs6141437, rs6142069, rs4911395, rs4911396, rs2268079, rsl054534, rs4911145, rs4911399, rs2284384, rs2300209, rs2268086, rs932388, rs2235597, rs4911148, rs2235596, rsl 1696338, rs6142098, rs4911408, rs6059685, rs6142109, rs6088408, rs6088409, rs6059691, rs6119463, rsl015362, rslO15361, rs6088411, rs6088412, rs6057994, rs6059692, rs8183502, rs6142129, rs6087567, rs6088521, rs734308, rs7261862, rsl 13721969, rs7263068, rs60517948, rsl 13240350, rs6579245, rs6120973, rs2104417, rs45563939, rs73283830, rsl010759, rs8115363, rs6060488, rs6060491, rs77480798, rsl 13522583, rsl2481228, rs6060524, rsl 118233, rs7273815, rsl2480408, rs6060535, rs7261284, rsl 1696527, rsl 11306810, rs73905926, rs2295356, rsl 13203744, rs6060547, rs6060557, rsl 1699793, rsl 1699690, rs6060564, rs56116518, rsl46367992, rs6058303, rs6060572, rs2425078, rs6058304, rs60646509, rsl 12339847, rs6060578, rs8124505, rsl 1696947, rs6060583, rs7263640, rs6060585, rsl 13014094, rsl7093026, rsl7093027, rsl3038622, rs6058309, rs45595739, rs6058310, rs6058311, rs58448091, rsl056196, rs73905955, rsl 11241953, rs6060588, rsl970357, rsl 1167275, rs79035779, rsl 17010355, rs56052651, rs57963833, rs55761608, rs36103066, rs78877130, rs2425141, rs2425142, rs2425143, rs2095818, rsl890470, rs28685274, rsl48527013, rs2425149, rs73902908, rsl 11597121, rsl 1700256, rs74785978, rs78421482, rs6060605, rsl 1696369, rs75331436, rs80156193, rs2378409, rs6060613, rs8115150, rs56904633, rs8122587, rs6060624, rs74355238, rs7273668, rsl0485510, rs7264414, rsl45839824, rs4504072, rs6060642, rs6060643, rs3787173, rs6058354, rs6060699, rs35448195, rsl 1699815, rs6060726, rs6071887, rs6028783, rs6124289, rs6124296, rs6072224, rsl 13622480, rsl2329575, rs41279278, rs2235808, rs2868095, rs3212184, rs6031587, rs6032127, rs2267868, rs79108023, rs6123359, rs209959, rs59132978, rs76792733, rsl7216707, rs209966, rsl2480880, rsl7217119, rs2274130, rs2274132, rs6091825, rs2296237, rs2296238, rs2296240, rs6091826, rs751089, rs912505, rs6127119, rs2104134, rs6123685, rs35971273, rs74324013, rs6014987, rs2236744, rs2236745, rs707555, rs4810149, rs4812042, rsl63782, rsl49265, rsl84673, rsl63783, rsl3720, rsl63796, rs3787421, rs6142696, rsl2624770, rs62207108, rs6142697, rs62207111, rsl2625155, rs2281733, rs28382100, rs2144677, rs3787428, rs3818344, rs28382047, rs28382040, rsl2624713, rs58007679, rsl886008, rs4369942, rs4266091, rs6142924, rs6142701, rs6142925, rs6142926, rs6142930, rs6142932, rs!473739, rs6142703, rs62207126, rs56806604, rs28382027, rs28382025, rs28382022, rs6142934, rs6142935, rs6142936, rs6142937, rs62204323,13856242423.3Attorney Docket No. 046483-7468W01(04021) rsl0888229, rsl 1204457, rs6142706, rs59254607, rs78331413, rs6142941, rs3746650, rs6143021, rs7269717, rs55758310, rs2379128, rs2427283, rsl 1698103, rs4925375, rs944890, rs6143024, rs6143025, rs2379120, rs200383755, rs72629024, rsl623866, rs2261092, rs6011066, rs6011067, rs2427535, rs2236510, rs6122159, rs4809331, rsl741708, rs4809221, rs2427536, rs2253823, rs2253829, rsl 1697610, rsl316200, rs6089771, rs7274760, rs6010647, rs6089979, rs6011095, rs6011096, rs8118848, rs6062344, rs6512309, rs6062357, rs7270745, rs6516366, rsl 1699915, rs79026609, rs6055748, rs8132508, rs7277968, rs62220727, rs7280197, rs2223041, rs2823024, rsl041404, rs2823029, rs2012931, rs6517199, rsl882961, rs2823139, rs6517423, rs2823271, rs2274802, rs2832158, rsl 153280, rs2409497, rs34784647, rsl7655810, rs2834317, rs2834318, rs2835256, rsl 12800821, rsl 1702405, rs78393308, rs218629, rs218632, rs218638, rs2003771, rs8134233, rs219786, rs219781, rs97959, rs364916, rs417191, rs364698, rs366381, rs375662, rs375572, rs376590, rs417173, rs387842, rs448014, rs377160, rs377527, rs377574, rs440551, rs397691, rs451163, rs451243, rs425864, rs399522, rs448482, rs397990, rs397996, rs448659, rs448849, rs415848, rs407095, rs416108, rs451370, rs451614, rs447296, rs449940, rs374314, rs365887, rs376519, rs379699, rs405582, rs442022, rs413852, rs414911, rs371189, rs415100, rs415124, rs372213, rs450183, rs409231, rs371945, rs394087, rs394110, rs382635, rs405901, rs395383, rs383609, rs428948, rs382937, rs452107, rs429326, rs452583, rs394211, rs394565, rs377284, rs445103, rs420925, rs393851, rs419941, rs7281354, rs2835428, rs2835431, rs2835432, rs2835435, rsl3048309, rs2835436, rs2845795, rs2226829, rs2269188, rsl 1909356, rs77659217, rs7275640, rs2269151, rs7281911, rs4607027, rs9985015, rs4819099, rs7281138, rs2838908, rs4819101, rs2838910, rs2838911, rsl3051228, rs2838913, rs4819104, rs35387814, rs9985044, rs8126556, rs914229, rs!0854470, rs4819111, rs755548, rs2236451, rs8133886, rs8128040, rs8128819, rs2236454, rs2274809, rsl2483377, rs2518814, rs2540644, rs4462879, rs8399, rs55813720, rsl7743432, rs55679525, rs8136354, rs!7810649, rs!7743444, rs2057754, rs73157293, rs73157294, rs2238740, rsl7810739, rs2238744, rsl7810780, rsl557846, rs6518522, rs2238751, rs2238753, rs73158820, rs7286581, rs73158822, rs73158827, rs7289180, rs916945, rs7286284, rs7284846, rs73158837, rsl 11696302, rs73158839, rs7285475, rs7285610, rsl7743642, rsl0483100, rsl47150592, rs8135308, rsl 17186487, rs9789916, rsl034728, rsl43496766, rs9789944, rs2238757, rs2238758, rs2283643, rs7285415, rs73158868, rs73158869, rsl 13672342, rs73158875, rs73158876, rs45604134, rsl052756, rs2240111, rs3765612, rs7285177, rs55754617,13956242423.3Attorney Docket No. 046483-7468W01(04021) rs55694607, rs2019746, rsl 7759598, rsl 12153746, rs61763401 , rs78907487, rs791 11189, rsl7759796, rs2329883, rsl71277, rs5759997, rs5760000, rs5760006, rs2070455, rsl2166151, rs6004074, rsl33872, rsl33885, rs2345019, rsl6986969, rs28372773, rsl 17965034, rs5763688, rsl043099, rs2267158, rs73881478, rs73881482, rsl2484511, rs75641972, rs56040857, rs5994366, rsl 1705351, rs2413030, rs2012451, rsl968023, rs5749334, rs56915796, rs9606878, rsl 81748715, rsl 12151426, rsl 11974230, rs73417750, rsl008790, rsl32645, rs56285319, rs7284379, rsl32651, rsl32652, rsl 1089781, rsl6996442, rs75183368, rs77563562, rsl0854687, rs5756113, rsl36153, rs9622363, rs2239785, rsl 15103799, rs73405714, rs58168942, rs5750556, rs4462884, rsl 1703601, rs8139974, rsl7001977, rs3827382, rsl0483205, rsl 12880707, rs73167093, rs73169098, rs5758066, rs5758069, rs5758071, rs5758072, rs5758077, rs!38303, rsl38311, rsl38319, rsl2165496, rsl38323, rsl38326, rsl38335, rsl38346, rsl38347, rsl38352, rs5758153, rs78831364, rs62240993, rsl29853, rsl33315, rsl33319, rsl33337, rs4820461, rs4820462, rs6002697, rs2071774, rs4820463, rs8135582, rs5996145, rs4422240, rs8142511, rs6002708, rs4822119, rs2413686, rs8141792, rs4822120, rs9607893, rs9611782, rs9611784, rs4822121, rs9623573, rs2294361, rs2294362, rsl2484310, rsl 1090090, rsl 1090092, rsl 1090093, rsl0854752, rsl 1090094, rsl 1090095, rs6002712, rs6002715, rsl057157, rs2413687, rs2092175, rs9607898, rs733278, rs6519319, rs2413690, rs8141826, rsl30395, rs738527, rs3887474, rsl2170295, rs62228096, rsl 1913069, rs62241216, rs79865452, rs361725, rsl31789, rs6735658, rsl 15926946, rs4614909, rs6432054, rs34333438, rs34368289, rs34060506, rs35384393, rs71413895, rs57069400, rsl062062, rsl345302, rs2310243, rsl3405355, rsl0179654, rsl2476968, rs6543118, rsl558619, rs76520363, rsl0439410, rs6731157, rs6745614, rs6758936, rs2270298, rs2041739, rs2080289, rs3771162, rs7556917, rs7584093, rsl 1465633, rs3213732, rsl0204757, rs7591246, rs6760621, rsl 1465641, rsl 1903946, rs6706002, rs6749014, rsl2712146, rsl420097, rs4851004, rs6732138, rs2287035, rs!7027071, rs3732126, rs3732125, rs!7027087, rs6710528, rs3732124, rs3732123, rs4851571, rs4851572, rsl035129, rs7594402, rs6710034, rs7589142, rs6543127, rs4851576, rs4851577, rs4851579, rsl592459, rsl592458, rsl035125, rs2160201, rsl833174, rs2293224, rs6743516, rs3771156, rsl420100, rs3771155, rsl0206291, rs885088, rs3771154, rs6759479, rs3755266, rs2110659, rs7559845, rs6726985, rs2310300, rs7581119, rs3755265, rs4479442, rs2058659, rs6734762, rsl 1465721, rsl 1465728, rs918000, rsl523206, rsl523205, rs78136548, rs77375846, rs3206843, rs79441289, rs62118909, rs2515391, rs2515392,14056242423.3Attorney Docket No. 046483-7468W01(04021) rs2441375, rs2251876, rs3820738, rs2515401, rsl 800930, rs2515402, rs3180234, rs3180235, rs2515403, rs2472188, rs957201, rs768627, rsl2475161, rs4849146, rsl0206428, rsl2469822, rs4849150, rs4145013, rs4145014, rsl 1123169, rsl2619508, rsl446246, rs7560701, rsl0864911, rs4849188, rsl 1689813, rsl374162, rs6707245, rs6720637, rsl0177634, rsl0175325, rsl0186105, rs4413174, rs9973599, rs6741265, rsl0210018, rs6723391, rs6723502, rs2716615, rs2581066, rsl7668924, rsl40179699, rsl 1893187, rsl7713396, rsl3422707, rs79154857, rsl7050272, rs6706968, rsl 1288732, rsl7005869, rsl 1122844, rsl 1122845, rsl 1885850, rsl81977837, rs72842369, rs4848692, rsl 1122848, rs34013653, rs61362138, rs34773350, rs6734261, rs3768903, rs36096257, rs2713245, rs613828, rs643796, rs487404, rs842354, rs7573390, rsl0171371, rs6728095, rs71348712, rsl3399952, rs6705916, rsl0193171, rs6739706, rsl2691869, rs4328685, rsl0210052, rsl 1688414, rs6745983, rsl l23184, rsl 1898465, rs4954161, rs6741007, rs6741637, rs6751833, rsl 1883531, rs6760237, rsl0496731, rs7608700, rs3739029, rs6729702, rs6430543, rs6430545, rsl992764, rsl530557, rs56383182, rs6430546, rs6730306, rs6758113, rs60793693, rs6430547, rs6430548, rs4954191, rs9653175, rs9653176, rsl0928521, rs6430552, rs74265412, rsl2469941, rs6430553, rs4954192, rs6738113, rsl2473839, rs6430554, rsl348790, rs2053727, rs62168869, rs6430555, rs74265413, rs55865348, rs6714498, rs7589297, rsl374292, rsl0176573, rsl348792, rs62168872, rsl2469411, rsl0928523, rsl374288, rs766271, rsl374287, rs2322251, rs62168891, rsl2151827, rsl2463645, rsl374289, rs3814355, rs3814354, rs56271357, rs4954585, rs4954588, rs6708702, rs77608322, rs74830256, rs79164567, rs79234446, rsl89352109, rsl371044, rsl0928355, rsl344980, rs7582403, rs2113794, rsl2987286, rs2627025, rs7598361, rs77964389, rsl 1889610, rs4664475, rsl0172023, rs58903550, rs6712533, rs34577613, rs4300824, rsl0165921, rs807624, rs7567320, rs7596796, rs7597232, rsl3399671, rs62114735, rs72768982, rsl0016, rsl3390359, rsl0182297, rsl0184861, rs72997116, rsl3416455, rsl 1688793, rsl0196949, rsl0174267, rsl3410936, rs!3397887, rsl3398569, rsl3398901, rs6744604, rsl2694970, rs2356510, rs34525522, rsl807921, rsl0194836, rsl0175732, rsl3393248, rsl403289, rsl3428776, rsl2694974, rs6437206, rs6719412, rsl 1683839, rs448513, rsl 16650458, rsl 1689799, rsl 1689800, rs2357772, rsl3397529, rs4347774, rsl2987408, rsl3015591, rsl0048715, rsl2692605, rs75166367, rs4664452, rs3788973, rs!3386912, rs6706926, rsl2467922, rs78472008, rs!2477178, rsl6846368, rs2284867, rs77372562, rs2300750, rsl6846375, rs6748542, rs6735909,14156242423.3Attorney Docket No. 046483-7468W01(04021) rs6759558, rs4664453, rs4664454, rsl 6846386, rsl 6846387, rsl 2473366, rs74378743, rsl6846389, rs3827491, rsl6846391, rsl0439290, rsl6846396, rs4338976, rs3788970, rs6746339, rs3788969, rs76099239, rs77335736, rs4664050, rs4664051, rs76818513, rsl 17759694, rsl 17027526, rsl 12075616, rs75229796, rsl2471175, rsl2471176, rs78455346, rs3788968, rs3788966, rsl 1886710, rs3761654, rsl2475870, rsl 1901711, rs74493538, rs75204721, rs78372490, rsl 125604, rsl 125605, rs4664457, rs76701499, rs3761652, rs7558987, rs2111486, rs918161, rs41463049, rs76267308, rs2287292, rs2287293, rs7590692, rsl3431848, rs6734769, rsl2464391, rs7602311, rs4664460, rs7565446, rs6718470, rsl2476567, rs4664462, rsl0439256, rsl6846585, rs58375444, rs57983132, rs58990349, rs2163215, rs59482537, rs77826516, rsl2469260, rs78222827, rs4667699, rs720643, rsl0497240, rsl0194498, rsl0211437, rsl0204297, rsl0168136, rsl0198504, rs!0210208, rsl0200983, rsl0210320, rs6749070, rs6708983, rs6749350, rsl3425312, rsl3389619, rs4422157, rs7571002, rsl3388721, rs60444855, rsl3399614, rs2340763, rs28670483, rsl6982470, rsl6982472, rs7570487, rsl2997119, rsl2475700, rs573225, rs504979, rs473351, rs575671, rs531772, rs565412, rs567074, rs479682, rs2685804, rs862662, rs853778, rs864929, rs35472707, rs68155726, rsl6856530, rs34355135, rs2302695, rsl7848164, rs2052298, rs2052297, rs2052296, rs62172631, rsl 1886318, rs62172632, rs7600336, rs2300447, rs2300446, rs2193195, rs2193194, rs2193193, rs2216239, rs3815572, rs2268370, rs9283479, rs9646731, rs4606889, rs4302191, rs6719440, rs6747692, rs2268369, rsl 1902433, rs34951037, rs2075246, rs982810, rs6433109, rs4668126, rs4668128, rs2302693, rs3821127, rs3821128, rs2239594, rs4668129, rs831040, rs831041, rs831042, rs2075255, rs2075254, rs831043, rs831044, rs56168972, rs57516605, rs831046, rs!096455, rs830956, rs830957, rs830959, rs830960, rsl421509, rs2241190, rs830983, rs3770637, rs6730118, rs747051, rsl6863549, rs863678, rsl3403839, rsl87355703, rsl348807, rsl520399, rsl607714, rsl402107, rsl520394, rs2222312, rsl033304, rs2139615, rsl005932, rs!3422369, rs!3403148, rs!992909, rsl251034, rsl251033, rs371695545, rsl513881, rs6706601, rs9789353, rs6705298, rs2364723, rs34551701, rsl7524059, rsl7400505, rs77480831, rs73034339, rsl 11373815, rs4491754, rs56065555, rs55831332, rs2276620, rs2276619, rs6734446, rs73034346, rsl 13926414, rs79747558, rs76786892, rs6736173, rs6736304, rs74812381, rs3731758, rsl0497515, rsl0497516, rsl45909820, rsl47804436, rs76781627, rs3816073, rs3765020, rs!6866323, rsl 16706874, rs78732561, rs73034359, rs79833237, rs73034362, rs75444105, rs73034364,14256242423.3Attorney Docket No. 046483-7468W01(04021) rs74981487, rs76274069, rs77266660, rs75894529, rsl 12902513, rsl 11989862, rs7584420, rsl82984727, rsl39426962, rs74738571, rsl2612917, rsl2616943, rsl 12749525, rs77498914, rs73034377, rs79673893, rs55714261, rs56357262, rs56233214, rs55821514, rs!40098008, rs77011751, rsl2615980, rs79399438, rsl l4460022, rsl2619401, rs3731756, rs6757474, rs6757481, rs75341252, rs74787974, rsl2613303, rsl85591978, rs77852792, rs74852352, rs76415010, rs73036332, rsl2613131, rs56165369, rsl 14914284, rs79276358, rs2195070, rs56367852, rs74735544, rsl 15855673, rsl 16146339, rs77079077, rsl2621108, rs72629796, rsl6866373, rs3829748, rs202214630, rs55675869, rsl 14248026, rs72648257, rs56145100, rsl2621078, rs56214710, rs3813247, rs3731745, rs56018860, rs3813246, rs3813245, rs744426, rs2288570, rs72646874, rs56372427, rs55706598, rs72646865, rsl560221, rs72646834, rs28715837, rs28378468, rs35833641, rs2288568, rs!3009158, rsl0930832, rs2303832, rs2303831, rs2288566, rs72677248, rsl6866416, rs55658446, rs72677228, rs2303829, rs72677219, rs2366752, rs56285382, rs56352103, rs55639922, rs75328144, rs72650085, rsl6866425, rs7590037, rs2288563, rs55847232, rs2742324, rs2562843, rsl569407, rs2243452, rs2742358, rs2246932, rs2562844, rs7606485, rsl366677, rs2742356, rs2562846, rs2742354, rs2562847, rsl0204913, rs2163008, rs2562848, rs2562849, rs2742353, rs2562850, rsl0221760, rs2742352, rs2252353, rs2252350, rs545894786, rs2742350, rs2742349, rs4894034, rs2627039, rs2562851, rs2627038, rsl3417645, rsl 13059495, rs2366753, rs2742345, rs2742344, rs2742343, rs2742342, rs2742341, rs4893852, rsl0203085, rs2742340, rs2742339, rsl0179811, rs2742337, rs2742336, rs2562842, rs2627034, rs2742335, rs2742334, rs2742333, rs2742332, rs2562841, rsl0176708, rsl3398235, rs2742330, rs2627044, rs2562837, rs2562835, rsl0183237, rs2742329, rsl0183361, rs2562833, rs2562832, rsl6866473, rs!7355446, rs2562852, rs2562853, rs2243804, rs2255480, rs2627042, rs2562854, rsl 1888217, rs2627037, rsl0497519, rs922984, rsl7355623, rs3754953, rs74805196, rs7585334, rsl0171049, rs4894037, rs2291309, rs2291310, rsl l895382, rs77841333, rs7604033, rs!6866519, rs4894040, rs7572955, rs4894041, rs2291311, rsl484120, rs2291312, rs4893853, rs72647888, rs72647887, rsl905520, rs4894048, rsl0221590, rs2054708, rsl0497522, rs7423101, rsl 1897386, rsl 1892354, rsl3421990, rsl2465449, rs72959397, rs4666979, rsl962724, rsl0451546, rsl0930990, rsl594617, rs72897100, rsl7343318, rsl0803955, rs6740226, rsl0166086, rsl 13254009, rsl965090, rsl2473989, rsl0166852, rsl6985161, rs6743746, rs858745, rsl706287, rsl !91809, rsl 191811, rs62109431, rs3769760, rsl513830, rsl44505847,14356242423.3Attorney Docket No. 046483-7468W01(04021) rs72932770, rs72932772, rs79633844, rs75141346, rs72932774, rs72932777, rsl 15628302, rsl43805266, rs72932780, rsl 14520702, rs7608755, rs72934751, rs6738618, rs72936838, rs72936839, rs72936842, rs72936847, rs72936870, rs72926769, rs72926800, rsl 15194657, rs72928613, rs2351524, rs72932588, rs72934512, rs72934519, rsl 1679740, rs889895, rsl 13889746, rs2709399, rs2709404, rs2709378, rs2709381, rs2286963, rs2287603, rs!0932343, rsl047883, rsl0804186, rsl0469763, rs4673543, rsl047891, rs715, rsl836744, rsl836742, rs6727172, rsl3025037, rsl595066, rsl 1895168, rsl595065, rsl595064, rsl972820, rsl836724, rsl2475523, rs4672612, rs934607, rs3791689, rsl836719, rs6728196, rs4673615, rs6710253, rs7561756, rsl3409566, rs9288430, rsl0497944, rsl0165449, rsl3395652, rsl0206846, rs9808028, rsl816531, rsl7804031, rsl0166172, rsl546718, rsl546719, rsl0185271, rsl533768, rs4638732, rs4563169, rsl 1682538, rsl 1682541, rs56111964, rsl 12905092, rs3768788, rs62189579, rsl0209675, rs3754590, rsl548945, rsl 1892032, rs2541385, rs2712169, rs7587010, rs2712184, rsl6856812, rsl2477491, rsl0932690, rsl6856934, rs4996257, rsl7462630, rsl0165754, rs73991530, rs73991535, rs73991536, rs907683, rsl 12068790, rs3755061, rs6747041, rs75478462, rs34799600, rs2840128, rsl 190117, rsl2694684, rsl0933114, rs79615915, rsl0933136, rsl0933138, rsl2694695, rsl 15857843, rsl 38130641 , rsl 15550436, rsl 14581794, rsl 16668967, rsl 15711654, rs34011391, rsl 16110773, rsl 16707100, rsl 16077538, rsl43748652, rsl 15673859, rsl 16722768, rsl 14833301, rs35669853, rsl40788792, rsl47430803, rs79653224, rsl50181834, rsl 16345901, rs78248499, rs79609806, rsl 14710433, rsl41508977, rsl 15753606, rsl 15093628, rsl 16430125, rsl42253580, rs74602746, rsl 15062063, rsl41507217, rsl43986050, rs76720531, rsl 16077429, rsl50845292, rsl 14874036, rsl49346355, rsl43845678, rs76216629, rs80037833, rsl 15305921, rsl6867027, rsl544673, rs7591557, rs6436885, rs7599184, rsl0933311, rs6436892, rs7602607, rs7579744, rs62193693, rs3731783, rs6854, rs6748332, rsl0185032, rs7608781, rs62193695, rsl3411443, rs!6827740, rs!2694886, rs3769990, rs78890542, rs7581418, rs7564129, rsl3430145, rsl3416929, rs55637820, rs2288147, rs60563689, rs6741145, rs2303353, rs7559702, rs2007131, rs906879, rsl3411316, rs2303357, rsl2619336, rsl0197001, rs2161892, rs7595464, rsl3394402, rsl0199752, rs6437000, rsl0194776, rsl6827801, rsl549339, rs7607338, rsl0187149, rs765458, rsl2469673, rsl0498257, rs59886388, rs7565408, rs3754981, rs57481522, rs62193731, rs7585887, rs!035620, rs2175147, rs3769989, rs6437001, rs4350740, rs6707708, rs4635521, rsl 1893395,14456242423.3Attorney Docket No. 046483-7468W01(04021) rs555015462, rs6437003, rs2303351, rs2303350, rs2303349, rsl 025107, rs2032953, rs6706191, rs6755467, rs6727422, rs6727962, rsl6827840, rs6739959, rs61332549, rs60445047, rs56295567, rs56161330, rs55878747, rsl0169827, rsl0206322, rsl0179264, rsl0202608, rsl0202782, rsl0202806, rs6437004, rs6738687, rs62197317, rs7565313, rs7606037, rs6761645, rs6437005, rs28690417, rsl2465438, rsl2465477, rsl0187005, rsl3423632, rs9750018, rs7598728, rsl0181630, rs6437008, rsl6827879, rs72983683, rs7569597, rs7584535, rsl2612219, rslO173555, rsl0177091, rsl2612801, rsl 1897387, rsl3415839, rsl3418595, rs62197345, rs7604042, rs55782278, rsl3428268, rs3731779, rsl2623587, rsl0201323, rsl 1686251, rsl3013142, rs6738386, rs36007169, rsl2987513, rsl0933409, rsl801251, rsl044480, rs838718, rs2278743, rs2278742, rsl0192297, rs2278738, rs934780, rs4665785, rs72810076, rs6728919, rs55799006, rsl3023418, rs56185549, rsl85521632, rsl 13304336, rs72801806, rs72801857, rs72801877, rs528043291, rsl260326, rs3817588, rs780092, rs814295, rs74928908, rs6744393, rs62131879, rsl0181342, rsl 16443177, rs62131881, rs62131882, rs62141278, rs62141279, rs2384627, rs62141281, rs6751087, rs62141290, rs62141291, rs62141292, rs60854669, rs965813, rs59876138, rs3811644, rs62138963, rs62138964, rs76013440, rs62138965, rsl919129, rs56725354, rs62138968, rs2141372, rs6719960, rs6547735, rs78170284, rsl 881395, rs7571558, rsl 881396, rs76586169, rs72613829, rs4665385, rs4665386, rsl881394, rs6745545, rsl3021718, rs888096, rs6717584, rs2160237, rs759384, rsl 1888123, rs2160236, rsl92040601, rs2301343, rsl3418865, rsl3035419, rs4952553, rs4952558, rsl 1685920, rs34120829, rsl2998882, rs35708913, rs4952588, rsl2623480, rsl2617964, rsl2614953, rsl49290349, rs7933, rsl 12694524, rsl 13542380, rs80323638, rsl49274878, rsl 13986438, rsl 14904276, rsl 11274231, rs77470734, rsl51004942, rsl49397893, rs41281455, rsl 13866579, rsl 14510001, rsl7030645, rsl 11539718, rs77288440, rs74814053, rs6748690, rs74382177, rs6722143, rs6707060, rs6743071, rs28470852, rs76215753, rs78681698, rsl 12972772, rs79629200, rs74469180, rs78314405, rsl 11947872, rsl3408002, rs76675804, rs74616425, rsl 1899863, rs79165612, rs78886764, rs76684055, rsl7030798, rs7609256, rs77059113, rs7556744, rs77620935, rsl2105394, rs77527404, rsl7406646, rs7599781, rsl2105626, rsl2105710, rsl7030818, rs6752448, rs76282560, rs7572923, rs7599799, rsl7030835, rs6746058, rsl7030845, rs77377889, rs7561287, rsl7030855, rsl7030859, rsl7039133, rs75330033, rs80147536, rs77101426, rs75135247, rsl7030890, rsl7334919, rs6746632, rs6747229, rsl7030925, rs77389971,14556242423.3Attorney Docket No. 046483-7468W01(04021) rs75607314, rs78497923, rs75386849, rsl 3422551, rs75097983, rs72865267, rsl 12282947, rs6544664, rs6544665, rsl 11753823, rs6708735, rs6737882, rs6544666, rs6544668, rs7578597, rs7564886, rsl7030946, rs6757251, rsl3405076, rs6544669, rsl388387, rslO18OOO5, rsl3405776, rsl3419380, rs7597135, rs7570748, rsl0169346, rs74821293, rs74600494, rs77791126, rsl0189235, rs76851696, rs79271345, rsl7030967, rs75514072, rs6751035, rs6751161, rs6726643, rs6726917, rs6752964, rsl 12340521, rsl 11898797, rs7591387, rs74907855, rsl7031000, rsl l l783562, rsl l3156595, rsl 12813837, rsl l4563746, rsl l2416866, rs77852659, rs77972916, rs75275342, rs78572881, rsl 12387154, rs77787499, rs76856054, rs77981966, rs77552263, rsl 11239033, rs78070307, rs79111706, rs4952996, rs62136376, rsl2621907, rsl2623703, rs6544743, rsl0174537, rs8410, rs62134207, rs56077086, rs4953152, rs687914, rsl 1684301, rs!867784, rs4952818, rs!447563, rsl2991646, rsl3010062, rs4567978, rs3813463, rs7566809, rsl0865282, rs6751866, rs941351, rs941352, rsl405833, rsl0182366, rsl527649, rs4459768, rs62134681, rs60113783, rsl3004944, rsl0454749, rs62165173, rs7582278, rs55761024, rsl058582, rs62165183, rs62165184, rsl7798852, rs35504023, rs7594279, rs782649, rs782650, rs782652, rs2627777, rs2627776, rs782567, rs782568, rsl0460508, rs2586954, rs2627779, rs4672074, rsl346783, rs7572523, rs2540917, rs243066, rs243061, rsl2614829, rs34532102, rs6736527, rsl0210126, rsl477040, rsl0189261, rsl0179846, rs6738988, rs6715876, rs75716079, rs72894568, rs78683917, rs61748094, rs61741513, rsl3431750, rs78287130, rs61330787, rs80153345, rs74402094, rs79599301, rsl49632984, rs268120, rs268134, rs77909321, rs268124, rs6740462, rsl39736529, rsl88158341, rs6738144, rs2280334, rs4544423, rsl 1686555, rsl2469835, rsl367478, rs9309401, rsl2105010, rs80280585, rs6748323, rs34684423, rs2418652, rs7584322, rsl7663700, rs55655347, rsl 1685700, rs759219, rsl 1678537, rs72832771, rs3771385, rsl38505214, rs80265494, rsl48002684, rs2421546, rs2421548, rs6730785, rs75761701, rs!881246, rs75821812, rs!2996463, rsl47086810, rs7571243, rs75361602, rs7600268, rs58830031, rsl528169, rs7598901, rs6749680, rs78777626, rsl 14415559, rs2091504, rs2091503, rs4852930, rs4852306, rsl45017004, rsl42800387, rs780395, rs780394, rs780393, rsl083923, rs780391, rsl083922, rs533493159, rsl083921, rsl88245139, rsl083919, rsl l4534317, rs7585119, rs7562047, rsl0189578, rsl42579560, rs7606483, rsl0865398, rsl 1688718, rs78003072, rs6729468, rs6744697, rsl3386124, rs6757996, rs62153184, rsl l l26402, rsl l4474332, rs7566315, rsl0190002, rs34927702, rs35760114, rs!40081968,14656242423.3Attorney Docket No. 046483-7468W01(04021)rs78444017, rs6727745, rs6745560, rs4852308, rs4346412, rsl 3009035, rs56658499, rs2421664, rsl3007607, rsl3022145, rs4852950, rsl3410232, rsl3018422, rsl3017182, rs79105219, rs6546867, rs4852963, rs7570683, rs2421582, rs2421583, rs2421584, rs2421586, rs7574240, rs7574268, rs72840111, rsl47704304, rsl49256246, rs34063934, rs56287599, rsl0208670, rs2969473, rs76229410, rs3772534, rs80040728, rs75820797, rs2289746, rs2301033, rsl 17321738, rs75831288, rs78619967, rsl2633175, rs795010, rs794999, rs7638232, rs7616006, rs7650082, rs7650294, rs9810259, rsl2491937, rs7641325, rs7611913, rs9289172, rs9812515, rs6765799, rs9810707, rs2257120, rs2257123, rsl882000, rsl847029, rsl2487598, rsl2496722, rsl3573, rsl053738, rs6438885, rs9289245, rs9857356, rs4450756, rsl607238, rs6772299, rsl999919, rsl999921, rs6781706, rs4234274, rsl868121, rs6762969, rsl868123, rsl868124, rs9879085, rs4679211, rs4679212, rs9813319, rs9870993, rs6795157, rsl374804, rsl992854, rsl992856, rsl992857, rsl868134, rsl3082246, rsl868135, rs4468935, rsl868136, rsl545381, rsl2695477, rs4679215, rs7622374, rs4679216, rs4679106, rs4679107, rs9865898, rs9828100, rsl 1914692, rsl968631, rsl968632, rsl530638, rsl530639, rsl 1720893, rs6765882, rs6768502, rs6781332, rsl447660, rs4679217, rsl 1916122, rsl 1920239, rs6438987, rs6438988, rs75348895, rs9865381, rs9865548, rs9880453, rsl 1712581, rs61606491, rs67177961, rs34871776, rs6798887, rsl 1719501, rsl2629398, rs9881832, rs9874893, rs34366795, rs4034942, rsl2631514, rs9809596, rs6810325, rs7650482, rs4642101, rs61664354, rs73027016, rsl500112, rs2369796, rs4854645, rs80120242, rs66564593, rsl0935111, rs9881242, rs59473547, rs7433301, rs2400272, rs76032120, rsl 16489422, rs74954362, rsl 11699702, rs4974494, rs4974485, rsl603824, rs35951257, rs4974496, rs2133307, rs34341902, rsl498731, rsl 111516, rs7643419, rs75705309, rs4974497, rs2400278, rs77863955, rs77820313, rs9450, rs78506634, rs74910485, rs6439478, rsl3075185, rs3773820, rs7629849, rs80040468, rs6798709, rsl 1925583, rs7623024, rsl 138273, rs7427492, rs7372770, rs!357762, rsl2637751, rsl 1927068, rs9289478, rs6768323, rs!880376, rs!880377, rs35933983, rs9827987, rs35718987, rs9832633, rsl40983487, rs7374325, rs4309773, rsl3089966, rsl3065773, rs9815894, rsl534028, rsl534027, rsl534026, rs55913793, rs4955555, rs6769885, rs4539979, rs4367113, rs9819532, rsl3081177, rs6439492, rs4572812, rs2373865, rs36006513, rs7630874, rsl0804632, rs56899746, rs6782563, rsl 1919458, rs62271513, rs62271514, rs6793487, rs4535272, rs4368544, rs4423809, rs62271515, rs4245902, rsl41367948, rs6771298, rs6774795, rs9714039, rsl3090969, rs6808670,14756242423.3Attorney Docket No. 046483-7468W01(04021) rsl 3071551, rsl 534025, rs9857242, rs9857995, rs4955525, rs4245903, rs7648616, rs4955534, rsl880374, rsl880375, rs2293293, rs2293294, rs6806810, rs9839705, rs9824185, rs4074521, rs4074522, rs2888670, rs4318591, rs4605591, rs4955542, rs4245905, rsl3075253, rs6779294, rs6779326, rsl534030, rsl534029, rs9848254, rsl880379, rsl880378, rs7623567, rs7633868, rs6764764, rs9838119, rs9838467, rs9838889, rs9838621, rs4955544, rs4955545, rsl3098546, rs4306899, rs4634170, rs4435682, rsl 1915964, rsl3089566, rs6763188, rs58491661, rs6775611, rsl868164, rs9883955, rs4678361, rs9840812, rs4431046, rs6767060, rs687339, rs684773, rsl278719, rs576771, rs56265409, rs6778297, rs66716710, rs2607775, rs2733550, rs9879434, rs7624084, rs6763931, rs724016, rs295300, rs4234470, rs3804771, rs4315664, rsl2495978, rs3811708, rs62283132, rs35787200, rs34280182, rs6794342, rs7635444, rs347686, rsl43710547, rs6440132, rs6776634, rs834906, rs6803862, rs62276843, rsl617267, rsl713842, rsl713846, rs938989, rsl727919, rsl713847, rsl727917, rs9840371, rs9844496, rsl629659, rsl358405, rsl527799, rs6440935, rsl727958, rsl727946, rsl727944, rsl727940, rsl624917, rsl713839, rsl713831, rsl727882, rsl713829, rsl727883, rsl727884, rs7647694, rs6769099, rs921318, rsl358403, rsl713822, rsl542254, rsl727957, rsl470663, rsl727954, rsl727953, rsl727952, rsl713817, rsl713815, rsl713813, rsl632688, rsl713811, rsl527800, rsl727949, rsl 713810, rsl727948, rsl727947, rs2695845, rsl727945, rsl713807, rs357488, rs357482, rs357480, rs357479, rs357477, rs357476, rs357473, rs357471, rs357468, rs357466, rs357465, rs401162, rs447429, rs398512, rs436852, rs454837, rs365119, rs377565, rs449361, rs437396, rs450115, rs453699, rs407060, rs56916293, rsl657621, rs896016, rs2689330, rs2596629, rsl84825, rs357506, rs357494, rs357495, rs242577, rs357497, rs357498, rs357499, rs760066, rs3817641, rsl3092272, rs34208188, rs4679797, rs2316337, rsl 13294272, rsl 13578858, rsl822397, rs66628080, rs56978441, rs60053317, rs73160604, rs75988348, rs74321159, rs553984210, rs9637450, rs73172091, rs2051076, rs2178175, rs9843242, rs9872796, rs74330815, rs!83363267, rs6791781, rs3774046, rs9828378, rs9837316, rs9841632, rs950644, rs36077239, rsl 1925227, rs56297506, rs3749234, rs7613970, rsl43867505, rs7651346, rs4686682, rs62291882, rs62291883, rs62291884, rs6807927, rs6783023, rs6785918, rs6762208, rs34619288, rs6791954, rs6803426, rs4568175, rsl3076556, rsl3061708, rs7646818, rsl3080101, rs4687477, rs7613002, rs9880232, rs35693823, rsl41465286, rs73175567, rsl3076013, rs6799330, rs6789741, rs2194411, rs73175602, rs4686710, rs4321562, rs!6860324, rs2247511, rs2247622, rs2251407, rs59950016,14856242423.3Attorney Docket No. 046483-7468W01(04021) rsl 0937233, rsl 0937234, rs9844949, rs3821815, rs5029970, rs61211338, rs61605278, rsl 11444674, rs2713721, rs577650, rs534834, rs78158637, rs76598712, rsl48422661, rs9823161, rs6777647, rs4635652, rs34967245, rs842225, rs79229020, rs76153126,rs34468408, rs6796626, rsl 1717090, rs2019472, rsl2631126, rs35260201, rs59171696, rs3796263, rs41284057, rsl3099700, rs2341225, rsl2631361, rsl3066853, rs2341184, rs7649443, rs35136822, rs34381158, rs6797085, rs6782349, rs2044861, rs2044860, rsl0461048, rsl0489880, rs6805920, rsl3077565, rs36035383, rs7624684, rs7624764, rs61394945, rs35112822, rs2340433, rs62282105, rs35665404, rs7619429, rsl073726, rs6800383, rs3903682, rsl3067147, rs6779689, rs34305944, rs6782876, rs3915512, rsl3085450, rs9840653, rs2929415, rsl89267552, rs2195919, rs2306623, rs2306856, rs905456, rs6800284, rs2070988, rs7372545, rsl3058903, rs2268759, rs35795531, rs2370860, rs2293307, rs28362645, rsl3078962, rs60889002, rs59889656, rsl2637881, rs784504, rsl49636734, rsl459250, rsl40502640, rs34293138, rs77495508, rsl42922893, rs28457212, rs4549265, rsl 12223611, rsl7051799, rs75353842, rs9827917, rs9838294, rs9838994, rs72951472, rsl 12642536, rsl 12279311, rs9826664, rsl3433728, rsl3433729, rs9881844, rs9838942, rs9839608, rsl l2329483, rsl3325153, rsl l2684399, rs9311470, rs36101994, rs7644763, rs2581815, rs9865094, rs9831409, rs7431952, rs9822734, rs9827052, rs28445246, rsl554125, rsl554127, rs6924, rs4681675, rs6445969, rs6445971, rs7610449, rs6445972, rs6445387, rs3774729, rs2037119, rs888406, rsl l721099, rs35667547, rs7039, rs58317931, rsl0510989, rs4990333, rsl427431, rs725699, rs4855441, rsl7006384, rsl7006395, rs73838648, rsl946426, rs62253045, rs28433034, rs62253051, rsl 1716109, rsl3097379, rs6777363, rsl3078066, rs7624235, rs7634376, rs7626717, rs7626718, rs7636802, rs6768731, rs6795463, rsl 1916348, rsl3080248, rs34165775, rs35017084, rs62251038, rs7613400, rs6778747, rsl529585, rsl3093918, rs35879809, rs9825822, rs9864805, rs9864949, rs9826548, rs6805563, rs6794889, rs6805924, rs6795249, rs6782552, rs6805945, rs9819188, rs9819504, rs9823839, rs!7638562, rs62252216, rs62252223, rs6804686, rs35759074, rsl2330279, rs35022873, rs62252236, rs62253173, rsl544978, rsl 1921388, rsl 1923382, rsl3071701, rs6793179, rsl 1919798, rsl49617956, rs7632921, rs7640614, rs4676901, rs6803815, rsl3074432, rsl3356, rs9828396, rs9834197, rsl436640, rsl3324964, rs6784619, rsl3066793, rs9845274, rs7614330, rs671779, rs704570, rs793490, rs2066702, rsl229984, rsl 1097693, rs28642089, rs2866203, rs28377022, rsl7029816, rs2903212, rs2866206, rsl3107325, rs78573682, rs223413, rs223401, rs223374,14956242423.3Attorney Docket No. 046483-7468W01(04021) rs223361, rs9991335, rsl 7035289, rsl 703531 1, rsl 1729069, rs2285720, rs57706909, rsl46360190, rs4290953, rs28522981, rs71606723, rs2390618, rs2893068, rsl072812, rs35843717, rs2139279, rs28705107, rs34111198, rs59861313, rsl850755, rsl3131552, rs6823887, rs6824326, rs34160919, rsl 1737613, rsl2641036, rsl 1723434, rs34086220, rs35744795, rs2049030, rs4605669, rsl028199, rs62312781, rs62312783, rs7697724, rsl 12249356, rsl6997944, rs7435527, rs75364706, rs79256711, rsl588463, rs7440006, rsl877066, rs4834156, rs7668501, rsl899548, rsl41876725, rs4560418, rsl443060, rs6850366, rs2120089, rs4016, rsl0006368, rs6534691, rsl216412, rs6534695, rsl967173, rs72719173, rsl39323761, rs28925904, rs67175590, rsl86017233, rs6850598, rs6535925, rs547507408, rs34267163, rsl0939692, rsl 1734663, rs994595, rsl354676, rs6449381, rs2874338, rs374595728, rsl075227, rs2643437, rs2616466, rs2643436, rsl382094, rs2616464, rs985935, rs2643435, rs2616473, rs2643453, rs2658124, rs6827524, rs9685330, rs973444, rs6815911, rsl7495325, rsl0461115, rs6816592, rs4434249, rs28694806, rs28452967, rs28648686, rs74715443, rs28811985, rsl076962, rsl0003400, rsl 1938354, rs34168360, rsl0017181, rsl0003288, rsl0213306, rsl585640, rs73804848, rsl7572286, rs35631011, rsl3120568, rs55944055, rs2970886, rs2970887, rs7667050, rs4361373, rs2970866, rs2946388, rs79618052, rs73249870, rs6825446, rs6847438, rsl0939141, rsl2644232, rs6830016, rs6831605, rsl0939142, rsl0470822, rs7658174, rs6448487, rs28454570, rsl0939144, rs4692137, rs2798282, rsl 11065364, rsl0024987, rsl3108218, rsl6844401, rs75501914, rs3860067, rsl68088, rs337643, rs2126526, rs34075114, rs62294474, rs337626, rs36071400, rs35547424, rsl 1947292, rs35771878, rs4634234, rsl 1727467, rs4833078, rs337602, rs337609, rs9522, rs302933, rs302935, rs302937, rs4975037, rs302948, rs278941, rs278937, rs35529250, rs4368643, rs4455452, rs4861125, rs9291207, rsl 1937643, rsl 13364695, rs56102337, rsl 1722932, rsl7611143, rsl840630, rs2768976, rs2768975, rs55839120, rsl0866421, rs6817395, rsl2233879, rs62325220, rs61015316, rs62325227, rs62325228, rs!2505040, rs6855607, rs62323567, rs62323568, rs62323569, rs62323589, rsl383180, rs2279252, rsl3141048, rsl3135890, rsl460989, rsl7804499, rs72649118, rs72655601, rs56049812, rs907446, rs72657825, rs4272041, rs7679463, rsl0023335, rs9992101, rsl 1724003, rs60529470, rs55940751, rsl7253722, rsl398016, rsl7319721, rs28418670, rsl398018, rs28394165, rsl0025351, rs4859681, rs4859682, rs2137154, rs2137153, rs2137152, rsl3146355, rs4318673, rs7675217, rs28687959, rs9992088, rsl l34124, rsl2509595,15056242423.3Attorney Docket No. 046483-7468W01(04021) rsl 6998073, rsl 1730582, rsl 17078377, rs2725221, rs2231142, rs4647939, rsl 680060, rsl250111, rsl7378658, rs28502775, rsl7379209, rs3805301, rs2639793, rs2555216, rs5002909, rs5002910, rs5002911, rs774993, rs774992, rs774989, rs774988, rs699861, rs38O53OO, rs902980, rsl0020710, rsl0019354, rs2639795, rs7683990, rs3805283, rsl0000208, rsl0213504, rsl0025074, rs2510771, rs28416638, rsl 13587193, rs9307144, rs6812098, rs5013417, rsl2639887, rsl43324366, rsl 1735831, rsl 1726102, rs3796822, rsl558487,rs4314449, rs4502870, rs6894574, rs9312760, rs6554623, rs7378954, rsl21434346, rsl0040110, rs967489, rs6896080, rsl0077141, rs56855707, rs76475084, rsl 12857876, rs7708070, rsl 1746047, rs80311787, rsl 15209326, rs429918, rsl 15926813, rs2522055, rs66542366, rs34626261, rsl7166294, rsl7624157, rsl 16332641, rs55928219, rsl0061901, rsl 14161496, rs4705987, rs6874885, rs7715447, rs57079115, rs4574536, rs66827546, rs62375204, rs4705989, rs62375234, rs6596102, rs73272725, rs62375243, rs4705880, rsl3718, rs56076449, rs56083805, rs62375251, rs72801473, rs62381537, rs4976276, rs7708460, rsl2659621, rs2292011, rs3776208, rsl0078851, rsl7797119, rsl3179823, rsl0952, rs2299024, rs9324851, rs9324854, rsl 1960868, rs899549, rsl031904, rs2578593, rs2578598, rs3776346, rs6580265, rs3776343, rs7734364, rsl0057800, rs3776338, rs3776331, rs3893579, rs3822393, rs3822392, rs246647, rs246644, rsl 1739101, rs35548690, rs246642, rs3822389, rs3756374, rs3822384, rs853167, rsl74047, rsl l750560, rs4705067, rs383915, rs408125, rs77010315, rs816026, rsl478350, rs864626, rs707185, rs815623, rs419652, rs426398, rs435903, rs386973, rs394730, rs442809, rs373619, rsl 1955459, rsl 1134691, rs58597371, rs57592039, rs2161396, rs76203059, rs539205478, rs4075958, rsl 16402366, rsl 1741640, rs4074995, rs35716097, rs55785724, rs2252316, rs6422344, rsl 1747964, rs57358849, rsl3179215, rs254458, rs371361, rs2619868, rsl57492, rs283131, rsl l2445233, rs59539451, rsl84935518, rs661309, rsl965924, rsl973195, rsl72836, rs612225, rsl 183436, rsl43198563, rs76425888, rs78952975, rsl 14873871, rs76497847, rs!060881, rs77495611, rs78762943, rs77755394, rs77449286, rsl48670552, rsl 14392491, rs75547547, rsl38297751, rsl38580268, rs76010420, rs79136786, rs76392483, rsl41807550, rsl 14411015, rsl l6783019, rsl 15191302, rsl 15550119, rsl 16472888, rsl 15695509, rsl 15045173, rs74717578, rs79508654, rsl92659043, rsl3157326, rs457648, rs455213, rs464499, rs464634, rs6881866, rsl 1740818, rs7709378, rs7714779, rsl7592391, rsl0036505, rs6873230, rsl0062185, rsl 134341, rs6884887, rs!867713, rs6866604, rsl838725, rs6859990, rsl 1741104, rsl 1745428, rs6891221, rs6451163, rs6451165,15156242423.3Attorney Docket No. 046483-7468W01(04021) rsl 1739938, rs62355681, rs73072594, rs6893208, rs376896, rs56277491, rs6860727, rs216385, rs216386, rs216389, rs216396, rsl25682, rsl2521993, rs3733801, rs2542713, rsl2153248, rsl0461725, rsl0512706, rs3843913, rs2962481, rsl501699, rs6451462, rs482375, rs7710885, rsl0058610, rs6896609, rsl827860, rsl827859, rsl395153, rs2967213, rs2967212, rsl0473169, rsl 1739050, rs7718076, rs6451477, rsl0067281, rsl0071562, rs6451482, rsl 1749592, rs!0077054, rsl506174, rsl0055349, rsl0036575, rs!0055925, rsl7718387, rs2005071, rsl 13983715, rsl 1743330, rs57367478, rsl389321, rs55988212, rsl911908, rs6555251, rs6555252, rsl2516498, rs72751899, rs72755310, rs4492117, rsl2517503, rs72755324, rs72755325, rs72755333, rs72755334, rs72755336, rsl2519758, rs56401540, rs72755339, rs5007472, rs4596388, rs4866870, rs4571479, rs72755352, rs4866874, rs72757321, rs72757327, rs72757339, rs56100685, rsl2519513, rsl39738798, rs4866768, rs!2518779, rs75921915, rs73754158, rs79804818, rs76136706, rs79468888, rsl2520384, rsl46944028, rs989255, rs78117246, rsl2523455, rs78999502, rs4866884, rsl6873839, rsl2515708, rs76255409, rsl 11565218, rsl6873866, rs76455323, rsl2513619, rs80173788, rs78142257, rsl 15171932, rs76451118, rsl3154781, rs7449277, rs729599, rsl6901990, rs7703497, rs6451778, rs4373287, rs6893319, rsl0040082, rs4395640, rs4866783, rsl0069220, rsl3356086, rs7718354, rs4591754, rs7356604, rs6895062, rs6871820, rs61448800, rsl2518560, rsl2520377, rsl2522861, rs2290697, rs4146620, rsl3187457, rsl3181690, rsl3162297, rs6875248, rs2407066, rsl3185048, rs7736958, rsl2656015, rs4865784, rs4865785, rs4865786, rs747671, rsl994870, rsl7248426, rs6866551, rs4865788, rs4865789, rsl3357971, rsl0039046, rs702634, rs4865796, rsl664781, rs6893522, rs80138475, rsl81822448, rsl l2838464, rs79756728, rs31226, rs79704759, rs78553795, rs6890486, rs6895649, rs3776694, rs6867281, rs6867302, rs6876640, rs7727248, rs3822496, rs3776692, rs3776691, rs3776689, rs61477070, rsl0059608, rsl0069589, rsl0042837, rsl0044749, rs73112684, rs75575055, rs73112694, rs6875937, rs59547873, rs6865570, rs7709659, rsl 15885520, rs57261959, rs73114718, rs440325, rs57766911, rs368151677, rs863818, rs34301, rs251409, rs34305, rs34308, rs7707989, rsl l742405, rs78660602, rs73116951, rs6898541, rs6449988, rs68083627, rs587189, rs662962, rs2928167, rsl479559, rs6453301, rs6453302, rs731123, rs7736027, rsl91808586, rsl677666, rsl623489, rsl 1952744, rsl677633, rsl677634, rsl643637, rs!677702, rsl677701, rs!643660, rsl650713, rsl643659, rsl650712, rsl650711, rsl643657, rs966762, rsl677689, rsl677688, rsl677687, rsl643648, rsl677685,15256242423.3Attorney Docket No. 046483-7468W01(04021) rsl 650707, rsl 643650, rs865647, rs865645, rs836818, rsl 643646, rsl 677670, rsl 478834, rsl478835, rsl650695, rsl643641, rsl643639, rsl643653, rsl677680, rsl643652, rs34580448, rsl 15912456, rs61749613, rsl0078496, rsl2659201, rs6452918, rsl 1742679, rs!986718, rs2973450, rs7727632, rs34710524, rs72717418, rs72717419, rs35664198, rs72717445, rs2672722, rsl 1134054, rs72698506, rsl2188597, rs56218301, rs55846849, rs36111336, rs72698510, rs76667725, rs72698512, rs72698513, rs72698514, rsl 15438441, rsl 1169, rs3315, rs72698516, rs72700688, rs72702717, rs56185908, rsl3159523, rs2455357, rs4869275, rs72787618, rsl874929, rsl49496, rsl52961, rs78677597, rs9496614, rs9386123, rs9403711, rs9399552, rs2295596, rsl7060480, rs3734353, rsl86858893, rs9390469, rsl87045419, rs6939850, rs6902071, rsl2189853, rs7766720, rs9486452, rs4946810, rs9372152, rsl 1759792, rsl728122, rsl728125, rs!728126, rsl739864, rs!728128, rsl728129, rsl728131, rsl728132, rsl739863, rsl739862, rsl728133, rs9285397, rs9480867, rs520942, rs9486920, rs522611, rs56229700, rs543629, rsl2524932, rs868943, rsl2524249, rsl0872142, rs7774952, rsl999929, rsl7083640, rsl2195224, rs62427623, rs62427624, rs62427626, rsl2211378, rsl2213206, rsl7705031, rsl739383, rsl777210, rsl 1154336, rs7740107, rs9402289, rsl044303, rs9388856, rsl413754, rs2236081, rs2236082, rs7775013, rs3777434, rs3777436, rs9372985, rs9385568, rs74755701, rs2608914, rs2608916, rs73542824, rsl44994895, rsl418702, rs975225, rs9791374, rsl0457001, rsl0457599, rs62428455, rsl2194836, rs62428456, rsl 1154708, rsl2197849, rs6908361, rs62428458, rs7745056, rsl2192750, rs6915521, rs4895949, rs62430561, rs6935677, rsl2210093, rs4895952, rs6902347, rsl2199972, rs4257872, rsl2193118, rs4077767, rs62430562, rsl2212715, rs62430581, rs9321388, rs9321389, rs6933214, rs6939899, rs62430582, rs58835706, rsl2200155, rsl2202394, rsl2191572, rsl2197909, rs7766945, rs62430584, rs60933911, rs28403922, rsl2205139, rs7756171, rs57161827, rs7761372, rs28538690, rs62430588, rs62430589, rs62430590, rs6936410, rs6937029, rs9493512, rs7738592, rs9493513, rs9493514, rs9493515, rs6935480, rs6940959, rsl2192605, rs9493517, rs9483529, rs9493518, rs9483530, rs9483535, rs4273707, rs4273708, rs6927627, rs6902225, rs9389047, rs7764524, rs9385632, rs9373036, rsl2211810, rsl2204720, rs9385633, rsl2214103, rs6941949, rsl338011, rs6923702, rs9399051, rs7751379, rs6569867, rs4895954, rs9389050, rs6913444, rs7756963, rs957183, rs6932057, rsl2197573, rs6913000, rsl40373654, rsl81940904, rsl2206291, rs7770031, rs6910042, rs4289671, rs9493535, rsl2208475, rsl2215649, rsl2208582, rs6569869, rs58010754, rsl2197255, rs6927764,15356242423.3Attorney Docket No. 046483-7468W01(04021) rsl 2196256, rs9493540, rs7766470, rsl2199738, rsl856291, rs9493544, rs7748926, rs7767651, rs7773069, rs59793266, rs62428599, rsl2196069, rs9483557, rs9375940, rs9385634, rs9385635, rs9389051, rs9402483, rs9375941, rs9375942, rs9402484, rsl0872402, rsl2193038, rsl2206438, rsl2193158, rs9493554, rs9402486, rs7763647, rs9373038, rs9483560, rs9402487, rs9389052, rs9402488, rsl2203712, rs74464144, rs62428628, rs9493563, rs62428629, rs!2215534, rs28620929, rs9402489, rs9399053, rs9399054, rs6912995, rs7754501, rsl2189904, rsl2204996, rs9389053, rs62428631, rsl2209655, rs9385637, rsl7299024, rs6935390, rs9389056, rs9375943, rs9321393, rs6907883, rs7746298, rslO485235, rs2208343, rsl832394, rs9389058, rsl415858, rs3756869, rs3756871, rs3756872, rs62430275, rs9402494, rs9385640, rs9389060, rs9385641, rsl2190309, rs9402497, rs3777796, rs55947866, rs9402498, rs56377439, rsl2192839, rs6940510, rs9373043, rs9399055, rs9389064, rs62430312, rs9389066, rs62430313, rsl7301249, rs79412930, rs62430314, rs5025269, rs5025270, rs5025271, rs4278037, rs75822474, rs9373044, rs9373045, rs9399057, rs9402501, rs28405267, rsl2173440, rsl2175835, rs9373046, rs9373047, rs9402502, rs6919155, rs62430315, rs62430317, rs62430318, rs62430319, rs79623938, rs62431677, rs62431680, rs62431681, rsl336520, rs79563827, rs62428663, rs62428664, rs62428665, rsl 17808688, rs62428666, rs79021277, rs3822939, rsl7643865, rs9493650, rs73007473, rs73007475, rs73007476, rs9373060, rs9373061, rs6903968, rs9402523, rs56224918, rs2636609, rs2677813, rs2636608, rs2636607, rs2327362, rs2677820, rs2636599, rs2677822, rs2677823, rs9285475, rs77869820, rsl2205960, rsl0457609, rs2327429, rs3777891, rs7765436, rs7742626, rs7739552, rs62432752, rs61225515, rs61383594, rs58469593, rsl 1753075, rs62434185, rsl533746, rs62434223, rsl554447, rs2842977, rsl 133785, rs3818299, rs3777423, rs4709373, rs4709374, rs56015409, rs35435543, rs8191852, rs920811, rs894818, rs3798179, rsl050026, rs3777398, rsl888727, rs998203, rs614890, rs2297374, rsl91198133, rsl0945657, rs316020, rs501470, rs506823, rs73015965, rs!43079629, rs3800032, rsl0458130, rs62388352, rs6920971, rsl2208162, rsl2528812, rs6914704, rs6916153, rs3800036, rs3800037, rs3800040, rs3800043, rs3778519, rs722587, rs2015853, rs3800090, rsl3204935, rs6912444, rs3778536, rs9503028, rs9367921, rs9297015, rs9370916, rs2299064, rs2237166, rs3778554, rs7764600, rs9503077, rsl0946313, rs75705948, rs73382439, rs746720, rs9465741, rsl41351489, rsl2211466, rs62397656, rs61484729, rsl0484631, rs58332063, rs62399260, rs62399288, rs57498505, rsl6884190, rs9465877, rs7752602, rs7752788, rs9350323, rs6901380, rs6906201, rs9350324,15456242423.3Attorney Docket No. 046483-7468W01(04021) rs6456398, rs6456400, rs6913868, rs9366382, rs9348457, rs9366383, rs9366384, rs9356769, rs9350325, rs9358395, rs9368283, rs6916577, rs6937555, rs7739578, rs7739596, rs9366421, rs9356791, rs9350408, rs4711000, rs6456469, rs7768871, rs7748819, rs6922033, rs6899545, rs6904385, rs6904682, rs6911827, rs6939340, rs9358491, rs4565291, rsl772977, rsl772975, rs879097, rs6939442, rs6918573, rsl770910, rsl087289, rs9295619, rs33914824, rs9379657, rs6935659, rsl0947554, rs4713884, rs6931945, rsl0947557, rs9462097, rs2395655, rsl 1961047, rs2395668, rs262936, rs262938, rsl2214118, rs755852, rs9357301, rsl 13491720, rs9381083, rs9381084, rsl015150, rs6930504, rsl3200335, rsl3198178, rsl l759908, rs9471936, rs56935405, rsl46734164, rsl 16255295, rs77807794, rs9471969, rsl 12391291, rsl 16750300, rs73416724, rsl 11547017, rs7763350, rsl 13634553, rsl214761, rs2396050, rsl 1965885, rs881858, rs833805, rs201691646, rs3799965, rs542444, rs3799973, rs7756472, rsl934328, rs6930053, rs6911664, rsl0485422, rs6904353, rs6915569, rsl934329, rs6458447, rs7748231, rsl0948236, rsl0948237, rsl928533, rsl2204049, rsl0948238, rsl3201287, rsl755056, rs485817, rs7764616, rs6458489, rs7760123, rs6921636, rs9472692, rs2143746, rs6940977, rs2274656, rs9472872, rs6458520, rs6903162, rsl38318676, rsl2213841, rs73736668, rs628782, rs2272903, rs2076309, rs2207136, rsl2209596, rs571503, rsl327271, rsl327282, rs2796905, rs2397046, rs2251549, rs2767729, rsl409884, rs2767730, rs9463688, rs9463689, rs6919930, rs56297668, rs28515748, rs9474014, rs9367433, rs9463690, rsl337846, rs72902108, rs9349583, rs72902111, rsl2204244, rs9474016, rs4144141, rs9463692, rs4090367, rs7741896, rs57892111, rs72902167, rs72902176, rs72902201, rs7449794, rsl414504, rs76572975, rs9395707, rs7751077, rsl2214235, rs9367447, rs9382004, rs2025747, rs6920806, rs6921803, rs7746090, rs9370043, rs9395708, rs9395709, rs9370044, rs9349593, rsl326611, rsl326610, rs932801, rs932802, rsl567215, rs4715230, rs2148460, rs9370046, rsl255999, rs2397058, rs9370047, rsl0948642, rsl507911, rsl326609, rs9395711, rs35999523, rs765525, rs986546, rs986547, rs4715231, rsl7753015, rs72899402, rsl750961, rs!326605, rs6914483, rs6914672, rs9370049, rs9395712, rs9370050, rs9382006, rs9367448, rsl326586, rsl326585, rsl0948643, rsl2055557, rs2025750, rs2025749, rs9382007, rs9395713, rs9357706, rs9395714, rs9395715, rs9349594, rsl409541, rsl2665434, rs9382011, rs9367450, rs9382012, rs966709, rs966708, rs966707, rs9382013, rs9382014, rs9382015, rs9370051, rs9382018, rs9382019, rsl42522748, rs6927544, rs9370052, rs9395716, rs3920621, rs2182508, rs9370054, rs4543373, rs4263578, rs9463715, rsl0948644, rs9474070, rsl0807430, rsl 160620,15556242423.3Attorney Docket No. 046483-7468W01(04021) rsl 1754528, rsl 1754532, rsl 326559, rsl 326560, rsl 326561 , rsl 326562, rs7765455, rs4715233, rs2104522, rsl326563, rs6900031, rs2397063, rs2894790, rsl0948647, rsl326567, rsl980834, rs2148459, rsl326569, rs!326570, rs9395723, rs!326573, rs6458786, rs9382031, rs6916797, rsl326576, rs2209638, rs75059606, rs9395728, rs9395729, rs9463720, rs6917984, rs7773970, rsl3202413, rs9474100, rs7764015, rs9474105, rs6908319, rs6458797, rs4715249, rs788509, rs788510, rs809292, rsl266905, rs!266916, rsl266922, rs45517932, rsl0807443, rsl884458, rs958203, rs6423287, rs6415165, rs7745053, rs76801519, rs7755335, rs2397120, rs4144184, rs7760615, rs36175277, rs34102057, rs34576365, rs77183015, rs9296694, rs7753187, rs7753323, rs7753564, rs7757768, rs7757925, rs7739622, rsl 13873355, rs6934115, rs4715356, rs7757068, rs3125265, rsl2189637, rs9382492, rs563123784, rs9475312, rs4441954, rsl2210599, rs9382498, rs4386822, rs4546489, rs4409174, rs4275061, rs4626423, rs9296787, rs7761740, rsl2213162, rs4398739, rsl45338431, rs9392827, rs35303881, rs6922083, rs9392137, rs6925389, rs9406043, rs2327010, rs2327009, rsl 1243202, rsl2198986, rsl2194650, rsl 1243203, rs55837820, rs62386963, rsl7673852, rs72827088, rs9942510, rs72912510, rs854922, rsl6881983, rs75689585, rsl 17820411, rsl3206900, rs35387650, rsl 1982462, rsl0245459, rs6959827, rsl0249739, rs9655773, rsl0261132, rsl0231704, rsl 12699345, rsl 13605241, rs73185883, rs73185884, rsl7495210, rsl2538702, rsl38929673, rs2694157, rs2694158, rsl 1764413, rsl7398575, rsl2705390, rsl7477177, rs62481856, rs2392929, rs6962980, rs6963273, rsl2705912, rs7796648, rs73234873, rsl348103, rs3779526, rsl345509, rs3808061, rs322834, rs322833, rs322832, rs3757387, rsl3227214, rs6467228, rs2693730, rs3817530, rsl 1556924, rs4721388, rs3918226, rs891511, rsl3225215, rs6464124, rsl7642575, rs7787908, rs7807134, rs7788234, rsl7715460, rs76331945, rs76747376, rs28764001, rsl 12864625, rsl 11720710, rsl 13731249, rsl 13032029, rsl 11386955, rsl 12258991, rs6966231, rs74882587, rs78219774, rs80311488, rs75885547, rs73475440, rsl7643028, rs75388874, rsl 13769875, rsl 12032351, rs4726061, rs4726062, rs4726063, rs6967946, rs9801653, rs78248188, rs73478069, rs74558374, rs79937579, rs4725416, rs4726067, rs870441, rs2374230, rs73478073, rsl 11748119, rs7457260, rsl860737, rsl860736, rs73478084, rs58461640, rs4725417, rs2536084, rs56012466, rsl0265221, rs6976065, rsl881632, rs2374300, rs9691493, rs62482826, rsl2670060, rs4582430, rsl920454, rsl0256316, rsl0949743, rs34052609, rs61122188, rs58969967, rsl0224079, rs!0242491, rsl2154725, rsl0241108, rs6459914, rs6972521, rs6944698, rsl0261098, rs!0264480,15656242423.3Attorney Docket No. 046483-7468W01(04021) rsl 11631734, rs73167161, rs2249337, rs2178428, rs3735576, rs3801906, rsl 0275919, rsl0226744, rsl0235856, rsl0226143, rs28431141, rsl3222019, rsl920452, rsl920449, rs28487953, rs28472693, rsl0239683, rsl0249636, rs71536007, rsl2698317, rsl 1765009, rs28731268, rsl 1771062, rsl 1770545, rs28529313, rsl 1505217, rs4716552, rs4716908, rs28649765, rs2051939, rsl0264279, rs2108192, rsl0269841, rs9333592, rs35225900, rsl 1576047, rs288766, rs!47880513, rs200865507, rsl225381, rsl225382, rsl225383, rsl225388, rsl731836, rsl731837, rsl675569, rsl675568, rsl675567, rsl731839, rsl731840, rsl617620, rsl616634, rsl731843, rsl731844, rsl731845, rsl731846, rsl675566, rsl731847, rs34044649, rs34652818, rs62481324, rsl0247896, rs6459952, rsl2698328, rs28591492, rs28380269, rs28691751, rsl 11239279, rs34596806, rs62480403, rs28507157, rs6976733, rsl2531716, rs9654678, rs7789438, rs6977899, rs4076780, rs28479099, rs4421245, rs6964302, rs56900386, rs59018066, rsl48455601, rsl 18063067, rs78037833, rsl524430, rsl524429, rs2365285, rsl 17728856, rsl0279504, rs77081024, rs6951593, rs883870, rs2530737, rsl 1765182, rsl 1972575, rs75353505, rsl0270726, rsl0252526, rs7383874, rsl2539909, rsl0950331, rsl2536482, rs4720922, rsl0227916, rs6968554, rsl0950659, rsl0249317, rsl7655457, rsl l772776, rsl l766613, rs75104284, rs73073181, rsl2538102, rs544353322, rs3846995, rs7782974, rs2686467, rs2528806, rs3094970, rs3094971, rs2686505, rs2528812, rs917252, rsl815051, rs939863, rs2528813, rs2686513, rs2528835, rs80301631, rsl7152552, rs28392961, rsl0245353, rs7798130, rs41469349, rs!0282436, rsl0267498, rsl0242536, rsl0951112, rsl0262483, rs57246313, rs56005128, rsl0950803, rsl 105420, rsl0241879, rs3757657, rsl81179233, rs35355140, rs2071265, rs35042646, rsl859168, rs7777128, rsl7428471, rsl7438292, rsl7502580, rsl 1563582, rs61127279, rs57768476, rs59783209, rsl 13269191, rs6977427, rs56897630, rsl 1763393, rs9648399, rs3088060, rs6942974, rsl0951369, rs3750117, rs4723235, rs28439161, rs2392210, rs6965942, rs4723238, rs4562213, rs4565371, rs6462450, rs4720097, rs6956397, rs7806813, rsl0280692, rsl609410, rs!0230500, rs7778958, rs7796184, rs7801701, rs7801986, rsl0486512, rsl0807866, rs4723240, rs4723241, rsl0231011, rsl0233749, rsl0951370, rsl0251079, rsl0281012, rs6948759, rsl0256717, rsl881749, rsl3228827, rsl0262141, rsl0265315, rs4454197, rs4604334, rs6951584, rsl609409, rsl0486697, rs7793162, rs6970558, rs62449449, rs62449453, rsl7714920, rs6978876, rs62452861, rs75913615, rs62452864, rs62452871, rs62452872, rs62452875, rs62452879, rsl38988531, rsl51040565, rs75603545, rsl 15762479, rs35503270, rsl 1761217,15756242423.3Attorney Docket No. 046483-7468W01(04021) rsl 1496034, rs28852211, rs73101770, rs79291900, rsl 1766300, rsl 1764171, rsl 1765266, rsl294866, rsl294864, rsl294863, rsl294861, rs700753, rs891867, rs6463354, rs6463356, rsl2702289, rs7780082, rs4724519, rs7800437, rs7804168, rsl2666798, rs34614572,rs34648469, rs28503901, rsl3242927, rsl3230300, rs7791301, rsl7540828, rs995794, rs28757789, rs67583356, rs2097880, rs2881491, rsl2668937, rsl2666569, rsl3225703, rs28616137, rsl2534770, rsl2532088, rsl2535456, rs36061487, rsl2702293, rs!2702294, rsl2702295, rsl2702296, rsl2702297, rsl2702298, rsl2702299, rsl2702300, rs6964742, rs9785020, rs9785022, rs9784985, rs6957572, rs6957879, rs6976373, rs6976393, rs73090642, rsl0277263, rsl0277420, rs6958251, rs6958583, rsl0282172, rsl3237826, rs73116822, rs73118808, rs73118816, rs2715119, rs7781924, rsl0267953, rsl43760919, rsl39824462, rsl3221342, rs9771330, rs9330365, rs9770123, rsl3241164, rsl3225240, rs!3243899, rsl3240925, rsl3229710, rs71518321, rs62432160, rs7800001, rs766333, rs7383796, rs2460432, rs313827, rs35072105, rs6978429, rs6460301, rsl3235168, rs34392598, rs34702628, rs34495733, rs79742506, rs3750170, rs6460556, rs41301394, rs2302429, rs6956241, rs2868782, rs59674745, rs60670836, rs55953411, rs73703313, rs73703314, rs7778518, rsl48783322, rs7779290, rs75504181, rsl7151202, rsl 17574221, rs74554481, rs2177993, rs2177989, rsl7151592, rs66977236, rsl0268139, rs6965245, rsl0235275, rsl0953304, rs6976611, rs6963486, rs7795371, rsl0240081, rs7801305, rsl0953349, rsl0263369, rs28605882, rs6465825, rs2057933, rs6973656, rs7786368, rs62462688, rsl0270542, rs848476, rs848483, rs848487, rs848492, rsl636665, rs848446, rs3735687, rsl38657567, rs6463533, rs35934045, rs34520461, rs60760028, rs6950388, rsl39157823, rsl3230509, rsl3230519, rs35347566, rs3824082, rs4724907, rs3735709, rs2211914, rsl3271310, rs2244648, rs6601600, rsl0101782, rs62523306, rsl2544197, rs79346194, rsl 1984773, rsl 1984866, rs7813263, rsl0955942, rs62528677, rsl0955943, rs62528692, rsl 1988434, rsl 1995536, rs6995862, rs6996081, rs9918814, rs9918815, rs4871028, rsl 1998247, rs68097758, rsl0087605, rsl0102995, rs28760377, rs55660329, rsl 106482, rsl0086797, rs60497698, rs58466445, rs28464637, rs9656934, rsl7822044, rs72673678, rsl0087551, rsl2546902, rsl2547479, rs4871718, rs67282053, rsl 1986346, rsl973732, rs7813041, rsl 1996625, rs4871825, rs7817522, rsl2386849, rsl401811, rsl2542032, rs66608823, rs77629956, rs7820543, rs7843503, rs7830028, rsl2545676, rs960887, rs60717250, rs7824793, rs7829101, rsl0955948, rsl 1780912, rs67872361, rs28530768,15856242423.3Attorney Docket No. 046483-7468W01(04021) rs73315941, rs66614869, rsl 12290548, rsl 0095205, rsl 0095532, rsl 2548273, rs! 519808, rsl 1995866, rs6469894, rs7829116, rsl519813, rs6469895, rs7822662, rs7822927, rsl0808506, rs66490854, rs7812488, rsl 15420097, rs7817016, rs!2543907, rs7821947, rs6469897, rs66507952, rsl0505376, rsl6893478, rs60754245, rs6993924, rsl 12611453, rs7016816, rsl2542895, rsl 112236, rs955293, rs2875931, rs7004815, rs7005228, rs2875928, rsl0090001, rs7013298, rsl2114445, rs2056304, rs6998730, rsl0101620, rsl 1780985, rs!0101943, rs57868486, rsl0955951, rsl6893517, rsl0095303, rs2292946, rs72675741, rsl 1780844, rs7833073, rs7007998, rsl7226296, rsl 12094354, rsl 1787175, rsl 1787250, rs6981402, rs6986231, rsl 120223, rsl0109558, rs62526967, rs3030310, rs57604049, rs79774420, rs77497750, rs76209931, rs7844497, rs2954017, rs28601761, rsl 12875651, rs7826703, rs7826864, rsl519847, rs!519842, rsl519841, rs!401826, rsl2541441, rs59017966, rs60883838, rs4733662, rsl2548036, rs7814497, rsl 1776164, rsl2681691, rs4736697, rs6471147, rs6984022, rs67935034, rs6982146, rsl2549256, rs28579238, rs76510996, rsl49539397, rs4398863, rs76072125, rs6990186, rsl0102728, rsl0103731, rs2304279, rs4961256, rs4437700, rs4874439, rs73373197, rsl 1786896, rs4074678, rs7838717, rs4977200, rs4977217, rs3757974, rs3757972, rs3757971, rs2306645, rsl7088488, rs4872526, rs76856898, rs7005025, rs75277916, rsl0448071, rs73214835, rsl 13629854, rs34861762, rsl0109414, rsl705690, rs73214850, rsl7724881, rsl7786924, rs73214858, rsl 1135910, rs71517871, rs7011265, rs6557878, rs6557879, rs57222145, rs62501771, rs62501776, rsl7241553, rs62501780, rsl7819816, rsl0104004, rsl3439370, rs62501972, rs4458838, rsl50979637, rsl84561571, rs2978286, rs34535252, rs4733503, rsl0503900, rs4633020, rsl0104033, rsl3253981, rs4733361, rs2466077, rs2466075, rsl0102889, rs58705931, rs4311627, rs76571516, rsl89529202, rs72634862, rs28374316, rsl0092449, rs66783138, rs72636310, rsl l6938314, rs900240, rs6983178, rs7827453, rs9643523, rs7834395, rs4403445, rs7007434, rsl0102740, rs!3257359, rs9298039, rsl0435601, rsl 1777673, rsl 1777706, rsl 1996592, rs2875973, rsl0957145, rsl0808710, rsl0957151, rs586377, rs608401, rs35735391, rsl7077419, rsl0808747, rsl 1557049, rs6472227, rs35165944, rs2173579, rs2936682, rs7003219, rs6995394, rsl2678260, rsl2680737, rs7011927, rs75505314, rsl2682220, rs62523461, rsl399562, rs2922785, rs60878530, rs58494441, rsl6939150, rs2921093, rs62498670, rsl7520086, rs2976841, rs2979163, rs2976846, rsl3270194, rs6601703, rs7827182, rs7823056, rs6995407, rsl3270194, rs7009054, rs6601703, rs7827182, rs7817376,15956242423.3Attorney Docket No. 046483-7468W01(04021) rs7823056, rs6995407, rsl 1787146, rs7012814, rs!461729, rsl073788, rs4566, rs9969643, rsl0095352, rs2307075, rs2953516, rs2976178, rs2033074, rs2033075, rsl2550043, rs4596617, rs4481558, rs4348460, rs4348461, rsl2543404, rsl2545684, rs2068005, rsl2677519, rs6471457, rs7814803, rs66477120, rsl2544778, rs2052720, rs3864655, rs7017996, rsl49180731, rsl l2123474, rs59515090, rsl2678709, rsl2676890, rsl2678729, rsl2676908, rs!2677807, rsl2677830, rs55890917, rs55716822, rsl2675372, rsl2678311, rs!2545296, rs72676935, rsl2543514, rs7832022, rs7813657, rs7814238, rs7836949, rs7833363, rs57653937, rs4008177, rs7017752, rs2554401, rs4639480, rs6471460, rsl2546263, rsl2545776, rsl2546282, rs7842400, rs7812489, rs7388010, rsl7645441, rsl046163, rs6471467, rs7462810, rs7460444, rs7462846, rs6471469, rs6471470, rs6471471, rs2554397, rs55663086, rs2722883, rs2722884, rsl3266255, rsl3254184, rs4735324, rs7844431, rs7826057, rs7835379, rsl226590, rs2780955, rs4743684, rs3818625, rsl0820599, rsl0820600, rs546232214, rsl0979879, rs2274786, rs557871513, rs2796035, rs787299, rs700122, rsl0733594, rsl0739373, rsl2350531, rs76674453, rs3827675, rsl0817564, rsl0982050, rsl2378445, rs28616789, rsl0982054, rsl 864721, rsl0982063, rs7853169, rs6478062, rs9697050, rsl0983126, rs6478237, rsl040850, rs34976241, rs34430369, rsl3292335, rs34140540, rsl2156498, rs56147233, rsl2005639, rsl3284925, rs56329744, rs62575433, rsl2377406, rs34804463, rs34513895, rs4836752, rsl0983234, rs62576082, rs62576093, rs35316886, rsl0817918, rs60847503, rsl0983295, rsl0983300, rsl0983301, rs35891915, rs62574187, rsl0983308, rs60203546, rsl441748, rsl2981, rsl3284547, rs6478585, rs624108, rs618275, rslO818775, rs7870270, rsl0760265, rsl6912523, rs2275510, rs700069, rs700074, rsl2686096, rs700080, rs700082, rs700089, rsl0818799, rsl2344903, rs4838038, rsl0985922, rsl0760271, rsl2238669, rsl3289976, rs7389288, rsl0819045, rsl0986700, rsl0819046, rs2841332, rsl0986724, rslO76O395, rsl0986759, rs4837129, rsl0987559, rsl0760476, rsl 0819268, rsl 0819269, rs4837197, rs3824528, rs2274426, rsl 0217290, rs7038077, rs6478915, rs73672505, rs74872096, rsl82912225, rsl034022, rs62584850, rs62584851, rs62584852, rs72755265, rs72755266, rs7852266, rs7852271, rs7852436, rs7852995, rs7028152, rs7028745, rs7045022, rs56262993, rs62584858, rs62584859, rs62586260, rsl 13141778, rsl 11903950, rs62586262, rs62586264, rs62586265, rs4302946, rs2005351, rs62586266, rs4545195, rs4480218, rs4323577, rs4545196, rs2417149, rs4644354, rs62586267, rs7027714, rsl6931489, rs62586269, rsl l5154450, rs72755277, rs55711781, rs56335269,16056242423.3Attorney Docket No. 046483-7468W01(04021) rs62586273, rs72755282, rs72755283, rs72755284, rsl 6931493, rs72755285, rs72755286, rs62586274, rs62586275, rs62586276, rsl 1999367, rs62583561, rs62583562, rsl0123409, rs4836675, rs913318, rs913322, rsl 108535, rsl 108532, rsl 108533, rs62583579, rs3780705, rs62583584, rs62583603, rsl47706265, rs76588272, rs72757235, rs62583606, rs76796731, rs61314466, rs79639102, rs76540153, rs41367050, rs78867009, rs78377535, rsl0739767, rs!0988553, rs60541956, rs79746999, rs76891739, rsl 7519156, rs78526807, rs77998122, rs78058713, rsl 1793982, rs76701800, rs77693339, rsl0793962, rsl 137827, rs550057, rsl39032120, rsl0993909, rs75318400, rs7021188, rsl0821551, rs80203447, rs!48384572, rsl 1103387, rsl475259, rsl0122824, rs28711320, rsl0810652, rsl0810655, rs537176512, rsl0121943, rsl0964603, rsl537373, rsl333042, rs6475611, rs7047414, rsl0971361, rs3780490, rs3780489, rs!0758192, rsl0124479, rsl0813954, rs2209948, rs!0971424, rs7864705, rs7865745, rs7868781, rsl0813955, rs7873182, rs7873077, rs7036812, rsl3288380, rs7019647, rs9802431, rsl0738919, rsl570777, rs7865742, rs307669, rs307684, rs4272470, rs307700, rsl3300356, rs61237993, rs7033145, rs7853437, rsl331260, rs4740743, rslO 122183, rsl373850, rsl0758779, rs2297442, rs59699173, rs77979581, rsl 17451470, rs6560203, rsl3302081, rs4745093, rsl 1142922, rsl 1142926, rs4744712, rsl 1144066, rs4745353, rs7851923, rs4745366, rs4237270, rs6560419, rs7043133, rs7043242, rs7043868, rs58302882, rs60864427, rsl 1142563, rs4744612, rs6560150, rsl0868884, rsl0868885, rsl328148, rs7045063, rs7861859, rslO868898, rsl7470958, rs4877691, rsl888327, rs80020015, rsl3290278, rs35103886, rsl3299917, rsl411662, rs4877233, rs35559314, rs955975, rsl 17355062, rs7847758, rs7040995, rs870151, rs4877118, rs6559369, rsl 1265853, rsl2346653, rs3858097, rsl 1521657, rs7020638, rsl 127851, rs2275848, rsl2342200, rs73524733, rs7867526, rs781649, rs2460138, rs2945799, rs28369681, and rsl2236906.10 The method of any one of claims 8-9, wherein the genomic editing is performed in a kidney cell of the subject.

11. The method of any one of claims 8-10, wherein the genomic editing is performed with a base editing method or a prime editing method, or a CRISPR-Cas9 based method.16156242423.3Attorney Docket No. 046483-7468W01(04021)12. The method of claim 8, which comprises down -regulating or up-regulating the gene associated with the kidney disease, and wherein the gene associated with the kidney disease comprises at least one selected from the group consisting of CHAC1, SLC34A1, SLC22A7, SLC6A19, ABCC2, SLC26A6, MIOX, CUBN, PCK1, BHMT, G0LGB1, SLC6A13, STRA6, ACSM2B, AGMAT, SLC7A9, GSTA2, DPEP1, HNF1A, SLC25A10, ACSM2A, SLC34A3, PBLD, GSTA1, SERPINF2, SLC47A1, LRP2, SLC22A5, SYN2, ITIH4, CYP24A1, NPLOC4, ACOT6, SLC2A9, POR, SH3YL1, CAPN12, TPCN2, ACSS2, TM6SF2, KMT2B, ATXN1L, TTBK1, GLIS1, GATM, SLC25A47, KLHDC7A, ALDH1L1, NAT8, CUX1, ACSM5, ULK3, KNL1, SLC2A4RG, SNX30, XPC, GCC1, PEMT, SMLR1, THUMPD1, AP5B1, STK36, F12, C9, PGC, GCDH, WIPI1, FAM177A1, ZGPAT, SLC22A18, CERS2, SALL1, SLC3A1, WDR25, SPEN, SLC22A2, DMGDH, GIPC2, CCDC158, SLC22A4, NFE2L1, MARVELD3, GSS, ESCO1, ATP5IF1, IGF2R, THBS3, MAST2, BBS1, ANXA9, RTEL1, RNF123, ATP5PO, APEH, CFAP74, ZC3HC1, SNUPN, CA3, NUSAP1, IPP, CHD9, SLC28A2, STYXL1, RBM12, H0XA13, DNAJC16, WDR73, DCDC1, KY, SLC39A8, PKHD1, CDK7, RASSF6, 0RC4, CELSR2, SPATA7, ABCG2, NOS3, RASIP1, LKAAEAR1, IZUM01, IHO1, MAP3K11, SPTBN1, LUZP1, WDR87, ACP2, EBPL, SPG7, EEF1AKMT2, TRIP10, TSPAN9, ZNF142, SHR00M1, BMP4, DUSP11, EXOC6, CST6, IFITM2, TNFRSF6B, CD34, EFNA3, TPRKB, PIK3R3, ATRAID, GATA5, ADAM15, MTX1, TMBIM1, HLX, PITX3, C15orfi9, CHGA, RP1L1, SEMA7A, FAAP24, SWAP70, C2orfl6, STAT5A, SNX32, APOL3, ERI2, PHETA2, BIN3, CCDC51, NDUFAF1, USP35, MDH2, PTPN12, TBC1D8, PNPT1, IBA57, ARL16, TMEM60, FAAP100, GPN1, TRIM49B, DNAJC17, PKD1L3, LAMC1, IDI2, ART4, DNMBP, NXPH4, ZNF468, ADAMTS7, PRKAR1B, MXD3, GUSB, GNAS, FKBP4, NFATC1, JMJD1C, FRMD8, STARD3, EDEM3, ADAMTSL4, SLC5A6, FDPS, PDLIM4, RPL3L, STRN3, ALPK3, LAMB2, APH1B, BSN, SLC39A13, NR1H3, ABO, DPM2, PMF1, ZNF260, UMOD, PDILT, CLDN14, RNF212, NEB, CFAP70, MARVELD2, MST1, SLC9A3, CGNL1, CLCNKA, PPARGC1A, SLC22A1, ILDR1, RMDN1, SLC25A17, VPS9D1, CCDC125, CBR1, AGBL2, MYH7B, ZNF585B, ZNF573, GAL3ST1, IFT172, ZNF585A, EXOC3, ZNF568, USP24, FBXW12, H0XD8, KNG1, MITF, KIAA1614, TBX4, ZNF607, TPPP, ZNF778, CYP2D6, PTPN3, NISCH, ERI1, CPNE7, TH, NR0B2, ELF3, CASP9, TJP3, FUT2, GRB7, CELA2B, CCDC17, IP6K2, TSPAN10, N0X01, GGT7, PAPP A, SLC25A29, BNIPL, BANP, ZNF571, FGF21, SLC45A4, TBX2, ATXN7, ATP12A, GSTA5, NASP,16256242423.3Attorney Docket No. 046483-7468W01(04021)CWH43, DUSP6, RAPH1, D0CK7, GCKR, TMEM51, PRRG2, ERBB2, CR1L, SRARP, TMEM1 16, SHR00M3, NC0A6, FAM83F, DCAF4, WDR1, PTPRJ, FRK, APOE, RERE, MC1R, DDX1, ZNF875, NDUFS4, SPATA2L, B4GALNT2, WDR72, PSEN2, TFCP2L1, MINDY1, CYP26C1, PCMTD2, ATP6V1B1, MY019, TOMM40, GIGYF2, CYP1A2, PTPN21, CHCHD10, KCNJ13, ABCD3, HEATR4, DYDC2, NDUFA6, ZDHHC5, CA2, DPP3, OGDHL, UBE2H, SCRIB, ZNF687, RALGPS1, QARS1, PLA2R1, NPHS1, ACOT4, ARHGEF26, CACNA1S, DAG1, TRIM51GP, CAND2, ACTN4, CELSR3, COL7A1, EPB41L5, FGFRL1, SORT1, RERG, CAND1, CBLB, METTL21A, ZNF461, ZNF436, FGFR4, MAMSTR, FAM47E, HOXA9, CASZ1, SCYL1, PGAP3, CCAR2, C2orf73, IMP3, SLC4A11, CDH15, C10orf53, ZNF713, DCDC2, C19orf73, TPM1, JPH2, EVC, SHARPIN, CFAP36, MAPK15, MISP3, EXD1, LOXL4, CEP89, PLEKHH2, ZNF148, SEMA4A, ZNF608, IQCN, MEP1A, ARMC9, PLXNB1, NMB, RAH, OBSCN, WBP2NL, LMNA, LAMA5, FAM149B1, SENP2, ALMS1, USP19, TMEM239, DGKH, TUBB3, PLEKHA1, MUC1, CPS1, PKD2, MFHAS1, VCL, ANXA11, IQANK1, Cl lorf49, METTL15, SPEG, ANO1, GNRH2, ISLR, TNFAIP6, FILIP1L, NEXN, GPR88, PKD1, FOXO3, MGP, COL18A1, PDLIM5, IL1RL1, CLDN23, NBEAL1, AMT, BEGAIN, MPRIP, ITIH3, DDI2, SVIL, CYP20A1, PCGF6, GABPB2, ADCY6, RUFY2, SPI1, STAB1, NAGA, SH2B3, MANBA, USP4, RIN3, GAB2, NINJ1, AHR, CTSS, TTN, LRP1, OPRL1, WDR81, SDCCAG8, MYBPC3, LACTB, CENPE, TET2, DAB2, PHF20, SIRT1, EHBP1L1, RBM47, WBP1L, PLEKHM2, ZNF641, RREB1, MADD, MSL1, SIPA1, PPM1J, SREBF1, FNIP1, TDRD12, NUDT19, TRAFD1, MYPN, SHISA8, TNFRSF13C, ZPBP2, CENPM, CTCFL, ARHGEF18, DENND5B, PRAG1, IKZF3, HSPA4, MMP11, SH2B2, SND1, TFEB, SLC22A31, RBM6, NT5C3A, CHRNB4, PDCD11, RSBN1L, UVRAG, MUTYH, EDEM2, RAD17, ATF1, INHBC, ACSF3, NARS2, SLC15A2, EML5, CCDC77, HINFP, RAPSN, QRICH1, NUP160, GABI, SREBF2, ABRAXAS2, UQCC1, SPATA5L1, FANCA, NSD1, STAG1, MPI, SCAPER, RBL2, IL12RB1, LIME1, RASA2, ZFP36L2, SIGIRR, ZNF276, PSD4, PDE7A, PCNX3, GATAD2A, RPL13, PHTF2, RPS2, SLC25A45, HERC4, PRR12, AN09, R3HCC1L, IRF3, GSDMB, R3HDM2, ITPKB, PRRC2C, CPNE1, RPRD2, ANKRD27, SEC24C, ANKRD11, THAD A, FAM102A, CCDC137, MTMR9, TCF20, WHAMM, ZBTB42, MMP24OS, GGNBP2, ARFRP1, HGS, ACPI, LASPI, PRMT7, XPO7, TBL3, PIGU, TNKS, SART1, RPAP1, UBE2D3, FOXA1, RSC1A1, LRWD1, SHF, C3orf84, USP38, FBXO42, ABCC10, ZNF598, ZNF816, C3orf62, GIPR, ACVR2A,16356242423.3Attorney Docket No. 046483-7468W01(04021)TRIM65, XP05, RTEL1-TNFRSF6B, AL691442.2, 0R4B1, OR4C3, WDR78, TREX1, C20orfl94, PMF1-BGLAP, 0R4X1, 0R4S1, AC092143.1, AC093227.2, H0XD12, NPBWR2, FAM47E-STBD1 and PAX4, optionally, the gene associated with the kidney disease comprises at least one selected from the group consisting of DPEP1, CHMP1A, ACSS2, WHAMM, TET2, DACH1, TNF, and CHAC1, optionally, the gene associated with the kidney disease comprises CHAC1.

13. The method of claim 8 or claim 12 which comprises administering to the subject a compound that down-regulates the gene associated with the kidney disease, and wherein the compound comprises: a small molecule inhibitor of the gene, a protein inhibitor of the gene, a nucleic acid that downregulates the gene by RNA interference, and / or an expression vector expressing the nucleic acid that downregulates gene by RNA interference, a compound for forming epigenome editing, optionally a catalytically inactive Cas protein fused to TET1, DNMT3A, a DNA methylase, histone acetyltransferases, or histone deacetylases, or a nucleotide expressing the same, a ribozyme that downregulates the gene, and / or an expression vector expressing the ribozyme, an expression vector comprising an expression cassette, wherein the expression cassette expresses CRISPR components that downregulate gene by CRISPR knockout or CRISPR knockdown, and a trans-dominant negative mutant protein of the gene, and / or an expression vector that expresses the trans-dominant negative mutant protein of the gene, optionally, the compound comprises a compound for epigenome editing at cg05124934, or a RNA interference molecule down-regulating CHAC1.

14. The method of claim 13, wherein the method comprises administering to the subject the nucleic acid that downregulates the gene by RNA interference, and wherein the nucleic acid is enriched in the kidney of the subject.16456242423.3Attorney Docket No. 046483-7468W01(04021)15. The method of claim 8 or claim 12, wherein the method comprises administering to the subject a compound that up-regulates the gene associated with the kidney disease, wherein the compound comprises the gene, the protein or mRNA product of the gene, a functional equivalence thereof, an expression vector expressing the same, or a compound for forming epigenome editing, optionally wherein the compound for forming epigenome editing comprises a catalytically inactive Cas protein fused to TET1, DNMT3A, a DNA methylase, histone acetyltransferases, or histone deacetylases, or a nucleotide expressing the same.

16. The method of any one of claims 13-15, wherein the compound that down-regulates or up-regulates the gene associated with the kidney disease is delivered using a lipid nanoparticle, a GalNAc conjugate, a polymeric nanoparticle, an adeno-associated virus (AAV), or an exosome.

17. The method of any one of claims 13-16, wherein the compound that down-regulates the gene associated with the kidney disease is an siRNA molecule, and wherein at least one of the following applies:(a) the siRNA is conjugated to a megalin (LRP2)-binding ligand that promotes receptor- mediated endocytosis into proximal tubular cells,(b) the siRNA is lipid-conjugated (cholesterol or polyunsaturated fatty acid) to enhance renal uptake and plasma protein binding, and(c) the siRNA comprises dual conjugation (GalNAc + lipid tail) to increase renal tubule accumulation.

18. The method of any one of claims 8-17, wherein the kidney disease causes a reduction in a filtration capacity of the kidney in the subject as compared to a healthy control subject.

19. The method of any one of claims 8-18, further comprises administering to the subject an effective amount of a compound selected from a SGLT2 inhibitor, an ACE inhibitor, an angiotensin receptor blocker, a mineralocorticoid receptor antagonist, an endothelin receptor antagonist, or a GLP1 receptor agonist.16556242423.3Attorney Docket No. 046483-7468W01(04021)20. The method of any one of claims 8-19, wherein the subject is a human.

21. A method of predicting a risk of kidney disease in a subject, stratifying the a subject based on a risk of kidney disease, and / or selecting a therapy for a subject with kidney disease, the method comprising(a) detecting the presence or absence of a risk allele in a single nucleotide polymorphism (SNP) associated with kidney disease in a sample of the subject, wherein a presence of the risk allele in the SNP indicates a heightened risk of kidney disease, or(b) detecting a CpG meQTL sites linked (LD r20.2) to a SNP associated with kidney disease, optionally wherein the detection is performed using PCR, sequencing, digital droplet PCR, or methylation-specific arrays.

22. The method of claim 21, further comprising collecting the sample from the subject.

23. The method of any one of claims 21-22, wherein the SNP is at least one selected from the group consisting of rs4924525, rsl2767621, rs4148384, rs56050010, rs55804858, rsl 12344408, rsl7216177, rs34456559, rs72838129, rs7920448, rsl 137968, rs72838134, rs72838141, rsl 11866537, rsl 13513789, rs72838143, rs72838146, rs72838149, rs72838150, rs56333232, rs8187707, rsl7216212, rs8187710, rsl 13741841, rsl 11281941, rsl 1816708, rs56080571, rs55725645, rsl46860861, rs7899966, rsl0883432, rs6584337, rsl 1190351, rsl0786579, rs7900025, rsl0128320, rsl986519, rs7917150, rs7915731, rs7902856, rs7088596, rsl2267374, rs4919412, rs72845694, rsl 1597439, rs7072014, rs284859, rs61869825, rs72846198, rs7076463, rs7831, rsl45384631, rsl90722793, rsl 1198455, rsl 1198458, rs2278202, rs3850765, rs7902176, rs8181474, rs4751890, rsl0901812, rs3824765, rs4962697, rs55668701, rsl39067922, rsl39217986, rs78593499, rs7078652, rsl2761149, rs2936540, rs3012069, rsl008982, rs7905095, rsl 133400, rs6602818, rs7094565, rs74962910, rsl 1254232, rsl 17035284, rs2669153, rsl41640975, rsl707275, rsl707277, rsl707278, rsl707280, rsl337311, rsl337310, rsl 1013566, rsl0828481, rs7081567, rsl2773508, rs7078949, rs7090769, rsl0828490, rs7093761, rs71493333, rs71493334, rs35241775, rsl 1592534, rsl0828509, rs7915768, rs2886851, rsl 1006779, rs3824590, rs3802517, rs34717952, rs933065,16656242423.3Attorney Docket No. 046483-7468W01(04021) rs2368268, rs4494226, rs4600119, rsl 1596317, rsl 1596400, rs7907415, rsl2778429, rs7907935, rsl2778301, rsl2767652, rs4489649, rs2790450, rs2807731, rs813694, rs28585535, rs2768665, rs6481598, rs34163498, rsl0827415, rs7923244, rsl 1009923, rs!2413778, rsl0827420, rs61840961, rsl6935716, rsl6935717, rs61840962, rs9418121, rsl0827439, rsl2249828, rsl 1253465, rs80282103, rsl 1253467, rsl 1812523, rs2050944, rsl 1253485, rs!0904577, rsl 1253488, rsl 1815185, rsl2254002, rsl2778891, rs35825568, rs61830965, rs36172393, rsl 1239536, rs72796498, rs61848597, rs35647145, rs2377942, rs7894727, rs6537530, rsl258179, rsl258182, rsl 1101238, rsl438928, rs3849145, rs4012536, rsl 1592181, rsl43788922, rsl0994860, rsl0821905, rs3808919, rs7077633, rs2393426, rsl013474, rsl427207, rsl2262629, rsl0821939, rsl0821944, rs725529, rs7090871, rsl2773075, rs3740353, rs9633556, rs9633557, rs3740352, rs2393729, rs2393728, rs7083045, rs7924036, rs4746729, rsl45701607, rsl0998000, rs7095603, rs7095607, rsl2415105, rsl2416503, rs7079974, rsl2241767, rsl2262121, rs7075996, rs3812637, rsl0824036, rs7087290, rsl0762586, rs816850, rsl 1002181, rs74410628, rs7078632, rs3127449, rs3127450, rsl439787, rsl866594, rs79037708, rs72809508, rs74577679, rsl 1002194, rs78740294, rs7907504, rs61096875, rs2673433, rs2673434, rs2448394, rs2719978, rs2448395, rs2673477, rs73291804, rsl 12728740, rs372893521, rs58640785, rsl 13797354, rs2619634, rs2673463, rsl877993, rs79221966, rs60674751, rsl2218866, rs7083734, rsl0824743, rsl l002931, rsl l002932, rsl l002933, rsl2414178, rsl2411493, rs7077812, rsl317617, rsl892501, rsl892500, rs2186235, rsl2769165, rs6480936, rs7900144, rsl 1002957, rsl0824749, rsl0824750, rs7898802, rs2279337, rsl 1598614, rs9943407, rs2819940, rsl43396142, rs59028692, rsl 1202957, rs9421581, rs9421590, rs376416910, rs368285394, rs376737866, rsl750274, rs72820049, rsl7343157, rs2477956, rsl7343533, rs72820074, rs2297312, rs7896106, rs7101264, rsl 1185825, rsl 12289686, rs61854360, rs61854426, rs61869183, rsl7127289, rs!7127307, rsl92403351, rs72823192, rsl0882018, rs66526527, rs2068888, rs!2260218, rs55744367, rsl0882171, rs7919934, rs7894625, rs7070948, rs7070947, rsl2769915, rsl 1187539, rsl0882272, rsl 17061060, rsl0786213, rsl0748632, rs4328157, rs9663482, rs4918943, rs2125060, rsl 1599170, rsl 1188622, rsl 1595809, rsl0882723, rsl 1593049, rs60450792, rsl 1188631, rsl 1188632, rs7896077, rsl 1598546, rsl2761705, rsl0509701, rs34999669, rsl0491070, rsl 1189526, rsl042752, rs!2417556, rs605923, rs3737445, rs61899413, rs3829258, rs665731, rs75919952, rsl2721043, rsl7120152, rs555639, rs2510897,16756242423.3Attorney Docket No. 046483-7468W01(04021) rs555649, rs2105782, rsl 784300, rsl 12119822, rs4938626, rs7775161 , rs7945293, rs4938654, rs4938659, rsl0790452, rsl893841, rs4935802, rsl2785310, rsl2808150, rsl2808357, rsl 1218783, rs75564112, rsl44399213, rsl42471120, rsl0790795, rsl0893488, rsl 12771035, rs59822672, rs876071, rs8705, rs61909096, rs500090, rs2510121, rs686486, rs670516, rs3763950, rs4756786, rsl 1369, rsl 1238, rsl043237, rsl 1023168, rsl 1605531, rs61883858, rsl 1023170, rsl 1023172, rsl431374, rsl0832240, rs7934671, rsl 1023178, rsl 1606558, rsl0832242, rsl2291662, rs34171876, rsl2795545, rs4757250, rsl0832246, rsl 1023198, rsl6930126, rs2060076, rsl 1023203, rsl0832248, rs!2806025, rs2882128, rsl0832525, rsl 1023747, rs2351958, rsl77546, rs59828007, rsl77551, rs59258722, rs4757483, rsl0734250, rs7481960, rs60835408, rs62650851, rsl 1564725, rsl 1564722, rs3842761, rs7481129, rs7395734, rs6578999, rs6579001, rs7123180, rs6579003, rsl 1043133, rsl 1043135, rs7121452, rsl058873, rsl058935, rs74045276, rsl 1748, rsl 134578, rs7945319, rs7947, rsl 17739035, rs9667408, rs4930004, rs6578283, rs9888189, rsl2287110, rs55763223, rsl971929, rs231890, rsl 1023996, rs6578296, rs463535, rs231873, rs233438, rs81205, rsl048046, rs72850026, rsl2277177, rs3764895, rs3764896, rsl056819, rsl2223953, rsl2361922, rsl2363207, rs61871197, rsl0832936, rs4758492, rsl 1024672, rs4758561, rs4758562, rsl 1024687, rsl2286120, rs2071117, rs3213614, rs4758576, rsl 1602817, rsl 1024746, rs4758590, rs7940694, rs737872, rs60898246, rs60026059, rs3825063, rs7127443, rs4758501, rs7946134, rs74869735, rsl6928966, rs4758504, rs6578306, rs6578307, rs7113131, rs6578308, rs4758622, rsl 16848871, rs7935248, rs3741343, rs6578312, rs4758458, rs7950766, rsl7309986, rs72874485, rs72874488, rs34667360, rs34357760, rs7937778, rsl6917735, rsl384903, rs34337978, rsl7310076, rs7931847, rs7128045, rsl351787, rsl l603799, rs! 1605717, rsl 1601602, rsl7244387, rsl2786351, rsl2797155, rsl2797712, rs34351528, rsl 1030269, rsl2787721, rs61889048, rsl2802830, rsl 1826837, rs35357280, rs34827038, rs7934085, rs7110074, rs34857148, rsl7652117, rs34906813, rs2582905, rs35031414, rsl39841307, rsl83380256, rsl 1030598, rs55937300, rs7938219, rs7933990, rs74528749, rsl7402305, rsl46685651, rsl41851059, rs4922556, rs7930738, rs294348, rs538000, rs294394, rsl88395, rs3925584, rsl 1602582, rs72906988, rs72908928, rsl45678014, rs55707359, rs55683589, rsl40914801, rs72908033, rs72908034, rsl0501318, rs72908050, rs72908052, rs72908056, rs72908057, rs72908060, rs72908065, rs79052740, rsl43391621, rsl51258518, rs72908086, rs72908091, rs72908092, rs72908098, rsl 12976598, rsl48157878, rs72908102, rsl 11771311,16856242423.3Attorney Docket No. 046483-7468W01(04021) rs7926726, rsl 984777, rs2306353, rsl 0838702, rsl 0839315, rsl 2416837, rsl 1040455, rsl2364577, rs4881721, rs28490238, rsl0902013, rsl 1245609, rsl 1245616, rs4066591, rsl0902022, rsl 1246496, rs80282099, rs7929989, rs71484844, rs4533026, rsl2795686, rsl0902380, rsl 1246655, rs7479178, rs528112218, rs7107218, rs4243961, rsl975200, rsl2271333, rsl2272771, rs4567498, rsl2292448, rs4309185, rs56895655, rs7105587, rs!912014, rs3862669, rs7120357, rsl783980, rs!785498, rs563888682, rs2524299, rsl74475, rsl74478, rsl2366107, rsl 1231284, rsl0897307, rsl 11438108, rsl 1231285, rsl0792364, rsl0897309, rsl0750977, rsl0897310, rsl944044, rs58077467, rs34400381, rs78829599, rs79280212, rsl47500819, rsl42601087, rsl0896005, rs35292734, rsl 12253806, rs4102217, rs3200401, rsl0896012, rsl783541, rsl787663, rsl 143756, rsl 144928, rs947791, rs56076708, rsl 1227217, rs2846139, rs58621819, rsl2789028, rs!346, rsl 17952737, rsl39847315, rsl 1227299, rs948494, rs948493, rs4930319, rsl786171, rsl 1227378, rsl 131544, rs632640, rs7933510, rs685334, rs684546, rs548435, rsl785639, rsl785633, rs947978, rs2236679, rsl0750784, rsl892940, rsl0896111, rsl0896112, rsl0791869, rs7110944, rs3016767, rs4930177, rsl 1601396, rsl2794121, rs73489638, rs56123976, rs4930178, rs4244813, rsl047029, rsl039594, rsl2577196, rsl2576299, rs7126018, rs2279861, rs2279862, rsl2416747, rsl0791872, rs7107191 , rs4930360, rsl0896115, rsl0791874, rs67780191, rs7948058, rs74863039, rsl0896116, rs61891449, rs55998145, rs7931458, rs4930362, rs7117630, rs6591213, rs7104253, rs905770, rs4930179, rs34043951, rs7104570, rs7105015, rs7105401, rs66810040, rs56321771, rs4930181, rs7125752, rs4630308, rsl0896118, rsl2418706, rsl2420203, rsl 1227474, rs7938676, rs7939111, rsl0791876, rs4930363, rs6591215, rs7115577, rs7940980, rs6591217, rs!546358, rs2282530, rs77754842, rsl2785321, rs79798028, rs2279865, rsl 18011533, rs7104378, rsl2099041, rs57691879, rs3892818, rs2277302, rs4930377, rs57634456, rsl 1550299, rs4930378, rs7943327, rsl7147644, rs7950407, rs7950790, rsl 1824771, rsl 1227495, rs7123176, rsl 11511881, rsl 1227497, rsl 1227498, rs56144989, rs2305535, rsl 1227499, rsl0501397, rsl 1227500, rsl 1227501, rsl 1227502, rsl 1822099, rs61561111, rsl 1227509, rsl 1227510, rsl 1227511, rsl 1227512, rs2298806, rsl0896124, rsl 1227514, rsl 1227515, rsl 1822028, rsl0896125, rs28414721, rsl2223478, rsl2223479, rs3819247, rs74869459, rs3816492, rs2305532, rs2305533, rs3741360, rsl2221821, rs755761, rsl0792015, rsl0750838, rsl0792016, rs!0896406, rsl0896408, rs76603088, rs3750966, rsl0896416, rs!2363597, rsl 1228482, rs7945151,16956242423.3Attorney Docket No. 046483-7468W01(04021) rsl 1228485, rs896973, rsl 005858, rsl 2280942, rsl 0896437, rsl 2798031, rs7929203, rs3019748, rsl2418948, rsl2418451, rs66592032, rsl2420758, rs9651718, rsl l228551, rsl2809032, rsl2800787, rsl 1228553, rsl2223972, rs55814684, rs7113988, rs4980598, rsl 1602223, rs7946918, rs647451, rs602652, rsl789167, rsl789164, rs4411303, rsl 1232979, rs7104619, rs2186797, rsl48865428, rsl 1822234, rsl 1236214, rs7102580, rs61389091, rsl 1236476, rsl 1823410, rs609799, rs575976, rs!0899104, rs72997616, rsl0899457,rs4944195, rsl0899458, rs4627115, rs4944196, rsl0793297, rsl0899460, rsl 1601866, rs4417308, rsl0899465, rsl0899466, rsl0899467, rs6592772, rsl0899468, rsl0793298, rsl0899469, rsl0793299, rsl0793300, rsl0899470, rsl0793301, rs4945265, rs4945266, rs7116611, rs4944198, rsl2574042, rsl2574044, rs55808581, rs7113042, rs72931639, rs58565853, rs72931642, rs4945267, rs4945268, rsl 1237456, rsl0793302, rsl0899472, rsl0899473, rsl 1601196, rsl0899474, rs7115850, rsl2281104, rs4945269, rsl 1237458, rsl0899475, rsl0899476, rsl0899477, rsl0899478, rsl0899479, rs2292573, rsl0899480, rsl2277648, rsl 1237460, rsl0501426, rsl0899481, rsl 1237462, rsl0899482, rsl 1237463, rsl0793303, rsl0899483, rsl 1237464, rsl0793304, rs4245459, rs4945270, rsl0899485, rsl0899486, rsl0751287, rsl0751288, rsl l237469, rs72931690, rsl 1601161, rsl 1601195, rsl 1237471, rsl0899487, rsl0793308, rsl2291726, rsl0899488, rsl0793309, rs4945273, rsl0793310, rsl567890, rsl567891, rs7128666, rs7112234, rsl2284390, rsl0793311, rsl0899491, rs4945274, rsl0899492, rsl 1237480, rs7939646, rs7941639, rsl0899493, rs7110387, rs4945275, rsl0431155, rs4944199, rsl0899495, rsl0899496, rsl0899497, rsl0899499, rsl0899500, rsl 1237485, rsl 1237487, rsl0899501, rs2063724, rsl 1237490, rs990706, rs79338137, rs!49013553, rs7928772, rsl0902235, rsl0902239, rsl0902243, rs7395402, rsl0902248, rs7396677, rsl0794356, rs7123912, rs7394958, rs7394912, rs7394436, rs7933889, rsl0902257, rs4072741, rs4075990, rs6597960, rs415895, rs75248620, rs7948688, rs7930281, rs7938316, rs!7039076, rs74735986, rs79589059, rs76727811, rs79685573, rs79872044, rs78768625, rs76722883, rsl7039089, rs79144950, rs74459373, rs78463444, rsl 17012212, rsl 18079645, rsl 17980587, rs76972589, rs2374686, rsl46120104, rsl 17616994, rs79264325, rsl7039104, rsl 17170723, rs80187574, rsl 17399660, rs3742003, rsl0849948, rs7976462, rs79209359, rsl2369009, rsl 1065961, rsl 1065967, rsl0849966, rs601663, rs608814, rs847900, rs57454118, rs7295396, rs737280, rs375329393, rs9706432, rsl0849979, rs7309970, rsl6941724, rsl2580246, rs4767284, rs60998439, rsl2319718, rsl 1066127,17056242423.3Attorney Docket No. 046483-7468W01(04021) rs7952986, rsl 1066128, rs79761579, rs58368428, rs74778442, rs7314282, rs7298532, rs2339973, rs4767364, rs60690688, rsl0850001, rs60549974, rs3519, rsl2423572, rs74187049, rs3741993, rsl6941909, rsl2423268, rs7295628, rsl005902, rs58249241, rs!2424641, rs7977534, rsl0161290, rsl0850024, rs77468840, rsl468252, rs60728177, rsl 1066308, rsl2423190, rs7953150, rsl0850043, rs77779680, rs78205093, rs2216475, rs7956523, rs!0850459, rsl0850462, rs7133396, rsl 1832443, rsl 17113238, rsl 1616030, rs719450, rs2280168, rs3759402, rsl800574, rsl83144890, rsl l69076, rsl0840641, rs7312404, rsl2301673, rs75989601, rsl0846582, rs4764132, rs61922971, rsl 1056376, rsl0846157, rsl0848574, rs555044, rs7969761, rsl0848644, rs73075659, rsl0771021, rs7296821, rs2239062, rs56196860, rsl 1614061, rs28990715, rsl81112800, rsl7688567, rs7977942, rs7980759, rs34623502, rsl7695429, rs79050656, rs!2426678, rs7296615, rs73047059, rsl6930370, rs632887, rs6489451, rs6869, rs4766091, rs55979725, rs899159, rsl259389, rsl234035, rs7300560, rsl234052, rsl234054, rs7958455, rsl234002, rs7136038, rs7305763, rsl0880224, rs824688, rsl688855, rsl994284, rs824700, rs824701, rsl095048, rsl095054, rsl095055, rsl095056, rsl732350, rs6582378, rs824716, rs824717, rs824718, rs844046, rs824722, rsl688884, rs865420, rsl463613, rs2629522, rs3852592, rsl683202, rs712106, rs824734, rs712114, rs712120, rsl2309460, rs4766230, rsl2815443, rs78470967, rsl7177326, rsl 1063202, rs2909380, rsl45878042, rs2544025, rs34922454, rs2228570, rs536750977, rsl82464338, rs2634675, rs3730071, rsl 126930, rs3782357, rs75022468, rs78097831, rs7313400, rs4898530, rs4463912, rs3205718, rs7132908, rs836968, rsl 1169571, rs319943, rs319944, rs2630353, rsl 13346821, rs2554861, rs829016, rs319938, rsl48940696, rsl48043157, rs2630367, rs319930, rs55874852, rs77481269, rs2554859, rs2554858, rs2046498, rsl095998, rs829023, rs706803, rs706804, rs829021, rs2277383, rs2293093, rs3847858, rs7974773, rs61914027, rs58617820, rs61914028, rs4761839, rsl 1610143, rsl 1612312, rs813469, rs813470, rs772222, rsl0876222, rsl 1169970, rs2242106, rsl 1169971, rs34437092, rs2252526, rs7301802, rs4762039, rs2854464, rs2359997, rs7306790, rsl0747655, rsl0876470, rsl 1170630, rsl7102221, rsl 1543260, rs7302925, rs2277339, rs3741580, rs7964492, rsl0877033, rs4128707, rs6581157, rs6650219, rs3751331, rs4335583, rs9971722, rsl0783857, rs7298370, rs6581159, rsl2308413, rs2372309, rs2888288, rs4272820, rsl 1172387, rs4373979, rs4534624, rsl0783859, rs6581161, rs4760346, rs4590915, rs4509811, rs3751327, rs3751326, rs!0783860, rs7959475, rsl0877043, rs4760352, rsl0877044,17156242423.3Attorney Docket No. 046483-7468W01(04021) rs4362183, rs4606520, rs7132521, rsl 0783864, rs2659662, rs2659659, rs2089377, rs2720191, rs3913866, rs7135728, rsl7120179, rsl7120182, rsl2820787, rs871907, rsl0877055, rsl911260, rsl0877056, rsl506890, rs4435045, rsl 1834807, rs7308860, rs7309322, rsl605329, rsl605330, rsl605331, rsl857941, rsl0783867, rsl0783868, rs4444117, rs4465402, rs7980024, rs7979813, rs7966544, rsl2369381, rsl 1514202, rsl 1495528, rs2466160, rs6581184, rs7133552, rsl0783873, rs982492, rs982493, rs4760188, rsl580976, rsl580977, rs2720179, rsl0877063, rsl 1172456, rs2720178, rs2720176, rsl395511, rsl567130, rsl0878301, rs4257020, rs7971777, rs4237904, rsl0784472, rsl0784473, rs4556591, rs4762101, rs4254112, rs4540868, rs7308104, rsl0784477, rs7308337, rs4536280, rsl0784478, rs4301828, rsl0784480, rs4762103, rs4762104, rsl0784481, rsl 1175835, rs2468388, rsl0878305, rs2248625, rs7976914, rs61921604, rs4992846, rsl0506473, rs59806226, rs61921608, rsl 1175978, rsl 12299942, rsl 1175981, rs3115954, rs77034711, rs77548748, rsl 1064333, rs2286730, rs9478, rs775636, rsl252424, rsl252423, rs710627, rs710624, rs775624, rs710623, rs710622, rs775628, rsl252410, rsl 152901, rsl 152900, rs800167, rs775661, rsl697233, rs775308, rsl252422, rsl 152896, rs775310, rs796508, rs811820, rs2248751, rsl658780, rsl 143954, rs710630, rs710629, rsl621634, rsl 152895, rsl252402, rsl252364, rsl082700, rsl066387, rsl066388, rsl066391, rsl066395, rsl082701, rsl066399, rsl082702, rsl 161092, rsl 184743, rsl 177317, rsl082709, rsl082708, rsl092475, rsl082711, rsl 143948, rsl252414, rs710798, rs775650, rs7136124, rs61918326, rsl0878963, rsl2827594, rs7959452, rsl0784774, rsl384, rs7296920, rsl275609, rs75565148, rs74556661, rsl2316443, rsl 1109717, rs7971664, rs2403151, rsl2579095, rs2403155, rsl7011446, rs56260363, rsl2579559, rsl2580431, rs9943755, rsl 1608921, rs61927574, rs61927575, rs61927576, rs76674639, rs2279574, rsl2369904, rsl0506965, rsl 1047939, rsl 1048037, rsl 1048063, rs4883201, rsl805776, rs3026261, rs4842695, rs60343103, rs2053196, rs2072593, rsl l4697502, rsl 13918189, rsl 1107523, rsl 1107530, rs!3377736, rs7995703, rs!84548, rs77279628, rs!2427994, rs4142040, rs872589, rs872587, rs913746, rs9521717, rs9521718, rs9521720, rs9521721, rs9515196, rs9515197, rs9559780, rs7333748, rs7333596, rs9555692, rs9559781, rs4773169, rs9555694, rs4773170, rs4773171, rs9559797, rs6492273, rs7787, rs9506541, rs7326074, rs55641580, rs55840438, rs2149077, rs7994814, rs4454823, rs4771085, rs2148758, rs7318048, rs56181982, rs7995310, rs2149129, rsl 1616427, rs2481951, rs61944748, rs!42386496, rs461189, rs465056, rs404234, rs457707, rs365873, rs2755233, rs2755236, rs73173150,17256242423.3Attorney Docket No. 046483-7468W01(04021) rsl 170178, rs!2585075, rs!2876965, rs71429406, rs!2872074, rsl2585865, rsl2877052, rsl0492439, rsl7645560, rs60039389, rsl2863254, rsl3378979, rs78087039, rsl 12435975, rsl 11658977, rs9567207, rsl 13541848, rs9562802, rs9526445, rs2252544, rs58325618, rs41284816, rs770379, rs770380, rs770383, rs770384, rs770386, rs770388, rs706602, rs706601, rs770391, rs770392, rs770393, rs770394, rs770395, rs770396, rsl239707, rsl239703, rs947383, rs947382, rs947380, rsl239696, rs!239695, rsl271766, rs!239693, rsl239692, rs!239691, rsl239690, rsl239689, rsl239688, rsl239687, rsl270717, rsl239686, rsl239684, rsl239683, rsl239682, rs476990, rsl239675, rsl239674, rs677585, rs484304, rs797512, rs797517, rs797519, rs2497087, rs797472, rs797536, rs797537, rsl772872, rs2794468, rsl272436, rs7989991, rs7990306, rs750176, rs9535492, rsl570603, rs9535494, rs4312209, rsl841677, rsl 1148198, rs2061624, rs9535495, rs9535496, rs9535497, rs9316505, rs9526693, rs9568476, rs9563002, rs9568481, rs4360838, rs8002319, rsl 1616586, rsl 1617765, rs9591371, rs7992624, rs7993060, rs9526698, rs7491820, rs8000150, rs8001874, rs9535519, rs7323313, rs9535522, rs7335786, rsl041017, rs9526703, rs9526706, rs74080784, rs73525441, rs716877, rs303937, rs303933, rs9543208, rs7489384, rs7489409, rs59660046, rs9318186, rs9530201, rsl7290460, rsl7218496, rsl l3319799, rsl l2091740, rs78396746, rsl7219517, rs7991281, rsl l2800422, rsl 11914166, rsl0507822, rs7338608, rs7337594, rsl7062027, rsl7311314, rsl7219984, rs2025532, rsl 11841167, rsl46537811, rsl41110431, rs77394627, rsl7311461, rsl0507823, rs76319853, rsl7062045, rsl2870505, rs78851859, rs78062845, rs7981330, rsl957452, rsl2432201, rs78523130, rsl 13911074, rsl 1848096, rsl2587475, rs34076421, rsl0133357, rs75741145, rsl2893211, rsl 1160626, rsl537763, rs2152370, rsl537761, rsl 1160627, rsl 1621508, rsl2882087, rs4900485, rs7493865, rs2273905, rs4900538, rsl951629, rs942021, rsl 1622216, rs35785423, rs4906246, rsl 1626274, rsl 1628569, rsl 1160698, rs35696698, rs34010412, rs7143468, rs911555, rs911554, rsl 17507755, rs67110142, rs2582565, rs8008126, rs28593146, rs587653404, rs564681644, rs8021296, rs6736, rs7152493, rs7148564, rs2231806, rs875908, rs2273171, rs61976859, rs7494025, rsl0151563, rsl2889162, rsl0135213, rsl0138200, rs6571403, rs6571404, rsl041088, rs9788563, rsl0151517, rsl741177, rsl884803, rsl956438, rs2064665, rsl 1157727, rsl2586183, rs9944008, rs60692740, rs4900987, rsl955927, rsl l850798, rsl l l57729, rs74244415, rsl0483600, rsl 1157731, rsl950510, rs7160591, rs73289637, rs79866668, rs58509432, rs73291657, rs73291663, rs3783419, rs2273326, rs72683923, rsl557010, rs3783412, rsl7563, rs2071047, rs2761884, rs2738265,17356242423.3Attorney Docket No. 046483-7468W01(04021) rs78748659, rsl 0144425, rs76936296, rs34642953, rs74555566, rs7141548, rsl 1620803, rsl0142814, rs28546344, rsl46194354, rs28707162, rs7158665, rs4901541, rsl254028, rs8016830, rs7157442, rs7153820, rs35211290, rs2882531, rs8012628, rs61995385, rs76163472, rs2093210, rs33912345, rsl7097602, rsl2889678, rsl0873205, rs7141506, rs6573781, rsl 11598706, rs3759757, rsl314911, rsl314916, rs727129, rsl7106213, rs58638884, rs56119720, rs72731550, rsl2893429, rs2293793, rsl0142359, rs61987137, rs61987138, rsl 1625677, rs61987140, rs7159760, rsl 1159028, rsl45538420, rs61988862, rs61988863, rs61988864, rs62004868, rsl 11511359, rs55910602, rsl 1621868, rs73295349, rs55746412, rs62004878, rs62004879, rsl 11424562, rs62004881, rs72719670, rs2070598, rsl860935, rsl2894709, rsl2887934, rsl45995745, rs7140952, rs56033314, rs2267872, rs8009555, rs6574551, rs!0144099, rs9972275, rs9972105, rs7145153, rs7350729, rs7145584, rs7159642, rs7160310, rs28758824, rs61989398, rs7155755, rs7156362, rs7156387, rs983228, rs983229, rs724802, rs61989399, rsl955625, rsl7110492, rs2160354, rs55884286, rs2295138, rsl80814424, rs3742553, rs3853417, rsl 1625151, rs59787626, rsl2881349, rs61981188, rs36014449, rs4904252, rsl955435, rsl0873367, rs34485385, rsl 1845293, rs35823815, rs3179969, rs60503594, rs2116445, rs7153464, rsl0142128, rsl0133955, rs4301958, rs7150111, rs60358112, rs72697283, rs2093595, rs73330136, rsl 12146012, rs73330137, rs72699835, rs8017636, rsl 12560164, rsl 1160096, rsl2588550, rs56258011, rs4905017, rsl2883201, rsl044780, rsl 1160318, rsl889371, rs881163, rsl 1160320, rsl0873469, rsl 1625405, rs56261560, rs2614489, rsl 1160508, rs7143531, rs2614453, rsl86694602, rsl 1633550, rsl 1634006, rsl2915406, rs34471260, rs28465416, rsl2911429, rsl 1070167, rsl 1630786, rs79401209, rs3900905, rs2925345, rs2412608, rs56383987, rs55973132, rs2271436, rsl47298709, rs7174075, rs59368522, rs74467424, rsl648286, rsl648285, rsl631533, rsl706837, rs28877685, rs4775822, rsl 1854234, rsl 1854294, rs28859291, rs2413783, rs7165889, rs4775832, rs4775834, rsl 1636018, rs4238377, rsl6941238, rs8033317, rs61300393, rsl46625690, rs2433611, rs2486274, rs8024550, rsl 145077, rs79876890, rsl2439429, rs28375625, rs28495639, rsl2905525, rs6416445, rs732761, rs2470176, rsl906402, rsl906403, rsl906404, rsl7730281, rsl 12744790, rs578595, rs551225, rsl664449, rsl664448, rsl706341, rsl706340, rs7177920, rsl 1854842, rs2440968, rsl664446, rs2007058, rs2591064, rs8038172, rs!706406, rsl706403, rs!664444, rs7161907, rs2668179, rs2591065, rsl l631792, rs2414502, rs878958, rsl567620, rs!3380261, rs7169351, rs7169074, rs7169100,17456242423.3Attorney Docket No. 046483-7468W01(04021) rs4774939, rsl 867644, rs4774946, rsl 292363, rsl 50932609, rsl 81 92246, rsl 994887, rsl 17047297, rs75079269, rsl 1857838, rs59066984, rs9944289, rs9944168, rs28817334, rs8031321, rs28422841, rs28392952, rs28698238, rs!868243, rs2453089, rsl 107113, rs2451184, rsl 15452326, rs58646822, rs956006, rsl2915597, rsl2904839, rsl2438162, rs4775517, rs4569205, rs4265758, rsl2437894, rsl0851714, rs4774442, rsl2913538, rs2729806, rs2652806, rs2652805, rs2652804, rs2729805, rs745338, rsl 16907180, rs74018963, rs74018964, rs74018965, rs74018967, rsl 11642201, rs55657486, rs61300710, rs74018111, rsl l3523730, rs2228513, rs74692183, rs77106746, rs79503123, rs76640183, rs33918653, rsl2439510, rsl2441199, rsl0851749, rs4776806, rs8042578, rs56385383, rs62005619, rsl 1632964, rsl 1637537, rs4601989, rs79483120, rs4776343, rsl 1638064, rs7165382, rs34708051, rsl866320, rs7166081, rsl6954772, rsl 1852677, rs28695177, rs58378691, rs62019060, rsl 15644060, rs7177798, rsl2593783, rs2472297, rs2168518, rs8026273, rs4886658, rs8028146, rs72730601, rs4886422, rs4886661, rs4243032, rs8029760, rs6495155, rs7178005, rsl2442392, rsl2442410, rsl2914536, rs8033754, rs8025412, rs56139080, rs8034430, rs57968453, rs335713, rs62027568, rs78430278, rsl910510, rsl532783, rs9672219, rs7177266, rs974718, rs74024021, rs74024022, rs74024023, rsl 15407087, rsl0468062, rs4886750, rs335695, rs335694, rs335693, rsl394122, rs335675, rs335676, rs335679, rs335724, rs335725, rs8035611, rs2648437, rs59839117, rs74024029, rs7182720, rs335728, rs74024030, rs58044283, rs61521312, rs8030469, rs74024032, rs79798377, rs74024035, rsl39211312, rs76428135, rsl37935316, rs2133409, rs75886617, rs74024040, rs74024041, rs74024047, rs75279464, rs74024048, rs74024051, rs74024052, rs74024053, rs78434972, rs58789594, rs59819402, rs7181550, rs78514161, rs78037048, rs56173902, rs8025372, rs57737646, rs59690620, rs334951, rsl45727191, rs7174365, rs74024059, rs7173697, rs55665712, rsl0851885, rs74024060, rs7177048, rs60847237, rs9745107, rs9745133, rs9745164, rs334947, rs7162085, rs8029069, rs8028990, rs8028995, rs!42931687, rs74024064, rs74024065, rs7174280, rs58170668, rs8038740, rs74024068, rs76618651, rs74024069, rs6495191, rs8031263, rs74024073, rs57971067, rs57141410, rs58717562, rs80297148, rs62027652, rs2959851, rsl498198, rsl498197, rs35743198, rsl2911337, rsl2909723, rsl2902022, rs56117933, rs79067624, rsl 12238647, rs57708073, rsl2438645, rsl 17355348, rsl 17288281, rs2135881, rsl 1852715, rs79754687, rs73507434, rsl 1072966, rs7165424, rs8039384, rs8039607, rs371891811, rs78366152, rsl 1259952, rsl7507300, rs7169629, rs6496791,17556242423.3Attorney Docket No. 046483-7468W01(04021) rs28521166, rsl2592350, rsl 1858729, rs7167563, rs7167604, rs6497202, rs77264130, rs62020772, rs77032376, rs78550103, rsl 1630039, rsl 1074115, rs2119011, rsl992283, rsl0775257, rsl2908494, rs7173103, rs7173429, rsl 1857807, rsl2439642, rs8038278, rs8039706, rs8038957, rsl2440648, rsl2440633, rs2130888, rs7174817, rs2130887, rs2399761, rs9673018, rs9673020, rsl2915382, rsl2905983, rsl491175, rs8024493, rsl573891, rs45557931, rsl567811, rs3743263, rs74032572, rs8037855, rsl2437561, rs45619933, rsl85005, rs246215, rs35591, rs3851711, rsl 13956264, rsl40185678, rs338781, rs338782, rs2531327, rs2754184, rs338783, rs338784, rs338787, rsl7135716, rs7203846, rsl800705, rsl85355445, rs4018130, rsl 1861948, rs78398423, rs45592239, rs7498751, rsl3334589, rsl3329952, rsl2917707, rs77924615, rsl3334633, rs7195855, rs2221448, rsl2598584, rsl63278, rsl63277, rsl63275, rsl63274, rs9926773, rs7189996, rs7190032, rsl2599015, rs34976834, rsl2925057, rs7202719, rs7202568, rs6497535, rs6497536, rs8052157, rs6497537, rs7198998, rs8058582, rs6497539, rsl2446383, rsl 1074484, rsl3330546, rsl2708641, rs7191235, rs7191654, rs7198224, rs7196889, rs7198205, rs7204599, rs2031082, rs2031083, rsl2597357, rs7184238, rs7185097, rs7193676, rs8182130, rsl2386036, rsl882708, rs2280765, rsl3338482, rsl203979, rs7189020, rsl 1647490, rs71374885, rs72768728, rs56015787, rsl469396, rs4787971, rs756950, rsl005588, rs4787974, rs4787975, rsl 1639554, rs4787979, rs233453, rs233460, rs233464, rs233469, rs233471, rsl2933850, rs28535114, rs9923875, rsl2923861, rs964002, rs9923148, rsl2930355, rsl2924688, rsl2102783, rsl2928569, rsl2924607, rs8046545, rs2071342, rs35979293, rs79684678, rs9790, rsl635404, rsl30025, rs73501791, rs8057701, rs78320503, rs495664, rs7200336, rs8058761, rsl 17986012, rsl 16971887, rsl465338, rsl965024, rs56210058, rs728538, rs2193098, rs4306507, rsl544638, rsl3336117, rs4784296, rsl2596721, rs62039768, rs62039771, rs8062173, rs57698767, rs62039772, rs62039773, rs62039775, rs8047872, rsl43024692, rsl6949932, rs74855061, rsl2927956, rs34869093, rsl 118252, rs68152003, rsl 1862746, rsl 1863789, rsl 1862845, rs7196485, rsl 1859591, rsl7303177, rsl6952242, rs72801818, rs72801825, rs7189726, rs8054299, rs8044205, rs72801853, rs60420081, rs62048543, rs7194519, rs62048544, rs3809634, rs9937521, rs28562191, rs9937053, rs9937354, rs9930333, rs9930397, rs9939973, rs9940646, rs9940128, rsl421085, rsl 1075985, rsl7817288, rsl 121980, rs7187250, rs7193144, rs62033399, rsl7817449, rs9972653, rsl 1075987, rs8050136, rs8051591, rs9935401, rs9931900, rs56313538, rs9936385, rs9923233, rs9923312, rsl 1075988, rsl 1075989,17656242423.3Attorney Docket No. 046483-7468W01(04021) rsl 1075992, rs9926289, rs9939609, rs7206629, rs72021 16, rs7202296, rs66908032, rs72803697, rs62033403, rs62033404, rs7206122, rs7190396, rs7185735, rs79994966, rs62033406, rs9941349, rsl0468280, rsl7817964, rs9930501, rs9930506, rs9932754, rs72805611, rs9922619, rs7188250, rs72805612, rsl 1075993, rsl 1642841, rsl6952577, rs2388407, rsl6953241, rs7200222, rsl2596433, rsl2929759, rs2292318, rs3785100, rs2285910, rs76501820, rsl 124993, rs6499165, rs8045705, rs2287970, rs8048032, rsl 1075728, rs74697196, rsl 1642115, rsl 1641050, rs3885612, rsl6958970, rs55751101, rsl2449005, rsl2596823, rs74026882, rsl 1646884, rs39999, rs8060588, rs56316408, rs8045142, rsl0500551, rs2217950, rs60010276, rs2118220, rs60472033, rs9788837, rs76407217, rs8053080, rs8047885, rs8054096, rsl0454066, rs75815213, rsl6959035, rs9933526, rs9921045, rs3743673, rsl 12668868, rsl 13052188, rs77944668, rsl2447883, rs57565297, rsl2595869, rsl865965, rsl2232410, rsl0163235, rs57488237, rsl0048108, rsl800566, rsl437135, rs2196574, rs2361839, rs689455, rsl 13680693, rsl 1075733, rs4985523, rsl47922055, rsl47983035, rsl 1639902, rsl035543, rs61344899, rsl 1075947, rsl858800, rs8049936, rs7498798, rs6499607, rs79193369, rsl7767491, rsl7767742, rs57652769, rs62042361, rs4627365, rs7202443, rs9925586, rs9932786, rsl3334483, rsl0459870, rs7193865, rs7194288, rs62050386, rsl2446534, rsl2444518, rsl2596682, rsl2597207, rs62050388, rs7201564, rs71386289, rsl484029, rsl 1150276, rsl0514496, rs55896457, rsl6953274, rsl6953276, rs55958632, rs8043750, rs!6953280, rs62050395, rsl6953281, rs62050422, rs62050423, rs9972739, rsl2598715, rs60512064, rsl2599299, rsl2445223, rsl 1150279, rsl 1150280, rsl 1641604, rsl2051123, rsl 1150281, rsl 1642153, rsl 1647859, rs55661884, rs7204337, rs7206242, rs7190998, rs7194714, rsl 1150282, rs4410098, rs4398122, rsl2447891, rs8053017, rs4889151, rs7192257, rs4889152, rs4889153, rs62048420, rsl 1859045, rs55863307, rs56055503, rsl6953530, rs62048424, rs4635359, rsl 1649447, rs59455907, rs58780057, rsl 1860841, rs34423425, rs55772308, rs4889154, rs4586444, rs4491516, rs4359453, rs4533300, rs4522433, rs4888092, rsl l644540, rs35968504, rs9931063, rs935942, rsl 18049419, rsl2925668, rsl2928588, rsl2933677, rs77204347, rs62048202, rs3785012, rs4782583, rs8050617, rsl2923987, rsl6963074, rs56796255, rsl 1646443, rs4782652, rs4510001, rsl874013, rs4783086, rs4783087, rs4843382, rs77626209, rs67782872, rs67785750, rsl0514617, rs6540124, rs6540125, rs7186900, rs7205205, rs7205819, rs6540127, rs7498866, rs7499535, rs7194478, rs6540128, rs4843282, rs7199429, rs7206461, rsl2919526,17756242423.3Attorney Docket No. 046483-7468W01(04021) rs7202314, rsl 2933782, rsl 2933332, rsl 2920047, rsl 11 17324, rs4843751 , rs8052540, rs8052276, rsl 1640695, rsl 1117332, rs8052854, rsl 1648707, rsl 1639873, rsl 1645107, rsl l645250, rsl l639761, rsl0863195, rsl2934520, rs4843768, rs7191387, rs7191581, rs7186583, rs7187459, rs4843772, rs4843773, rs7206128, rsl 1117346, rs579740, rs35643952, rs34789784, rs9939155, rs9941273, rs9929579, rs4566167, rs9926404, rs7200693, rsl2325600, rs4290474, rs9922341, rs!54656, rs7503401, rs2322286, rsl903280, rs61130577, rs35309210, rsl 1078058, rsl 1078059, rs9910495, rsl 1078060, rsl 1078061, rsl0852806, rsl6945729, rs9912833, rsl 1867186, rsl 1867213, rsl 1867266, rsl 1869842, rs60556358, rs34382539, rs62061038, rs4792246, rsl2325909, rsl2325911, rs73977843, rs7212658, rs6502181, rs7209139, rs8081668, rs28735420, rsl7626180, rsl 1652817, rs35701443, rs9893867, rs62088028, rs57937546, rs4791603, rs57437384, rs7215329, rsl 1658854, rsl0438712, rs8080011, rs4792555, rs4792557, rs4792558, rs73979047, rsl 1870422, rsl242483, rs746900, rs4646396, rsl2945144, rs35656361, rs9892560, rs9894321, rsl2941371, rs750546, rs936108, rs4646394, rs4646390, rs4646388, rs4646387, rsl 1651620, rs80097125, rs6502602, rs6502603, rs747770, rs4646385, rsl 1656215, rs4646368, rs4646359, rs4646358, rs4646356, rsl 1871667, rsl2942059, rs9894492, rs2131704, rs77017480, rs60355329, rs739830, rs2386316, rsl 1204343, rs4924992, rsl2937053, rs7207681, rsl0491097, rsl2602013, rsl2945111, rs4924994, rs8071408, rsl2939559, rs72838831, rsl 1658544, rs9910918, rs3901427, rs2453606, rs8078465, rs4531795, rsl 12323053, rs2453580, rs2018675, rsl41572615, rsl961669, rsl 11653425, rsl 15778474, rsl 15473784, rs2440158, rsl 971851 , rs36034566, rsl51167535, rs73275664, rs7503922, rs7502556, rsl2150665, rsl2937411, rs9889726, rsl l2901, rs525767, rs523120, rsl6968529, rs72821519, rsl l868029, rs4794813, rs4239222, rs4795384, rs2934966, rsl43517926, rsl 136201, rs34093201, rsl 104761, rsl7616543, rsl 12673090, rsl 17862245, rs573503384, rsl 13826025, rsl92858632, rsl 17374443, rs!43879261, rsl40262628, rs!90222807, rsl7678959, rs76375500, rs9909777, rs!7678990, rsl49754556, rsl7679086, rsl48396384, rsl41218028, rs77444159, rsl48449981, rs77893013, rs45612441, rsl40695349, rsl40263623, rsl46970846, rsl42550986, rs9891944, rsl41838399, rsl41464238, rsl39522626, rsl41005253, rsl90936664, rsl42892792, rsl89784411, rsl92794752, rsl 17577021, rsl92145896, rsl43250098, rsl 17293524, rsl89122060, rsl46780027, rsl38740713, rsl41810431, rsl50588974, rsl7679361, rsl41825199, rsl82939541, rsl88841379, rsl7617263, rsl86922993, rs74939509, rs4134998, rs4135005,17856242423.3Attorney Docket No. 046483-7468W01(04021) rs4135012, rs4135019, rs4135027, rs4135030, rsl 17488810, rs8079103, rsl 16865519, rs75309102, rsl37891066, rsl47747703, rsl40987324, rsl43494424, rs77015611, rsl90676187, rs77209292, rsl40872469, rsl 17494298, rsl40235616, rsl45108176, rsl41223821, rsl45105278, rs33998939, rsl86956796, rsl82610022, rs35783632, rsl 17736199, rs41283423, rs2229773, rsl41158879, rsl90192989, rsl82057668, rsl 16430199, rsl 17989407, rsl45033369, rs!49530458, rs77924872, rs!40144680, rsl44629348, rsl7680704, rsl 1867902, rs79875164, rsl43836380, rs2306581, rs4796791, rs34638441, rsl0840, rs880690, rs8066100, rs76280636, rs2074292, rs4792846, rs62071986, rsl97907, rsl97911, rsl97913, rsl97915, rsl662594, rs4968248, rsl052504, rsl623402, rsl662597, rsl 1658276, rs2920397, rsl 1654971, rsl97916, rs7225428, rsl97920, rsl0853086, rs2072317, rsl 1655668, rsl97922, rsl97923, rsl838105, rs8065527, rsl 1079744, rs3885731, rs3890958, rs62075895, rsl6941404, rs!2600452, rs4794426, rs77694071, rsl42760320, rsl 12875011, rs56093336, rs594398, rs35513882, rs8078806, rsl463761, rsl 16440021, rsl 1870618, rsl 12123549, rs67560975, rsl533922, rsl533920, rs598905, rs2898945, rsl6949120, rs80277878, rs76022681, rsl2943759, rs7501581, rs7224610, rsl2951993, rsl7822403, rs72837328, rs55688501, rs55815590, rs72837329, rs72837330, rs62058023, rsl7833884, rs62058026, rs9894517, rs9902064, rs792405, rs792365, rs71387499, rsl2949598, rs2643126, rs304265, rsl 1653697, rs6503921, rs8076752, rs7206932, rsl 1868647, rs9915951, rs9916000, rs78224430, rsl292070, rs60167359, rs9905761, rsl 1657044, rs28559726, rs9895661, rs2240736, rsl89987386, rs7210758, rs4968645, rs7212455, rsl 13731184, rs8866, rs34685754, rsl2601759, rsl 1656743, rs62086884, rs4791295, rs28855509, rs74564337, rs62086889, rs78186330, rs62086897, rs62086898, rs62086899, rs62086903, rs62086904, rs62086906, rsl89628481, rsl92988621, rsl 83763906, rs200026262, rs62086907, rs62086908, rs7405987, rs8076753, rs78794747, rs79778350, rs62084669, rs77536355, rs35229997, rs7226002, rs62084681, rs75236169, rs62084682, rs!2752, rs7214869, rs7214119, rs8075764, rs6504576, rs62084689, rs62084692, rs62084694, rs62084697, rs4638, rs62084703, rs74354868, rs75885145, rs7214557, rs7503050, rs7503056, rs7503206, rs7503810, rs62084708, rs78192857, rs35040337, rs28580652, rs74976757, rs62084740, rs74900486, rs75544834, rs9674669, rsl 84478609, rs9330556, rs62084742, rs34937122, rs78352159, rs62084744, rs76877263, rs62084752, rs28512206, rs62084755, rs75868869, rs3764855, rs3863515, rs7216182, rs883541, rsl46388015, rs36068942, rs56038313, rsl2452519, rs56156468, rsl l3292722, rs746991, rsl41015869,17956242423.3Attorney Docket No. 046483-7468W01(04021) rs6146151, rs4788885, rsl642797, rs! 642802, rsl641542, rs! 642803, rs!642807, rs! 641536, rsl641535, rsl641534, rsl641532, rs2541011, rs2543554, rsl641528, rsl641525, rs2955610, rsl641522, rsl641521, rsl641520, rsl641519, rs2541010, rs2543556, rsl641517, rsl641516, rs7216615, rs2061387, rs7217432, rsl 1870078, rs3744008, rs9903200, rs2410859, rs9900122, rs2290771, rs2004452, rs936396, rs936393, rs936391, rs9906971, rs9894009, rs58363746, rs57287238, rsl463485, rs936394, rs9897770, rs4588035, rsl2103594, rsl 1867560, rsl 1867582, rsl 1869977, rs8082060, rsl 1870142, rs55699990, rs55992471, rs56098714, rsl 1867315, rsl 1867339, rs8081606, rs2034945, rs2034946, rs2034947, rs56901103, rs72860389, rs9674908, rs2199048, rs56040381, rs72860390, rs66584478, rs3744017, rs3744020, rs3744021, rsl055129, rs56000661, rs59623743, rs60059537, rs78866233, rs7207180, rs34974290, rs3744028, rs9902371, rs61730171, rs2748425, rs34337072, rs4490057, rs4366775, rsl2938284, rs3816263, rsl442850, rs9893434, rs2585408, rs7211681, rs7209156, rs67050149, rsl2948708, rs8081274, rs4797782, rsl 12006560, rsl 17441302, rsl 17159665, rsl 18035855, rsl41172991, rs45579846, rsl2960229, rs9957194, rsl48477096, rs973730, rsl3381941, rs2658450, rsl40148428, rsl318652, rs2850567, rs7407412, rs77637769, rs2847125, rs73427772, rsl 1661119, rs2850576, rs2959514, rs3017644, rs45613238, rsl 1665314, rs2959517, rsl 1659957, rsl 1660772, rs6508540, rsl 1660450, rsl 1659365, rsl 1083274, rs6508544, rs4625812, rsl 17385602, rsl 1877859, rs7226385, rs7234061, rsl l7723077, rs9961451, rs67945028, rs7226554, rsl2455558, rs7232531, rs527616, rsl6942751, rsl62009, rsl51245, rs875426, rs4315413, rsl46750662, rsl50233857, rsl356505, rsl518166, rsl 518167, rsl401007, rsl518171, rs7244875, rs7244636, rs35735971, rsl 1876609, rsl6977323, rs4890432, rs4407138, rs8098753, rsl518143, rsl356501, rs4890439, rs28597806, rs62092069, rsl424392, rsl424394, rs7238152, rs918817, rs918818, rs918819, rsl607338, rsl 1876807, rsl0502839, rsl2958322, rs79926430, rs62090594, rs34233878, rs!0163551, rsl0438961, rsl7740231, rs9807214, rs!0083997, rs7237237, rs56122603, rsl2457237, rsl2456693, rs9952412, rs9945126, rs3736242, rs357897, rsl288797, rsl 12311990, rs72934723, rsl 1659764, rs72936874, rsl84332798, rsl785418, rsl87882656, rs66922415, rsl0871777, rs476828, rsl 1152213, rs8097210, rs8089364, rsl2969709, rs921971, rsl2958167, rsl2954782, rsl942872, rsl2955983, rs2045439, rsl2970134, rsl 1660069, rs35476226, rs67713315, rs56804022, rs8083289, rs!2956871, rsl2960928, rs590215, rs34893777, rs2168708, rsl2966550, rs56069042, rsl 119497, rs76632317, rs74781103,18056242423.3Attorney Docket No. 046483-7468W01(04021) rs79078733, rs77505623, rs76149329, rs79601081, rsl 16886631, rs8089191, rs59277369, rs34212978, rs4987719, rsl 1151938, rs6566789, rsl 17334014, rs470335, rs470933, rsl 1876196, rs470907, rs8096658, rs62096864, rs562952, rs4799053, rs549752, rsl 17011420, rs304933, rsl0438902, rs4799117, rs4799118, rs4799120, rs4807624, rs34188292, rs4804592, rsl 16886975, rs59431306, rs77279095, rsl60838, rsl67479, rsl0419627, rs2974751, rs!0410950, rs73507341, rs2305780, rs6511912, rs74183052, rsl42096538, rs74183053, rs3760702, rs2241358, rs4809184, rs4809185, rs4808301, rs6512029, rs8109755, rsl0411669, rs7247749, rsl2972998, rsl0414131, rs7253443, rs4808302, rs4809189, rs6512030, rs35663425, rs34239025, rs62123690, rs393540, rs845371, rs411130, rs379494, rsl 1667505, rsl 1575926, rs845328, rs433821, rs845332, rs399343, rs55881864, rsl469024, rsl075403, rsl0416600, rs8110070, rs8113367, rs4531856, rsl2608504, rs7247222, rs7256111, rsl2973608, rsl2980403, rsl2610373, rsl 1086102, rsl 1670056, rs60570301, rsl 1086119, rs4808154, rsl2610715, rs74736618, rsl 1878358, rs2240012, rsl50611747, rsl 17843432, rsl87429064, rs56255430, rs2905426, rs2905427, rs2965185, rs886449, rsl003531, rs2301800, rsl2981430, rsl 17415941, rsl46982937, rsl0413027, rs718202, rsl 1085020, rsl0417797, rsl 11590167, rsl2976336, rs79645906, rs8104077, rs3786900, rs73927890, rsl269214, rs3814995, rs28608841, rs28555503, rs3816390, rsl0404069, rs4806414, rsl0407224, rsl0417545, rsl0405372, rsl0425441, rs4805207, rs28701616, rsl0411176, rsl2975869, rsl529957, rs7246657, rs6508710, rsl2972195, rs558072242, rs573082306, rsl2982333, rsl2709812, rsl823061, rs67293224, rs7408563, rs7259968, rs6508711, rs6508713, rs6508714, rs6508715, rs6508716, rsl3345148, rs7257672, rs7257495, rsl0404602, rs200494406, rsl0412043, rsl2104381, rsl2104380, rsl0415937, rsl0414904, rs28402338, rs!0417844, rsl373991, rsl0405407, rsl2709813, rsl3345116, rs4803347, rs7247259, rs35085437, rs3745765, rs4803229, rsl559229, rs6508719, rs4452075, rs4803460, rsl035479, rs3803895, rs28623164, rs7252346, rs!2979470, rs2891699, rs9676967, rs8112610, rs8109632, rs7255407, rs7256130, rs2112923, rs3760825, rs2112922, rsl0420754, rs59224125, rs2081096, rs7253091, rs28605784, rs28373708, rsl382357, rs2045908, rs7253114, rs2126977, rs7248733, rs2291004, rs6508732, rs6508733, rs4803195, rs4803210, rs4803215, rs9797618, rs2291002, rsl0425795, rsl0404031, rsl0406379, rsl0412786, rsl564206, rsl564208, rs954504, rs4803231, rsl0420552, rsl0420268, rs8110865, rs4803233, rs4802024, rsl975939, rs9304568, rs4802029, rs28512414, rs6508736, rs9941475, rs4803262, rs4803263, rsl0408619, rs4802051, rs4803276,18156242423.3Attorney Docket No. 046483-7468W01(04021) rsl 0412510, rs3829688, rs!3744, rsl 0403173, rs4803287, rs!2461113, rsl 2459015, rs! 531549, rsl975937, rs8103647, rs8100646, rs35863684, rsl0402671, rsl0417576, rsl0407568, rsl0409605, rsl6958861, rsl6958863, rs2972447, rs2972446, rs2927742, rs2927740, rs3101747, rs2927739, rs9749368, rs2972452, rs2927746, rs2927747, rs2909105, rs2972448, rs3112433, rs2909085, rs2909088, rsl2979640, rsl 1083432, rs62108337, rs2287229, rs958305, rs968073, rs56317671, rs7246461, rs2972434, rs3112434, rs2909093, rsl974714, rs3095724, rs2972439, rs2909100, rs2972445, rsl291, rs241933, rs241932, rs8112706, rsl0048511, rsl71376, rs8111875, rs241950, rsl0420746, rs6508742, rs9304569, rsl0409402, rsl0409487, rs4803509, rs7257125, rsl0401968, rs3848626, rs8101752, rsl 12553171, rsl 1878269, rs8104076, rs4803524, rsl0420891, rsl2975057, rsl 1879180, rs8182498, rs8104454, rs4482405, rs4802135, rs201066921, rs8101858, rs7250868, rsl0401637, rs4803541, rs4803543, rs4239516, rsl 1083441, rs3786869, rs4802144, rs8113273, rs8108434, rs8109053, rs4802147, rsl2608883, rs28460297, rs4802151, rsl0404159, rs8113521, rs8109835, rs4803573, rsl0415548, rs705495, rsl725499, rs833927, rs705493, rs705491, rs353411, rs353410, rs353407, rs56300335, rs353404, rs353402, rsl725494, rs60450113, rs353428, rs353427, rs353426, rs353424, rs353421, rs353419, rs353418, rs353417, rs353416, rsl643469, rs377606551, rsl725485, rsl725482, rsl725481, rsl643463, rsl725480, rsl643461, rs833895, rsl643460, rs833914, rs28517878, rs61355521, rs34943246, rs8104873, rsl046268, rsl046278, rsl 1670591, rsl 1670641, rs78907076, rsl 11760718, rs737204, rs2379622, rs3760903, rsl 11211909, rs62131485, rs62131486, rs34150601, rs8102677, rs35747067, rs2084109, rs34966575, rsl867696, rs2379623, rs34853245, rs35364374, rsl47213895, rs28377909, rsl41727248, rs34716810, rs9304588, rs541195759, rs268679, rs34033973, rs268691, rsl74865, rs7255928, rsl0421779, rsl0425814, rs62106981, rs268696, rs3901215, rs2246095, rsl0425765, rs2262082, rs200729649, rs201777248, rs56113850, rsl0411377, rs2965142, rs419010, rs429358, rs7412, rs!800437, rs4802274, rsl6980013, rs915915, rs281380, rs60068692, rs606400, rs7251671, rs35430308, rs3810186, rs73046788, rsl87500064, rsl44782308, rsl2461216, rs73058052, rsl273636, rsl290751, rsl0407646, rsl062967, rs7256559, rs7256855, rs7256165, rs4801939, rs4803007, rs4801940, rs4801941, rs4803008, rs4803009, rs4801942, rs3960272, rs7257653, rsl 11951394, rs7259073, rs35231921, rs35901334, rs55759769, rs75406521, rsl 1666550, rsl 1670858, rsl 1670922, rs9304741,rs1044467, rsl808106, rs8111196, rs8111514, rs8112137, rs2115090, rsl 123975, rsl049230,18256242423.3Attorney Docket No. 046483-7468W01(04021) rsl049232, rs75383787, rs8108787, rs4804395, rs3745546, rsl2986062, rsl 864009, rs72992633, rs3865461, rsl0420976, rs6603079, rsl 1166440, rs2128416, rs72858515, rs72858521, rs3790638, rs284324, rsl2073762, rs36083532, rs6660242, rs811855, rsl 1121627, rs7528419, rsl2740374, rs72646553, rsl 149168, rsl765756, rsl 144595, rs201433929, rs556883943, rsl2129649, rs41283072, rs78366259, rsl2724682, rsl2722725, rs9429742, rs7516386, rsl7602729, rs57445665, rsl801133, rs34710782, rsl 1205303, rs6587723, rsl2048493, rs6693697, rs7554686, rsl 1811885, rs2762860, rs509345, rs471738, rsl776276, rsl 1580960, rs267738, rsl969442, rs2902811, rs2091219, rs6703620, rs6657593, rs6694158, rs7366148, rs6587552, rs6587553, rs2902810, rs2864700, rs3806387, rs3806386, rsl0749659, rsl524773, rs2140709, rs3738481, rsl5740, rs4970993, rs4970936, rs4970939, rsl2134957, rs4970940, rs6668894, rsl 1204769, rsl 1810447, rsl2039334, rsl2049116, rsl2039542, rsl2040729, rs6704195, rsl84026197, rs7514185, rs7536234, rsl 1204771, rsl0788798, rs7522608, rsl 1810510, rsl2093562, rsl 16222163, rsl2117163, rs4970941, rs6697617, rsl 1204777, rsl0788799, rsl 1204778, rs7523731, rsl 1204779, rsl 1204780, rs6676190, rs61819219, rsl 13869543, rs7522302, rs4970997, rs6656450, rs4970998, rs6702344, rs4970999, rs4971000, rs4360524, rs56033976, rs4357530, rs4971002, rs4971003, rs4971005, rs4971006, rs4971007, rs4971008, rs5023311, rs7546304, rsl2569193, rs56299877, rs4512652, rs56090305, rsl 1807526, rs6674970, rsl 1204782, rsl2087892, rsl 1807847, rsl 12627384, rs2067606, rs41305062, rs4522000, rsl0888411, rsl92154135, rs4971032, rs4970948, rs5022636, rs2800946, rs2800947, rs2769273, rs2025900, rs2769269, rs2769268, rs2769267, rsl752385, rs72640764, rs72640780, rsl079314, rsl 1588775, rs6690852, rs45619934, rs2862161, rs4661653, rs872222, rs6696951, rs6427184, rs9426886, rs4971100, rs2070803, rs423144, rs72704117, rs760077, rsl80921974, rsl40959946, rsl 14760481, rsl0908480, rsl 1264409, rs708611, rs72706174, rsl 13544820, rs822494, rsl40953793, rs74404550, rs2736609, rs2758607, rs2251636, rs2758608, rs2758609, rs2072929, rs2295363, rs2254669, rs2803312, rs2459988, rs2803310, rs2459989, rs2459990, rsl 108262, rs6693908, rs6701689, rs6694101, rs6684574, rs6684579, rs925905, rs2503713, rs698696, rsl2731820, rs36043745, rs2843156, rs2843155, rs903903, rs903911, rs7530619, rsl 13689711, rs6673221, rs76082781, rs74572798, rs78397470, rs77903064, rs74638219, rs557190940, rsl 13767154, rsl853395, rsl329964, rsl745611, rs!0917833, rs200802410, rs80263076, rsl41257545, rs3845534,rs4442348, rs662871, rs520131, rsl0800544, rs6665349, rsl0912848, rs2421841, rs4916394,18356242423.3Attorney Docket No. 046483-7468W01(04021) rs7536695, rs72717888, rsl 2024335, rsl 0489250, rs6665614, rsl 1584244, rsl 1584664, rsl39031539, rsl 1805471, rsl0911278, rsl7277295, rsl0797996, rs9425591, rsl0752946, rs9425316, rsl0752957, rs3213563, rs2301455, rsl 1576862, rs6680309, rs74127154, rs61820953, rs61820965, rs6678628, rs6678812, rs7553759, rs7522843, rs7514517, rsl0913143, rsl0913923, rs4256775, rs72723045, rs72707408, rsl2048020, rsl 1800333, rsl 1812056, rs3795503, rs61808068, rsl2138049, rs4350171, rs6673768, rs9425634,rs78444298, rs41264582, rs6674490, rs4651259, rs4650681, rsl0911748, rs7533879, rsl407277, rs4651264, rs4651267, rs6424989, rsl0732977, rs7522964, rs7556158, rs6658346, rs4233121, rs4142137, rs6703061, rs4518850, rs4506426, rsl2046623, rsl2039585, rsl2032711, rs7539353, rs7542383, rs7554402, rsl2406189, rs2891253, rs3955272, rs78539703, rsl89822718, rs7535459, rs2179189, rs!569479, rs4651336, rs2891258, rs7512414, rs34109355, rsl 1261022, rs322906, rs322901, rs322898, rs322895, rs427790, rs322877, rs322876, rs322875, rs322874, rs322873, rs2624882, rs2648772, rs7524630, rs7547363, rsl2727107, rsl536095, rsl0919656, rsl7632055, rsl 1583806, rsl2062849, rs2164524, rsl2037054, rs3850625, rsl42356235, rs35383942, rs72744832, rs3806357, rs9427716, rs6656372, rs4073666, rs3923212, rsl2125605, rsl2033840, rs4951254, rs2153904, rs2808454, rs7536934, rs56166793, rs79965342, rsl0779335, rs41318015, rs41303061, rsl 14278335, rsl 15633767, rsl 13552928, rs76408327, rsl 14558185, rsl 15799666, rs76432854, rsl 15939077, rsl 16277419, rs79344540, rsl 16694119, rs79638354, rs76403726, rs75306383, rsl 15066447, rs78915104, rsl 14130945, rs74630957, rs75660657, rsl 16746400, rsl 14577368, rs78521412, rs76267745, rs79121421, rsl 16778462, rs3120789, rsl 1581934, rs34008349, rs4951588, rs3767863, rs340882, rsl 7022700, rsl 7022807, rs4275425, rs6540832, rs6540833, rs6540834, rsl 1120328, rs4072973, rs3902966, rsl2757404, rsl2736454, rs7535253, rsl2132412, rs829391, rs829392, rsl7045771, rs2810778, rs2810779, rsl 1118448, rs59789715, rs!694593, rsl694594, rs2642438, rs867772, rs7514450, rs61830291, rs6694031, rs2150871, rsl2407545, rs76440733, rs73089725, rs74483800, rsl 1803959, rs41303115, rsl6846855, rsl2401963, rsl2405686, rsl2405707, rsl2405723, rsl2403195, rsl l801443, rs55685166, rsl 1802395, rsl 1808186, rs73089760, rs73089765, rsl6846872, rsl6846874, rs73089770, rsl7851754, rs73091738, rs55865118, rs73091740, rs73091742, rs2150873, rs2183837, rs73091761, rs78002062, rsl6846908, rsl6846910, rs60979561, rs74140276, rs!0495263, rsl888831, rsl6846972, rsl6846985, rs73093463, rsl2401556, rsl2410460, rsl 12787790,18456242423.3Attorney Docket No. 046483-7468W01(04021)rs144473177, rs73093495, rs6701743, rs! 513600, rs78335667, rsl2403391, rsl2407061, rsl 1806820, rs73099023, rs73099026, rsl6847098, rsl 12620261, rsl2404416, rs73100804, rs73100814, rsl7605533, rsl0495258, rs80318211, rsl83801039, rsl89924669, rsl2134624, rs6682260, rs4653919, rs6673893, rs9728020, rs9727721, rs589359, rsl765787, rsl765786, rsl765785, rsl765780, rsl765795, rs2808579, rsl615409, rs766288, rs7523139, rsl765781, rsl 1122311, rs3120734, rsl655305, rsl765791, rs2806558, rs!757048, rs9792839, rs57746659, rsl 15418738, rs754984, rs2749153, rsl0926978, rsl2079656, rs3943093, rs2451668, rsl0926991, rs201734360, rs6665809, rsl 173642, rsl 173643, rsl 173645, rs544984, rs592594, rs592961, rs593881, rs594672, rsl 148919, rs538165, rsl093918, rs499096, rs530150, rs677289, rs480394, rs969228, rsl093915, rs563114, rs475555, rs482041, rs507037, rs2282719, rs9438876, rsl l2750178, rsl l4165349, rs75460349, rs79598313, rs61551751, rs57778433, rs74061781, rs74061784, rsl 11257457, rs7543544, rsl 13035001, rs2474294, rs74061800, rs77997265, rs9438563, rs7417012, rs9438522, rs9438524, rs2486674, rs9508, rs6688791, rs534121, rs555530875, rs 184110320, rsl0914324, rs55657710, rsl2406196, rsl2409630, rs35509903, rs55657908, rs79825075, rs6697017, rsl2122125, rs499600, rsl2090153, rs7517146, rs513464, rs688540, rsl92336534, rs72692227, rs3820201, rsl 183394, rs4927209, rsl2239399, rs2802861, rsl230005, rsl7113967, rs77049555, rs75384410, rs4912285, rs76423990, rsl7113998, rs7525717, rs75490687, rsl 1206818, rs334739, rs6587912, rs334734, rs334733, rs72664856, rs332823, rs333147, rs333145, rs333142, rs333140, rs333136, rs333162, rsl67987, rs333166, rsl44397465, rsl 1207719, rsl977653, rsl 12992163, rsl 12389260, rs636497, rs634341, rsl 168036, rsl 168027, rsl627591, rsl2062275, rsl2403207, rsl 168018, rsl 1207981, rsl2074528, rsl 1207986, rs2131925, rs2131926, rsl0889343, rsl629122, rsl748195, rs6690733, rsl0889347, rsl0157265, rs2366638, rsl 168097, rsl 168099, rs72683129, rs4655729, rs6658330, rs6700896, rs7542446, rsl2034502, rsl7127849, rs!2127475, rs57274629, rsl 1809906, rs4655761, rs2376015, rsl2042779, rsl2042807, rsl938500, rsl2043644, rsl 1208711, rsl 1208712, rs4655583, rs4655584, rs4655585, rs2375805, rs2889195, rsl 1208717, rsl 1208718, rsl 1208719, rs4655792, rs4655793, rs4655795, rs72480644, rs6588156, rs6588158, rs6698842, rsl 118392, rs2815374, rs4655726, rs4655727, rsl 166698, rs7514180, rs72723588, rsl7108214, rsl 1587424, rsl 1163481, rsl 14520032, rs4040605, rs2880024, rsl3303065, rs4970392, rs3121554, rs3121555, rs3128126, rs3121560, rs9442364, rsl 1584036, rsl2142465, rs2289731, rsl889854, rsl889853,18556242423.3Attorney Docket No. 046483-7468W01(04021) rs2289732, rs3765972, rs2636314, rs2708628, rs2784738, rs2748456, rs2661868, rs301799, rsl 1121182, rsl l589090, rs751790, rs55858268, rsl2403339, rs6678982, rsl2401496, rsl2122737, rs79769442, rs55830087, rsl 1121207, rsl 1578142, rs4908770, rs56305243, rsl 1121213, rsl 1121214, rsl 1121221, rsl 1121222, rs4908774, rs7553298, rs4908508, rs821397, rsl094360, rsl2037294, rsl094353, rs2970548, rs821400, rs821388, rs821387, rs821385, rs821383, rs849158, rs9701898, rs9661608, rs9661951, rsl775992, rsl764295, rsl775985, rsl775986, rsl764287, rsl775987, rsl775989, rs9651138, rs7528385, rsl2756841, rsl0873718, rsl0747324, rs432254, rs420515, rs369999, rs401657, rs383558, rs430956, rs2785083, rs2764470, rs580828, rs488345, rs519319, rs539544, rs7514579, rs7516400, rs6692801, rs236329, rs56041528, rs41353346, rs72725120, rsl 191238, rs3917615, rs654320, rs632424, rs675365, rs677673, rs646075, rs640645, rs635689, rs651877, rs646407, rs865643, rs640336, rs621634, rs3817996, rsl051412, rs6040076, rs6040079, rs6104644, rs2206815, rs2423510, rs6074170, rs6077884, rs6040095, rs6032919, rs8183037, rs6134000, rs2057055, rs2057054, rs2057053, rs73083362, rs6040098, rs2423512, rs2179688, rs2143621, rs6108676, rs910116, rs75668019, rs2327295, rsl883800, rs6032923, rs6032924, rs6032925, rs6032926, rs6032927, rs973542, rs6077888, rs2423514, rs6040102, rsl033517, rs6074174, rs6104651, rs62187537, rs62187539, rs62187541, rs62187544, rs7274616, rs55977660, rs6131468, rs4814229, rs6042066, rs6042071, rs6033697, rs6033698, rs6042088, rs6033709, rs6033710, rs8124053, rs36018423, rs6042117, rs6042118, rsl 1087052, rs6109893, rs6109894, rs6033715, rs6042131, rs4814237, rs6042158, rs6042160, rs6033726, rs6033728, rs6033729, rs6109912, rs6033732, rs6042170, rs6042172, rs6042175, rs5019244, rs750424, rs6033744, rs4814240, rs6042207, rs6042208, rs6134916, rs6042238, rs!028508, rs2317651, rs2317652, rs6042270, rs6079133, rs6079138, rsl 1699735, rs6033807, rs3088080, rs6891, rs9575, rs6105165, rs6105308, rs6035270, rsl2625157, rs67676850, rs6050602, rs73077077, rs2422859, rs6037526, rs2236089, rs6141766, rs6141767, rs6141328, rs75744141, rs291671, rs291675, rs291695, rs291688, rs2050209, rs2050210, rs4911371, rs6057936, rs6088342, rs4911373, rs2378026, rs6059552, rsl883708, rs6059555, rs8119076, rs6142050, rs6059577, rs6142051, rs4911379, rs6141431, rs9753690, rs9753679, rs7263727, rs7264201, rs7264204, rs6142058, rs2050208, rs6142060, rs4911380, rsl 1697074, rs6142062, rs6141432, rs6141433, rs4911381, rs6141434, rs6141435, rs4911139, rsl883707, rs!883706, rsl883705, rs4012234, rs6141436, rs4911384, rs6142067, rs6142068, rs6141437, rs6142069, rs4911395, rs4911396, rs2268079,18656242423.3Attorney Docket No. 046483-7468W01(04021) rsl054534, rs4911 145, rs4911399, rs2284384, rs2300209, rs2268086, rs932388, rs2235597, rs4911148, rs2235596, rsl 1696338, rs6142098, rs4911408, rs6059685, rs6142109, rs6088408, rs6088409, rs6059691, rs6119463, rsl015362, rslOl 5361, rs6088411, rs6088412, rs6057994, rs6059692, rs8183502, rs6142129, rs6087567, rs6088521, rs734308, rs7261862, rsl 13721969, rs7263068, rs60517948, rsl 13240350, rs6579245, rs6120973, rs2104417, rs45563939, rs73283830, rsl010759, rs8115363, rs6060488, rs6060491, rs77480798, rsl 13522583, rsl2481228, rs6060524, rsl 118233, rs7273815, rsl2480408, rs6060535, rs7261284, rsl 1696527, rsl 11306810, rs73905926, rs2295356, rsl 13203744, rs6060547, rs6060557, rsl 1699793, rsl 1699690, rs6060564, rs56116518, rsl46367992, rs6058303, rs6060572, rs2425078, rs6058304, rs60646509, rsl 12339847, rs6060578, rs8124505, rsl 1696947, rs6060583, rs7263640, rs6060585, rsl 13014094, rsl7093026, rsl7093027, rsl3038622, rs6058309, rs45595739, rs6058310, rs6058311, rs58448091, rsl056196, rs73905955, rsl 11241953, rs6060588, rsl970357, rsl l l67275, rs79035779, rsl l7010355, rs56052651, rs57963833, rs55761608, rs36103066, rs78877130, rs2425141, rs2425142, rs2425143, rs2095818, rsl890470, rs28685274, rsl48527013, rs2425149, rs73902908, rsl 11597121, rsl 1700256, rs74785978, rs78421482, rs6060605, rsl 1696369, rs75331436, rs80156193, rs2378409, rs6060613, rs8115150, rs56904633, rs8122587, rs6060624, rs74355238, rs7273668, rsl0485510, rs7264414, rsl45839824, rs4504072, rs6060642, rs6060643, rs3787173, rs6058354, rs6060699, rs35448195, rsl 1699815, rs6060726, rs6071887, rs6028783, rs6124289, rs6124296, rs6072224, rsl 13622480, rsl2329575, rs41279278, rs2235808, rs2868095, rs3212184, rs6031587, rs6032127, rs2267868, rs79108023, rs6123359, rs209959, rs59132978, rs76792733, rsl7216707, rs209966, rsl2480880, rsl7217119, rs2274130, rs2274132, rs6091825, rs2296237, rs2296238, rs2296240, rs6091826, rs751089, rs912505, rs6127119, rs2104134, rs6123685, rs35971273, rs74324013, rs6014987, rs2236744, rs2236745, rs707555, rs4810149, rs4812042, rs!63782, rs!49265, rsl84673, rs!63783, rs!3720, rs!63796, rs3787421, rs6142696, rsl2624770, rs62207108, rs6142697, rs62207111, rsl2625155, rs2281733, rs28382100, rs2144677, rs3787428, rs3818344, rs28382047, rs28382040, rsl2624713, rs58007679, rsl886008, rs4369942, rs4266091, rs6142924, rs6142701, rs6142925, rs6142926, rs6142930, rs6142932, rsl473739, rs6142703, rs62207126, rs56806604, rs28382027, rs28382025, rs28382022, rs6142934, rs6142935, rs6142936, rs6142937, rs62204323, rsl0888229, rsl 1204457, rs6142706, rs59254607, rs78331413, rs6142941, rs3746650,18756242423.3Attorney Docket No. 046483-7468W01(04021) rs6143021, rs7269717, rs55758310, rs2379128, rs2427283, rsl 1698103, rs4925375, rs944890, rs6143024, rs6143025, rs2379120, rs200383755, rs72629024, rsl623866, rs2261092, rs6011066, rs6011067, rs2427535, rs2236510, rs6122159, rs4809331, rsl741708, rs4809221, rs2427536, rs2253823, rs2253829, rsl 1697610, rsl316200, rs6089771, rs7274760, rs6010647, rs6089979, rs6011095, rs6011096, rs8118848, rs6062344, rs6512309, rs6062357, rs7270745, rs6516366, rsl 1699915, rs79026609, rs6055748, rs8132508, rs7277968, rs62220727, rs7280197, rs2223041, rs2823024, rsl041404, rs2823029, rs2012931, rs6517199, rsl882961, rs2823139, rs6517423, rs2823271, rs2274802, rs2832158, rsl l53280, rs2409497, rs34784647, rsl7655810, rs2834317, rs2834318, rs2835256, rsl 12800821, rsl 1702405, rs78393308, rs218629, rs218632, rs218638, rs2003771, rs8134233, rs219786, rs219781, rs97959, rs364916, rs417191, rs364698, rs366381, rs375662, rs375572, rs376590, rs417173, rs387842, rs448014, rs377160, rs377527, rs377574, rs440551, rs397691, rs451163, rs451243, rs425864, rs399522, rs448482, rs397990, rs397996, rs448659, rs448849, rs415848, rs407095, rs416108, rs451370, rs451614, rs447296, rs449940, rs374314, rs365887, rs376519, rs379699, rs405582, rs442022, rs413852, rs414911, rs371189, rs415100, rs415124, rs372213, rs450183, rs409231, rs371945, rs394087, rs394110, rs382635, rs405901, rs395383, rs383609, rs428948, rs382937, rs452107, rs429326, rs452583, rs394211, rs394565, rs377284, rs445103, rs420925, rs393851, rs419941, rs7281354, rs2835428, rs2835431, rs2835432, rs2835435, rsl3048309, rs2835436, rs2845795, rs2226829, rs2269188, rs! 1909356, rs77659217, rs7275640, rs2269151, rs7281911, rs4607027, rs9985015, rs4819099, rs7281138, rs2838908, rs4819101, rs2838910, rs2838911, rsl3051228, rs2838913, rs4819104, rs35387814, rs9985044, rs8126556, rs914229, rsl0854470, rs4819111, rs755548, rs2236451, rs8133886, rs8128040, rs8128819, rs2236454, rs2274809, rsl2483377, rs2518814, rs2540644, rs4462879, rs8399, rs55813720, rsl7743432, rs55679525, rs8136354, rsl7810649, rsl7743444, rs2057754, rs73157293, rs73157294, rs2238740, rsl7810739, rs2238744, rsl7810780, rs!557846, rs6518522, rs2238751, rs2238753, rs73158820, rs7286581, rs73158822, rs73158827, rs7289180, rs916945, rs7286284, rs7284846, rs73158837, rsl 11696302, rs73158839, rs7285475, rs7285610, rsl7743642, rsl0483100, rsl47150592, rs8135308, rsl 17186487, rs9789916, rsl034728, rsl43496766, rs9789944, rs2238757, rs2238758, rs2283643, rs7285415, rs73158868, rs73158869, rsl 13672342, rs73158875, rs73158876, rs45604134, rsl052756, rs2240111, rs3765612, rs7285177, rs55754617, rs55694607, rs2019746, rsl7759598, rsl 12153746, rs61763401, rs78907487, rs79111189,18856242423.3Attorney Docket No. 046483-7468W01(04021) rsl 7759796, rs2329883, rs! 71277, rs5759997, rs5760000, rs5760006, rs2070455, rsl 2166151 , rs6004074, rsl33872, rsl33885, rs2345019, rsl6986969, rs28372773, rsl 17965034, rs5763688, rsl043099, rs2267158, rs73881478, rs73881482, rsl2484511, rs75641972, rs56040857, rs5994366, rsl 1705351, rs2413030, rs2012451, rsl968023, rs5749334, rs56915796, rs9606878, rsl81748715, rsl 12151426, rsl 11974230, rs73417750, rsl008790, rsl32645, rs56285319, rs7284379, rsl32651, rsl32652, rsl 1089781, rsl6996442, rs75183368, rs77563562, rsl0854687, rs5756113, rsl36153, rs9622363, rs2239785, rsl 15103799, rs73405714, rs58168942, rs5750556, rs4462884, rsl 1703601, rs8139974, rsl7001977, rs3827382, rsl0483205, rsl l2880707, rs73167093, rs73169098, rs5758066, rs5758069, rs5758071, rs5758072, rs5758077, rsl38303, rsl38311, rsl38319, rsl2165496, rsl38323, rsl38326, rsl38335, rsl38346, rsl38347, rsl38352, rs5758153, rs78831364, rs62240993, rs!29853, rsl33315, rsl33319, rsl33337, rs4820461, rs4820462, rs6002697, rs2071774, rs4820463, rs8135582, rs5996145, rs4422240, rs8142511, rs6002708, rs4822119, rs2413686, rs8141792, rs4822120, rs9607893, rs9611782, rs9611784, rs4822121, rs9623573, rs2294361, rs2294362, rsl2484310, rsl 1090090, rsl 1090092, rsl 1090093, rsl0854752, rsl 1090094, rsl 1090095, rs6002712, rs6002715, rsl057157, rs2413687, rs2092175, rs9607898, rs733278, rs6519319, rs2413690, rs8141826, rsl30395, rs738527, rs3887474, rsl2170295, rs62228096, rsl 1913069, rs62241216, rs79865452, rs361725, rsl31789, rs6735658, rsl 15926946, rs4614909, rs6432054, rs34333438, rs34368289, rs34060506, rs35384393, rs71413895, rs57069400, rs!062062, rsl345302, rs2310243, rsl3405355, rsl0179654, rsl2476968, rs6543118, rsl558619, rs76520363, rsl0439410, rs6731157, rs6745614, rs6758936, rs2270298, rs2041739, rs2080289, rs3771162, rs7556917, rs7584093, rsl 1465633, rs3213732, rsl0204757, rs7591246, rs6760621, rsl 1465641, rsl 1903946, rs6706002, rs6749014, rsl2712146, rsl420097, rs4851004, rs6732138, rs2287035, rsl7027071, rs3732126, rs3732125, rsl7027087, rs6710528, rs3732124, rs3732123, rs4851571, rs4851572, rsl035129, rs7594402, rs6710034, rs7589142, rs6543127, rs4851576, rs4851577, rs4851579, rsl592459, rsl592458, rsl035125, rs2160201, rsl833174, rs2293224, rs6743516, rs3771156, rsl420100, rs3771155, rsl0206291, rs885088, rs3771154, rs6759479, rs3755266, rs2110659, rs7559845, rs6726985, rs2310300, rs7581119, rs3755265, rs4479442, rs2058659, rs6734762, rsl 1465721, rsl 1465728, rs918000, rsl523206, rsl523205, rs78136548, rs77375846, rs3206843, rs79441289, rs62118909, rs2515391, rs2515392, rs2441375, rs2251876, rs3820738, rs2515401, rs!800930, rs2515402, rs3180234, rs3180235,18956242423.3Attorney Docket No. 046483-7468W01(04021) rs2515403, rs2472188, rs957201, rs768627, rs 12475161, rs4849146, rsl0206428, rs!2469822, rs4849150, rs4145013, rs4145014, rsl 1123169, rsl2619508, rsl446246, rs7560701, rsl0864911, rs4849188, rsl 1689813, rsl374162, rs6707245, rs6720637, rsl0177634, rsl0175325, rsl0186105, rs4413174, rs9973599, rs6741265, rsl0210018, rs6723391, rs6723502, rs2716615, rs2581066, rsl7668924, rsl40179699, rsl 1893187, rsl7713396, rs!3422707, rs79154857, rsl7050272, rs6706968, rsl 1288732, rsl7005869, rsl 1122844, rsl 1122845, rsl 1885850, rsl81977837, rs72842369, rs4848692, rsl 1122848, rs34013653, rs61362138, rs34773350, rs6734261, rs3768903, rs36096257, rs2713245, rs613828, rs643796, rs487404, rs842354, rs7573390, rslOl 71371, rs6728095, rs71348712, rsl3399952, rs6705916, rsl0193171, rs6739706, rsl2691869, rs4328685, rsl0210052, rsl 1688414, rs6745983, rsl 123184, rsl l898465, rs4954161, rs6741007, rs6741637, rs6751833, rsl 1883531, rs6760237, rsl0496731, rs7608700, rs3739029, rs6729702, rs6430543, rs6430545, rsl992764, rsl530557, rs56383182, rs6430546, rs6730306, rs6758113, rs60793693, rs6430547, rs6430548, rs4954191, rs9653175, rs9653176, rsl0928521, rs6430552, rs74265412, rsl2469941, rs6430553, rs4954192, rs6738113, rsl2473839, rs6430554, rsl348790, rs2053727, rs62168869, rs6430555, rs74265413, rs55865348, rs6714498, rs7589297, rsl374292, rsl0176573, rsl348792, rs62168872, rsl2469411, rsl0928523, rsl374288, rs766271, rsl374287, rs2322251, rs62168891, rsl2151827, rsl2463645, rsl374289, rs3814355, rs3814354, rs56271357, rs4954585, rs4954588, rs6708702, rs77608322, rs74830256, rs79164567, rs79234446, rsl89352109, rsl371044, rsl0928355, rsl344980, rs7582403, rs2113794, rsl2987286, rs2627025, rs7598361, rs77964389, rsl 1889610, rs4664475, rsl0172023, rs58903550, rs6712533, rs34577613, rs4300824, rsl0165921, rs807624, rs7567320, rs7596796, rs7597232, rsl3399671, rs62114735, rs72768982, rsl0016, rsl3390359, rsl0182297, rsl0184861, rs72997116, rsl3416455, rsl 1688793, rsl0196949, rsl0174267, rsl3410936, rsl3397887, rsl3398569, rsl3398901, rs6744604, rs!2694970, rs2356510, rs34525522, rsl807921, rsl0194836, rsl0175732, rsl3393248, rsl403289, rsl3428776, rsl2694974, rs6437206, rs6719412, rsl 1683839, rs448513, rsl 16650458, rsl 1689799, rsl 1689800, rs2357772, rsl3397529, rs4347774, rsl2987408, rsl3015591, rslOO48715, rsl2692605, rs75166367, rs4664452, rs3788973, rsl3386912, rs6706926, rsl2467922, rs78472008, rsl2477178, rsl6846368, rs2284867, rs77372562, rs2300750, rsl6846375, rs6748542, rs6735909, rs6759558, rs4664453, rs4664454, rsl6846386, rsl6846387, rsl2473366, rs74378743,19056242423.3Attorney Docket No. 046483-7468W01(04021) rsl 6846389, rs3827491, rsl 6846391 , rsl 0439290, rsl 6846396, rs4338976, rs3788970, rs6746339, rs3788969, rs76099239, rs77335736, rs4664050, rs4664051, rs76818513, rsl 17759694, rsl 17027526, rsl 12075616, rs75229796, rsl2471175, rsl2471176, rs78455346, rs3788968, rs3788966, rsl 1886710, rs3761654, rsl2475870, rsl 1901711, rs74493538, rs75204721, rs78372490, rsl 125604, rsl 125605, rs4664457, rs76701499, rs3761652, rs7558987, rs2111486, rs918161, rs41463049, rs76267308, rs2287292, rs2287293, rs7590692, rsl3431848, rs6734769, rsl2464391, rs7602311, rs4664460, rs7565446, rs6718470, rsl2476567, rs4664462, rsl0439256, rsl6846585, rs58375444, rs57983132, rs58990349, rs2163215, rs59482537, rs77826516, rsl2469260, rs78222827, rs4667699, rs720643, rsl0497240, rsl0194498, rsl0211437, rsl0204297, rsl0168136, rsl0198504, rsl0210208, rsl0200983, rsl0210320, rs6749070, rs6708983, rs6749350, rsl3425312, rs!3389619, rs4422157, rs7571002, rsl3388721, rs60444855, rsl3399614, rs2340763, rs28670483, rsl6982470, rsl6982472, rs7570487, rsl2997119, rsl2475700, rs573225, rs504979, rs473351, rs575671, rs531772, rs565412, rs567074, rs479682, rs2685804, rs862662, rs853778, rs864929, rs35472707, rs68155726, rsl6856530, rs34355135, rs2302695, rsl7848164, rs2052298, rs2052297, rs2052296, rs62172631, rsl 1886318, rs62172632, rs7600336, rs2300447, rs2300446, rs2193195, rs2193194, rs2193193, rs2216239, rs3815572, rs2268370, rs9283479, rs9646731, rs4606889, rs4302191, rs6719440, rs6747692, rs2268369, rsl 1902433, rs34951037, rs2075246, rs982810, rs6433109, rs4668126, rs4668128, rs2302693, rs3821127, rs3821128, rs2239594, rs4668129, rs831040, rs831041, rs831042, rs2075255, rs2075254, rs831043, rs831044, rs56168972, rs57516605, rs831046, rsl096455, rs830956, rs830957, rs830959, rs830960, rsl421509, rs2241190, rs830983, rs3770637, rs6730118, rs747051, rsl6863549, rs863678, rsl3403839, rsl87355703, rsl348807, rsl520399, rsl607714, rsl402107, rsl520394, rs2222312, rsl033304, rs2139615, rsl005932, rsl3422369, rsl3403148, rsl992909, rsl251034, rs!251033, rs371695545, rs!513881, rs6706601, rs9789353, rs6705298, rs2364723, rs34551701, rsl7524059, rsl7400505, rs77480831, rs73034339, rsl 11373815, rs4491754, rs56065555, rs55831332, rs2276620, rs2276619, rs6734446, rs73034346, rsl 13926414, rs79747558, rs76786892, rs6736173, rs6736304, rs74812381, rs3731758, rsl0497515, rsl0497516, rsl45909820, rsl47804436, rs76781627, rs3816073, rs3765020, rsl6866323, rsl 16706874, rs78732561, rs73034359, rs79833237, rs73034362, rs75444105, rs73034364, rs74981487, rs76274069, rs77266660, rs75894529, rsl 12902513, rsl 11989862, rs7584420,19156242423.3Attorney Docket No. 046483-7468W01(04021) rsl 82984727, rsl 39426962, rs74738571 , rs!2612917, rsl 2616943, rsl 12749525, rs77498914, rs73034377, rs79673893, rs55714261, rs56357262, rs56233214, rs55821514, rsl40098008, rs77011751, rsl2615980, rs79399438, rsl l4460022, rsl2619401, rs3731756, rs6757474, rs6757481, rs75341252, rs74787974, rsl2613303, rsl85591978, rs77852792, rs74852352, rs76415010, rs73036332, rsl2613131, rs56165369, rsl 14914284, rs79276358, rs2195070, rs56367852, rs74735544, rsl 15855673, rsl 16146339, rs77079077, rsl2621108, rs72629796, rsl6866373, rs3829748, rs202214630, rs55675869, rsl 14248026, rs72648257, rs56145100, rsl2621078, rs56214710, rs3813247, rs3731745, rs56018860, rs3813246, rs3813245, rs744426, rs2288570, rs72646874, rs56372427, rs55706598, rs72646865, rsl560221, rs72646834, rs28715837, rs28378468, rs35833641, rs2288568, rsl3009158, rsl0930832, rs2303832, rs2303831, rs2288566, rs72677248, rsl6866416, rs55658446, rs72677228, rs2303829, rs72677219, rs2366752, rs56285382, rs56352103, rs55639922, rs75328144, rs72650085, rsl6866425, rs7590037, rs2288563, rs55847232, rs2742324, rs2562843, rsl569407, rs2243452, rs2742358, rs2246932, rs2562844, rs7606485, rsl366677, rs2742356, rs2562846, rs2742354, rs2562847, rsl0204913, rs2163008, rs2562848, rs2562849, rs2742353, rs2562850, rsl0221760, rs2742352, rs2252353, rs2252350, rs545894786, rs2742350, rs2742349, rs4894034, rs2627039, rs2562851, rs2627038, rsl3417645, rsl 13059495, rs2366753, rs2742345, rs2742344, rs2742343, rs2742342, rs2742341, rs4893852, rsl0203085, rs2742340, rs2742339, rsl0179811, rs2742337, rs2742336, rs2562842, rs2627034, rs2742335, rs2742334, rs2742333, rs2742332, rs2562841, rsl0176708, rsl3398235, rs2742330, rs2627044, rs2562837, rs2562835, rsl0183237, rs2742329, rsl0183361, rs2562833, rs2562832, rsl6866473, rsl7355446, rs2562852, rs2562853, rs2243804, rs2255480, rs2627042, rs2562854, rsl 1888217, rs2627037, rsl0497519, rs922984, rsl7355623, rs3754953, rs74805196, rs7585334, rsl0171049, rs4894037, rs2291309, rs2291310, rsl 1895382, rs77841333, rs7604033, rsl6866519, rs4894040, rs7572955, rs4894041, rs2291311, rs!484120, rs2291312, rs4893853, rs72647888, rs72647887, rsl905520, rs4894048, rsl0221590, rs2054708, rsl0497522, rs7423101, rsl 1897386, rsl 1892354, rsl3421990, rsl2465449, rs72959397, rs4666979, rsl962724, rsl0451546, rsl0930990, rsl594617, rs72897100, rsl7343318, rsl0803955, rs6740226, rsl0166086, rsl 13254009, rsl965090, rsl2473989, rsl0166852, rsl6985161, rs6743746, rs858745, rsl706287, rsl !91809, rsl 191811, rs62109431, rs3769760, rsl513830, rsl44505847, rs72932770, rs72932772, rs79633844, rs75141346, rs72932774, rs72932777, rsl 15628302,19256242423.3Attorney Docket No. 046483-7468W01(04021) rsl43805266, rs72932780, rsl 14520702, rs7608755, rs72934751, rs6738618, rs72936838, rs72936839, rs72936842, rs72936847, rs72936870, rs72926769, rs72926800, rsl 15194657, rs72928613, rs2351524, rs72932588, rs72934512, rs72934519, rsl 1679740, rs889895, rsl 13889746, rs2709399, rs2709404, rs2709378, rs2709381, rs2286963, rs2287603, rsl0932343, rsl047883, rsl0804186, rsl0469763, rs4673543, rsl047891, rs715, rsl836744, rs!836742, rs6727172, rs!3025037, rsl595066, rsl 1895168, rsl595065, rsl595064, rsl972820, rsl836724, rsl2475523, rs4672612, rs934607, rs3791689, rsl836719, rs6728196, rs4673615, rs6710253, rs7561756, rsl3409566, rs9288430, rsl0497944, rsl0165449, rsl3395652, rsl0206846, rs9808028, rsl 816531, rsl7804031, rsl0166172, rsl546718, rsl546719, rsl0185271, rsl533768, rs4638732, rs4563169, rsl 1682538, rsl 1682541, rs56111964, rsl 12905092, rs3768788, rs62189579, rsl0209675, rs3754590, rsl548945, rsl 1892032, rs2541385, rs2712169, rs7587010, rs2712184, rsl6856812, rsl2477491, rsl0932690, rsl6856934, rs4996257, rsl7462630, rsl0165754, rs73991530, rs73991535, rs73991536, rs907683, rsl 12068790, rs3755061, rs6747041, rs75478462, rs34799600, rs2840128, rsl 190117, rsl2694684, rsl0933114, rs79615915, rsl0933136, rsl0933138, rsl2694695, rsl l5857843, rsl38130641, rsl l5550436, rsl l4581794, rsl l6668967, rsl 15711654, rs34011391, rsl 16110773, rsl 16707100, rsl 16077538, rsl43748652, rsl 15673859, rsl 16722768, rsl 14833301, rs35669853, rsl40788792, rsl47430803, rs79653224, rsl50181834, rsl 16345901, rs78248499, rs79609806, rsl 14710433, rsl41508977, rsl 15753606, rsl 15093628, rsl 16430125, rsl42253580, rs74602746, rsl 15062063, rsl41507217, rsl43986050, rs76720531, rsl 16077429, rsl50845292, rsl 14874036, rsl49346355, rsl43845678, rs76216629, rs80037833, rsl 15305921, rsl6867027, rsl544673, rs7591557, rs6436885, rs7599184, rs!0933311, rs6436892, rs7602607, rs7579744, rs62193693, rs3731783, rs6854, rs6748332, rsl0185032, rs7608781, rs62193695, rsl3411443, rsl6827740, rsl2694886, rs3769990, rs78890542, rs7581418, rs7564129, rs!3430145, rsl3416929, rs55637820, rs2288147, rs60563689, rs6741145, rs2303353, rs7559702, rs2007131, rs906879, rsl3411316, rs2303357, rsl2619336, rsl0197001, rs2161892, rs7595464, rsl3394402, rsl0199752, rs6437000, rsl0194776, rsl6827801, rsl549339, rs7607338, rslOl 87149, rs765458, rsl2469673, rsl0498257, rs59886388, rs7565408, rs3754981, rs57481522, rs62193731, rs7585887, rsl035620, rs2175147, rs3769989, rs6437001, rs4350740, rs6707708, rs4635521, rsl 1893395, rs555015462, rs6437003, rs2303351, rs2303350, rs2303349, rsl025107, rs2032953, rs6706191,19356242423.3Attorney Docket No. 046483-7468W01(04021) rs6755467, rs6727422, rs6727962, rsl 6827840, rs6739959, rs61332549, rs60445047, rs56295567, rs56161330, rs55878747, rsl0169827, rsl0206322, rsl0179264, rsl0202608, rsl0202782, rsl0202806, rs6437004, rs6738687, rs62197317, rs7565313, rs7606037, rs6761645, rs6437005, rs28690417, rsl2465438, rsl2465477, rsl0187005, rsl3423632, rs9750018, rs7598728, rsl0181630, rs6437008, rsl6827879, rs72983683, rs7569597, rs7584535, rsl2612219, rsl0173555, rsl0177091, rsl2612801, rsl 1897387, rsl3415839, rsl3418595, rs62197345, rs7604042, rs55782278, rsl3428268, rs3731779, rsl2623587, rsl0201323, rsl l686251, rsl3013142, rs6738386, rs36007169, rsl2987513, rsl0933409, rsl801251, rsl044480, rs838718, rs2278743, rs2278742, rsl0192297, rs2278738, rs934780, rs4665785, rs72810076, rs6728919, rs55799006, rsl3023418, rs56185549, rsl85521632, rsl 13304336, rs72801806, rs72801857, rs72801877, rs528043291, rsl260326, rs3817588, rs780092, rs814295, rs74928908, rs6744393, rs62131879, rsl0181342, rsl 16443177, rs62131881, rs62131882, rs62141278, rs62141279, rs2384627, rs62141281, rs6751087, rs62141290, rs62141291, rs62141292, rs60854669, rs965813, rs59876138, rs3811644, rs62138963, rs62138964, rs76013440, rs62138965, rsl919129, rs56725354, rs62138968, rs2141372, rs6719960, rs6547735, rs78170284, rsl881395, rs7571558, rsl881396, rs76586169, rs72613829, rs4665385, rs4665386, rsl881394, rs6745545, rsl3021718, rs888096, rs6717584, rs2160237, rs759384, rsl 1888123, rs2160236, rsl92040601, rs2301343, rsl3418865, rsl3035419, rs4952553, rs4952558, rsl 1685920, rs34120829, rsl2998882, rs35708913, rs4952588, rsl2623480, rsl2617964, rsl2614953, rsl49290349, rs7933, rsl 12694524, rsl 13542380, rs80323638, rsl49274878, rsl 13986438, rsl 14904276, rsl 11274231, rs77470734, rsl51004942, rsl49397893, rs41281455, rsl l3866579, rsl 14510001, rsl7030645, rsl 11539718, rs77288440, rs74814053, rs6748690, rs74382177, rs6722143, rs6707060, rs6743071, rs28470852, rs76215753, rs78681698, rsl 12972772, rs79629200, rs74469180, rs78314405, rsl 11947872, rs!3408002, rs76675804, rs74616425, rsl 1899863, rs79165612, rs78886764, rs76684055, rsl7030798, rs7609256, rs77059113, rs7556744, rs77620935, rsl2105394, rs77527404, rsl7406646, rs7599781, rsl2105626, rsl2105710, rsl7030818, rs6752448, rs76282560, rs7572923, rs7599799, rsl7030835, rs6746058, rsl7030845, rs77377889, rs7561287, rsl7030855, rsl7030859, rsl7039133, rs75330033, rs80147536, rs77101426, rs75135247, rsl7030890, rsl7334919, rs6746632, rs6747229, rsl7030925, rs77389971, rs75607314, rs78497923, rs75386849, rsl3422551, rs75097983, rs72865267, rs! 12282947,19456242423.3Attorney Docket No. 046483-7468W01(04021) rs6544664, rs6544665, rsl 11753823, rs6708735, rs6737882, rs6544666, rs6544668, rs7578597, rs7564886, rsl7030946, rs6757251, rsl3405076, rs6544669, rsl388387, rslO18OOO5, rsl3405776, rsl3419380, rs7597135, rs7570748, rsl0169346, rs74821293, rs74600494, rs77791126, rsl0189235, rs76851696, rs79271345, rsl7030967, rs75514072, rs6751035, rs6751161, rs6726643, rs6726917, rs6752964, rsl 12340521, rsl 11898797, rs7591387, rs74907855, rsl7031000, rsl 11783562, rsl 13156595, rsl 12813837, rsl 14563746, rsl 12416866, rs77852659, rs77972916, rs75275342, rs78572881, rsl 12387154, rs77787499, rs76856054, rs77981966, rs77552263, rsl 11239033, rs78070307, rs79111706, rs4952996, rs62136376, rsl2621907, rsl2623703, rs6544743, rsl0174537, rs8410, rs62134207, rs56077086, rs4953152, rs687914, rsl 1684301, rsl867784, rs4952818, rsl447563, rsl2991646, rsl3010062, rs4567978, rs3813463, rs7566809, rs!0865282, rs6751866, rs941351, rs941352, rsl405833, rsl0182366, rsl527649, rs4459768, rs62134681, rs60113783, rsl3004944, rsl0454749, rs62165173, rs7582278, rs55761024, rsl058582, rs62165183, rs62165184, rsl7798852, rs35504023, rs7594279, rs782649, rs782650, rs782652, rs2627777, rs2627776, rs782567, rs782568, rsl0460508, rs2586954, rs2627779, rs4672074, rsl346783, rs7572523, rs2540917, rs243066, rs243061, rsl2614829, rs34532102, rs6736527, rsl0210126, rsl477040, rsl0189261, rsl0179846, rs6738988, rs6715876, rs75716079, rs72894568, rs78683917, rs61748094, rs61741513, rsl3431750, rs78287130, rs61330787, rs80153345, rs74402094, rs79599301, rsl49632984, rs268120, rs268134, rs77909321, rs268124, rs6740462, rsl39736529, rsl88158341, rs6738144, rs2280334, rs4544423, rsl 1686555, rsl2469835, rsl367478, rs9309401, rsl2105010, rs80280585, rs6748323, rs34684423, rs2418652, rs7584322, rsl7663700, rs55655347, rsl 1685700, rs759219, rsl 1678537, rs72832771, rs3771385, rsl38505214, rs80265494, rsl48002684, rs2421546, rs2421548, rs6730785, rs75761701, rsl881246, rs75821812, rsl2996463, rsl47086810, rs7571243, rs75361602, rs7600268, rs58830031, rsl528169, rs7598901, rs6749680, rs78777626, rsl 14415559, rs2091504, rs2091503, rs4852930, rs4852306, rsl45017004, rsl42800387, rs780395, rs780394, rs780393, rsl083923, rs780391, rsl083922, rs533493159, rsl083921, rsl88245139, rsl083919, rsl 14534317, rs7585119, rs7562047, rsl0189578, rsl42579560, rs7606483, rsl0865398, rsl 1688718, rs78003072, rs6729468, rs6744697, rsl3386124, rs6757996, rs62153184, rsl 1126402, rsl 14474332, rs7566315, rsl0190002, rs34927702, rs35760114, rs!40081968,rs78444017, rs6727745, rs6745560, rs4852308, rs4346412, rsl3009035, rs56658499,19556242423.3Attorney Docket No. 046483-7468W01(04021) rs2421664, rs! 3007607, rs!3022145, rs4852950, rsl3410232, rs! 3018422, rsl 3017182, rs79105219, rs6546867, rs4852963, rs7570683, rs2421582, rs2421583, rs2421584, rs2421586, rs7574240, rs7574268, rs72840111, rsl47704304, rsl49256246, rs34063934, rs56287599, rsl0208670, rs2969473, rs76229410, rs3772534, rs80040728, rs75820797, rs2289746, rs2301033, rsl 17321738, rs75831288, rs78619967, rsl2633175, rs795010, rs794999, rs7638232, rs7616006, rs7650082, rs7650294, rs9810259, rsl2491937, rs7641325, rs7611913, rs9289172, rs9812515, rs6765799, rs9810707, rs2257120, rs2257123, rsl882000, rsl847029, rsl2487598, rsl2496722, rsl3573, rsl053738, rs6438885, rs9289245, rs9857356, rs4450756, rsl607238, rs6772299, rsl999919, rsl999921, rs6781706, rs4234274, rsl 868121, rs6762969, rsl868123, rsl868124, rs9879085, rs4679211, rs4679212, rs9813319, rs9870993, rs6795157, rsl374804, rsl992854, rs!992856, rsl992857, rs!868134, rsl3082246, rsl868135, rs4468935, rsl868136, rsl545381, rsl2695477, rs4679215, rs7622374, rs4679216, rs4679106, rs4679107, rs9865898, rs9828100, rsl 1914692, rsl968631, rsl968632, rsl530638, rsl530639, rsl 1720893, rs6765882, rs6768502, rs6781332, rsl447660, rs4679217, rsl 1916122, rsl 1920239, rs6438987, rs6438988, rs75348895, rs9865381, rs9865548, rs9880453, rsl 1712581, rs61606491, rs67177961, rs34871776, rs6798887, rsl 1719501, rsl2629398, rs9881832, rs9874893, rs34366795, rs4034942, rsl2631514, rs9809596, rs6810325, rs7650482, rs4642101, rs61664354, rs73027016, rsl500112, rs2369796, rs4854645, rs80120242, rs66564593, rsl0935111, rs9881242, rs59473547, rs7433301, rs2400272, rs76032120, rsl 16489422, rs74954362, rsl 11699702, rs4974494, rs4974485, rsl603824, rs35951257, rs4974496, rs2133307, rs34341902, rsl498731, rsl 111516, rs7643419, rs75705309, rs4974497, rs2400278, rs77863955, rs77820313, rs9450, rs78506634, rs74910485, rs6439478, rsl3075185, rs3773820, rs7629849, rs80040468, rs6798709, rsl 1925583, rs7623024, rsl 138273, rs7427492, rs7372770, rsl357762, rsl2637751, rsl 1927068, rs9289478, rs6768323, rsl880376, rsl880377, rs35933983, rs9827987, rs35718987, rs9832633, rs!40983487, rs7374325, rs4309773, rsl3089966, rsl3065773, rs9815894, rsl534028, rsl534027, rsl534026, rs55913793, rs4955555, rs6769885, rs4539979, rs4367113, rs9819532, rsl3081177, rs6439492, rs4572812, rs2373865, rs36006513, rs7630874, rsl0804632, rs56899746, rs6782563, rsl 1919458, rs62271513, rs62271514, rs6793487, rs4535272, rs4368544, rs4423809, rs62271515, rs4245902, rsl41367948, rs6771298, rs6774795, rs9714039, rsl3090969, rs6808670, rsl3071551, rsl534025, rs9857242, rs9857995, rs4955525, rs4245903, rs7648616, rs4955534,19656242423.3Attorney Docket No. 046483-7468W01(04021) rsl 880374, rsl 880375, rs2293293, rs2293294, rs6806810, rs9839705, rs9824185, rs4074521, rs4074522, rs2888670, rs4318591, rs4605591, rs4955542, rs4245905, rsl3075253, rs6779294, rs6779326, rsl534030, rsl534029, rs9848254, rsl880379, rsl880378, rs7623567, rs7633868, rs6764764, rs9838119, rs9838467, rs9838889, rs9838621, rs4955544, rs4955545, rsl3098546, rs4306899, rs4634170, rs4435682, rsl 1915964, rsl3089566, rs6763188, rs58491661, rs6775611, rsl868164, rs9883955, rs4678361, rs9840812, rs4431046, rs6767060, rs687339, rs684773, rsl278719, rs576771, rs56265409, rs6778297, rs66716710, rs2607775, rs2733550, rs9879434, rs7624084, rs6763931, rs724016, rs295300, rs4234470, rs3804771, rs4315664, rsl2495978, rs3811708, rs62283132, rs35787200, rs34280182, rs6794342, rs7635444, rs347686, rsl43710547, rs6440132, rs6776634, rs834906, rs6803862, rs62276843, rsl617267, rsl713842, rsl713846, rs938989, rsl727919, rsl713847, rsl727917, rs9840371, rs9844496, rsl629659, rsl358405, rsl527799, rs6440935, rsl727958, rsl727946, rsl727944, rsl727940, rsl624917, rsl713839, rsl713831, rsl727882, rsl713829, rsl727883, rsl727884, rs7647694, rs6769099, rs921318, rsl358403, rsl713822, rsl542254, rsl727957, rsl470663, rsl727954, rsl727953, rsl727952, rsl713817, rsl713815, rsl713813, rsl632688, rsl713811, rsl527800, rsl727949, rsl713810, rsl727948, rsl727947, rs2695845, rsl727945, rsl713807, rs357488, rs357482, rs357480, rs357479, rs357477, rs357476, rs357473, rs357471, rs357468, rs357466, rs357465, rs401162, rs447429, rs398512, rs436852, rs454837, rs365119, rs377565, rs449361, rs437396, rs450115, rs453699, rs407060, rs56916293, rsl657621, rs896016, rs2689330, rs2596629, rsl 84825, rs357506, rs357494, rs357495, rs242577, rs357497, rs357498, rs357499, rs760066, rs3817641, rsl3092272, rs34208188, rs4679797, rs2316337, rsl 13294272, rsl 13578858, rsl822397, rs66628080, rs56978441, rs60053317, rs73160604, rs75988348, rs74321159, rs553984210, rs9637450, rs73172091, rs2051076, rs2178175, rs9843242, rs9872796, rs74330815, rsl83363267, rs6791781, rs3774046, rs9828378, rs9837316, rs9841632, rs950644, rs36077239, rsl 1925227, rs56297506, rs3749234, rs7613970, rsl43867505, rs7651346, rs4686682, rs62291882, rs62291883, rs62291884, rs6807927, rs6783023, rs6785918, rs6762208, rs34619288, rs6791954, rs6803426, rs4568175, rsl3076556, rsl3061708, rs7646818, rsl3080101, rs4687477, rs7613002, rs9880232, rs35693823, rsl41465286, rs73175567, rsl3076013, rs6799330, rs6789741, rs2194411, rs73175602, rs4686710, rs4321562, rs!6860324, rs2247511, rs2247622, rs2251407, rs59950016, rsl0937233, rsl0937234, rs9844949, rs3821815, rs5029970, rs61211338, rs61605278,19756242423.3Attorney Docket No. 046483-7468W01(04021) rsl 11444674, rs2713721, rs577650, rs534834, rs78158637, rs76598712, rsl48422661, rs9823161, rs6777647, rs4635652, rs34967245, rs842225, rs79229020, rs76153126, rs34468408, rs6796626, rsl 1717090, rs2019472, rsl2631126, rs35260201, rs59171696, rs3796263, rs41284057, rsl3099700, rs2341225, rsl2631361, rsl3066853, rs2341184, rs7649443, rs35136822, rs34381158, rs6797085, rs6782349, rs2044861, rs2044860, rsl0461048, rsl0489880, rs6805920, rsl3077565, rs36035383, rs7624684, rs7624764, rs61394945, rs35112822, rs2340433, rs62282105, rs35665404, rs7619429, rsl073726, rs6800383, rs3903682, rsl3067147, rs6779689, rs34305944, rs6782876, rs3915512, rsl3085450, rs9840653, rs2929415, rsl89267552, rs2195919, rs2306623, rs2306856, rs905456, rs6800284, rs2070988, rs7372545, rsl3058903, rs2268759, rs35795531, rs2370860, rs2293307, rs28362645, rsl3078962, rs60889002, rs59889656, rsl2637881, rs784504, rsl49636734, rsl459250, rsl40502640, rs34293138, rs77495508, rsl42922893, rs28457212, rs4549265, rsl 12223611, rsl7051799, rs75353842, rs9827917, rs9838294, rs9838994, rs72951472, rsl 12642536, rsl 12279311, rs9826664, rsl3433728, rsl3433729, rs9881844, rs9838942, rs9839608, rsl 12329483, rsl3325153, rsl 12684399, rs9311470, rs36101994, rs7644763, rs2581815, rs9865094, rs9831409, rs7431952, rs9822734, rs9827052, rs28445246, rsl554125, rsl554127, rs6924, rs4681675, rs6445969, rs6445971, rs7610449, rs6445972, rs6445387, rs3774729, rs2037119, rs888406, rsl 1721099, rs35667547, rs7039, rs58317931, rsl0510989, rs4990333, rsl427431, rs725699, rs4855441, rsl7006384, rsl7006395, rs73838648, rsl946426, rs62253045, rs28433034, rs62253051, rsl 1716109, rsl3097379, rs6777363, rsl3078066, rs7624235, rs7634376, rs7626717, rs7626718, rs7636802, rs6768731, rs6795463, rsl 1916348, rsl3080248, rs34165775, rs35017084, rs62251038, rs7613400, rs6778747, rsl529585, rsl3093918, rs35879809, rs9825822, rs9864805, rs9864949, rs9826548, rs6805563, rs6794889, rs6805924, rs6795249, rs6782552, rs6805945, rs9819188, rs9819504, rs9823839, rsl7638562, rs62252216, rs62252223, rs6804686, rs35759074, rs!2330279, rs35022873, rs62252236, rs62253173, rsl544978, rsl 1921388, rsl 1923382, rsl3071701, rs6793179, rsl 1919798, rsl49617956, rs7632921, rs7640614, rs4676901, rs6803815, rsl3074432, rsl3356, rs9828396, rs9834197, rsl436640, rsl3324964, rs6784619, rsl3066793, rs9845274, rs7614330, rs671779, rs704570, rs793490, rs2066702, rsl229984, rsl 1097693, rs28642089, rs2866203, rs28377022, rsl7029816, rs2903212, rs2866206, rsl3107325, rs78573682, rs223413, rs223401, rs223374, rs223361, rs9991335, rsl7035289, rsl7035311, rsl 1729069, rs2285720, rs57706909,19856242423.3Attorney Docket No. 046483-7468W01(04021) rsl 46360190, rs4290953, rs28522981, rs71606723, rs2390618, rs2893068, rs!072812, rs35843717, rs2139279, rs28705107, rs34111198, rs59861313, rsl850755, rsl3131552, rs6823887, rs6824326, rs34160919, rsl 1737613, rsl2641036, rsl 1723434, rs34086220, rs35744795, rs2049030, rs4605669, rsl028199, rs62312781, rs62312783, rs7697724, rsl 12249356, rsl6997944, rs7435527, rs75364706, rs79256711, rsl588463, rs7440006, rs!877066, rs4834156, rs7668501, rsl899548, rs!41876725, rs4560418, rsl443060, rs6850366, rs2120089, rs4016, rsl0006368, rs6534691, rsl216412, rs6534695, rsl967173, rs72719173, rsl39323761, rs28925904, rs67175590, rsl86017233, rs6850598, rs6535925, rs547507408, rs34267163, rsl0939692, rsl 1734663, rs994595, rsl354676, rs6449381, rs2874338, rs374595728, rsl075227, rs2643437, rs2616466, rs2643436, rsl382094, rs2616464, rs985935, rs2643435, rs2616473, rs2643453, rs2658124, rs6827524, rs9685330, rs973444, rs6815911, rsl7495325, rsl0461115, rs6816592, rs4434249, rs28694806, rs28452967, rs28648686, rs74715443, rs28811985, rsl076962, rsl0003400, rsl 1938354, rs34168360, rsl0017181, rsl0003288, rsl0213306, rsl585640, rs73804848, rsl7572286, rs35631011, rsl3120568, rs55944055, rs2970886, rs2970887, rs7667050, rs4361373, rs2970866, rs2946388, rs79618052, rs73249870, rs6825446, rs6847438, rsl0939141, rsl2644232, rs6830016, rs6831605, rsl0939142, rsl0470822, rs7658174, rs6448487, rs28454570, rsl0939144, rs4692137, rs2798282, rsl 11065364, rsl0024987, rsl3108218, rsl6844401, rs75501914, rs3860067, rsl68088, rs337643, rs2126526, rs34075114, rs62294474, rs337626, rs36071400, rs35547424, rsl 1947292, rs35771878, rs4634234, rsl 1727467, rs4833078, rs337602, rs337609, rs9522, rs302933, rs302935, rs302937, rs4975037, rs302948, rs278941, rs278937, rs35529250, rs4368643, rs4455452, rs4861125, rs9291207, rsl 1937643, rsl 13364695, rs56102337, rsl 1722932, rsl7611143, rsl840630, rs2768976, rs2768975, rs55839120, rsl0866421, rs6817395, rsl2233879, rs62325220, rs61015316, rs62325227, rs62325228, rsl2505040, rs6855607, rs62323567, rs62323568, rs62323569, rs62323589, rsl383180, rs2279252, rsl3141048, rsl3135890, rsl460989, rsl7804499, rs72649118, rs72655601, rs56049812, rs907446, rs72657825, rs4272041, rs7679463, rsl0023335, rs9992101, rsl 1724003, rs60529470, rs55940751, rsl7253722, rsl398016, rsl7319721, rs28418670, rsl398018, rs28394165, rsl0025351, rs4859681, rs4859682, rs2137154, rs2137153, rs2137152, rsl3146355, rs4318673, rs7675217, rs28687959, rs9992088, rsl 134124, rsl2509595, rsl6998073, rsl 1730582, rsl 17078377, rs2725221, rs2231142, rs4647939, rsl680060,19956242423.3Attorney Docket No. 046483-7468W01(04021) rsl 25011 1, rsl 7378658, rs28502775, rsl 7379209, rs3805301, rs2639793, rs2555216, rs5002909, rs5002910, rs5002911, rs774993, rs774992, rs774989, rs774988, rs699861, rs38O53OO, rs902980, rsl0020710, rsl0019354, rs2639795, rs7683990, rs3805283, rsl0000208, rsl0213504, rsl0025074, rs2510771, rs28416638, rsl 13587193, rs9307144, rs6812098, rs5013417, rsl2639887, rsl43324366, rsl 1735831, rsl l726102, rs3796822, rsl558487, rs4314449, rs4502870, rs6894574, rs9312760, rs6554623, rs7378954, rsl21434346, rsl0040110, rs967489, rs6896080, rsl0077141, rs56855707, rs76475084, rsl 12857876, rs7708070, rsl 1746047, rs80311787, rsl 15209326, rs429918, rsl 15926813, rs2522055, rs66542366, rs34626261, rsl7166294, rsl7624157, rsl 16332641, rs55928219, rsl0061901, rsl 14161496, rs4705987, rs6874885, rs7715447, rs57079115, rs4574536, rs66827546, rs62375204, rs4705989, rs62375234, rs6596102, rs73272725, rs62375243, rs4705880, rsl3718, rs56076449, rs56083805, rs62375251, rs72801473, rs62381537, rs4976276, rs7708460, rsl2659621, rs2292011, rs3776208, rsl0078851, rsl7797119, rsl3179823, rsl0952, rs2299024, rs9324851, rs9324854, rsl 1960868, rs899549, rsl031904, rs2578593, rs2578598, rs3776346, rs6580265, rs3776343, rs7734364, rsl0057800, rs3776338, rs3776331, rs3893579, rs3822393, rs3822392, rs246647, rs246644, rsl 1739101, rs35548690, rs246642, rs3822389, rs3756374, rs3822384, rs853167, rsl74047, rsl l750560, rs4705067, rs383915, rs408125, rs77010315, rs816026, rsl478350, rs864626, rs707185, rs815623, rs419652, rs426398, rs435903, rs386973, rs394730, rs442809, rs373619, rsl 1955459, rsl 1134691, rs58597371, rs57592039, rs2161396, rs76203059, rs539205478, rs4075958, rsl 16402366, rsl 1741640, rs4074995, rs35716097, rs55785724, rs2252316, rs6422344, rsl 1747964, rs57358849, rsl3179215, rs254458, rs371361, rs2619868, rsl57492, rs283131, rsl l2445233, rs59539451, rsl84935518, rs661309, rsl965924, rsl973195, rsl72836, rs612225, rsl 183436, rsl43198563, rs76425888, rs78952975, rsl 14873871, rs76497847, rsl060881, rs77495611, rs78762943, rs77755394, rs77449286, rs!48670552, rsl 14392491, rs75547547, rsl38297751, rs!38580268, rs76010420, rs79136786, rs76392483, rsl41807550, rsl 14411015, rsl 16783019, rsl 15191302, rsl 15550119, rsl l6472888, rsl l5695509, rsl l5045173, rs74717578, rs79508654, rsl92659043, rsl3157326, rs457648, rs455213, rs464499, rs464634, rs6881866, rsl 1740818, rs7709378, rs7714779, rsl7592391, rsl0036505, rs6873230, rsl0062185, rsl 134341, rs6884887, rsl867713, rs6866604, rsl838725, rs6859990, rsl 1741104, rsl 1745428, rs6891221, rs6451163, rs6451165, rsl 1739938, rs62355681, rs73072594, rs6893208, rs376896, rs56277491, rs6860727, rs216385,20056242423.3Attorney Docket No. 046483-7468W01(04021) rs216386, rs216389, rs216396, rs!25682, rsl2521993, rs3733801, rs2542713, rsl2153248, rsl0461725, rsl0512706, rs3843913, rs2962481, rsl501699, rs6451462, rs482375, rs7710885, rsl0058610, rs6896609, rsl827860, rsl827859, rsl395153, rs2967213, rs2967212, rsl0473169, rsl 1739050, rs7718076, rs6451477, rsl0067281, rsl0071562, rs6451482, rsl 1749592, rsl0077054, rsl506174, rsl0055349, rsl0036575, rsl0055925, rsl7718387, rs2005071, rsl 13983715, rsl 1743330, rs57367478, rsl389321, rs55988212, rsl911908, rs6555251, rs6555252, rsl2516498, rs72751899, rs72755310, rs4492117, rsl2517503, rs72755324, rs72755325, rs72755333, rs72755334, rs72755336, rsl2519758, rs56401540, rs72755339, rs5007472, rs4596388, rs4866870, rs4571479, rs72755352, rs4866874, rs72757321, rs72757327, rs72757339, rs56100685, rsl2519513, rsl39738798, rs4866768, rsl2518779, rs75921915, rs73754158, rs79804818, rs76136706, rs79468888, rsl2520384, rs!46944028, rs989255, rs78117246, rsl2523455, rs78999502, rs4866884, rsl6873839, rsl2515708, rs76255409, rsl 11565218, rsl6873866, rs76455323, rsl2513619, rs80173788, rs78142257, rsl 15171932, rs76451118, rsl3154781, rs7449277, rs729599, rsl6901990, rs7703497, rs6451778, rs4373287, rs6893319, rsl0040082, rs4395640, rs4866783, rsl0069220, rsl3356086, rs7718354, rs4591754, rs7356604, rs6895062, rs6871820, rs61448800, rsl2518560, rsl2520377, rsl2522861, rs2290697, rs4146620, rsl3187457, rsl3181690, rsl3162297, rs6875248, rs2407066, rsl3185048, rs7736958, rsl2656015, rs4865784, rs4865785, rs4865786, rs747671, rsl994870, rsl7248426, rs6866551, rs4865788, rs4865789, rsl3357971, rsl0039046, rs702634, rs4865796, rsl664781, rs6893522, rs80138475, rsl 81822448, rsl 12838464, rs79756728, rs31226, rs79704759, rs78553795, rs6890486, rs6895649, rs3776694, rs6867281, rs6867302, rs6876640, rs7727248, rs3822496, rs3776692, rs3776691, rs3776689, rs61477070, rsl0059608, rsl0069589, rsl0042837, rsl0044749, rs73112684, rs75575055, rs73112694, rs6875937, rs59547873, rs6865570, rs7709659, rsl 15885520, rs57261959, rs73114718, rs440325, rs57766911, rs368151677, rs863818, rs34301, rs251409, rs34305, rs34308, rs7707989, rsl 1742405, rs78660602, rs73116951, rs6898541, rs6449988, rs68083627, rs587189, rs662962, rs2928167, rsl479559, rs6453301, rs6453302, rs731123, rs7736027, rsl91808586, rsl677666, rsl623489, rsl 1952744, rsl677633, rsl677634, rsl643637, rsl677702, rsl677701, rsl643660, rsl650713, rsl643659, rsl650712, rsl650711, rsl643657, rs966762, rsl677689, rsl677688, rsl677687, rsl643648, rsl677685, rsl650707, rsl643650, rs865647, rs865645, rs836818, rsl643646, rsl677670, rsl478834,20156242423.3Attorney Docket No. 046483-7468W01(04021) rsl478835, rs! 650695, rsl643641, rs! 643639, rsl643653, rs! 677680, rs!643652, rs34580448, rsl 15912456, rs61749613, rsl0078496, rsl2659201, rs6452918, rsl 1742679, rsl986718, rs2973450, rs7727632, rs34710524, rs72717418, rs72717419, rs35664198, rs72717445, rs2672722, rsl 1134054, rs72698506, rsl2188597, rs56218301, rs55846849, rs36111336, rs72698510, rs76667725, rs72698512, rs72698513, rs72698514, rsl l5438441, rsl l l69, rs3315, rs72698516, rs72700688, rs72702717, rs56185908, rsl3159523, rs2455357, rs4869275, rs72787618, rsl874929, rsl49496, rsl52961, rs78677597, rs9496614, rs9386123, rs9403711, rs9399552, rs2295596, rsl7060480, rs3734353, rsl86858893, rs9390469, rsl87045419, rs6939850, rs6902071, rsl2189853, rs7766720, rs9486452, rs4946810, rs9372152, rsl 1759792, rsl728122, rsl728125, rsl728126, rsl739864, rsl728128, rsl728129, rsl728131, rsl728132, rsl739863, rsl739862, rs!728133, rs9285397, rs9480867, rs520942, rs9486920, rs522611, rs56229700, rs543629, rsl2524932, rs868943, rsl2524249, rsl0872142, rs7774952, rsl999929, rsl7083640, rsl2195224, rs62427623, rs62427624, rs62427626, rsl2211378, rsl2213206, rsl7705031, rsl739383, rsl777210, rsl 1154336, rs7740107, rs9402289, rsl044303, rs9388856, rsl413754, rs2236081, rs2236082, rs7775013, rs3777434, rs3777436, rs9372985, rs9385568, rs74755701, rs2608914, rs2608916, rs73542824, rsl44994895, rsl418702, rs975225, rs9791374, rsl0457001, rsl0457599, rs62428455, rsl2194836, rs62428456, rsl 1154708, rsl2197849, rs6908361, rs62428458, rs7745056, rsl2192750, rs6915521, rs4895949, rs62430561, rs6935677, rsl2210093, rs4895952, rs6902347, rsl2199972, rs4257872, rsl2193118, rs4077767, rs62430562, rsl2212715, rs62430581, rs9321388, rs9321389, rs6933214, rs6939899, rs62430582, rs58835706, rsl2200155, rsl2202394, rsl2191572, rsl2197909, rs7766945, rs62430584, rs60933911, rs28403922, rsl2205139, rs7756171, rs57161827, rs7761372, rs28538690, rs62430588, rs62430589, rs62430590, rs6936410, rs6937029, rs9493512, rs7738592, rs9493513, rs9493514, rs9493515, rs6935480, rs6940959, rs!2192605, rs9493517, rs9483529, rs9493518, rs9483530, rs9483535, rs4273707, rs4273708, rs6927627, rs6902225, rs9389047, rs7764524, rs9385632, rs9373036, rsl2211810, rsl2204720, rs9385633, rsl2214103, rs6941949, rsl338011, rs6923702, rs9399051, rs7751379, rs6569867, rs4895954, rs9389050, rs6913444, rs7756963, rs957183, rs6932057, rsl2197573, rs6913000, rsl40373654, rsl81940904, rsl2206291, rs7770031, rs6910042, rs4289671, rs9493535, rsl2208475, rsl2215649, rsl2208582, rs6569869, rs58010754, rsl2197255, rs6927764, rsl2196256, rs9493540, rs7766470, rsl2199738, rsl856291, rs9493544, rs7748926, rs7767651,20256242423.3Attorney Docket No. 046483-7468W01(04021) rs7773069, rs59793266, rs62428599, rsl 2196069, rs9483557, rs9375940, rs9385634, rs9385635, rs9389051, rs9402483, rs9375941, rs9375942, rs9402484, rsl0872402, rsl2193038, rsl2206438, rsl2193158, rs9493554, rs9402486, rs7763647, rs9373038, rs9483560, rs9402487, rs9389052, rs9402488, rsl2203712, rs74464144, rs62428628, rs9493563, rs62428629, rsl2215534, rs28620929, rs9402489, rs9399053, rs9399054, rs6912995, rs7754501, rs!2189904, rsl2204996, rs9389053, rs62428631, rsl2209655, rs9385637, rsl7299024, rs6935390, rs9389056, rs9375943, rs9321393, rs6907883, rs7746298, rsl0485235, rs2208343, rsl832394, rs9389058, rsl415858, rs3756869, rs3756871, rs3756872, rs62430275, rs9402494, rs9385640, rs9389060, rs9385641, rsl2190309, rs9402497, rs3777796, rs55947866, rs9402498, rs56377439, rsl2192839, rs6940510, rs9373043, rs9399055, rs9389064, rs62430312, rs9389066, rs62430313, rsl7301249, rs79412930, rs62430314, rs5025269, rs5025270, rs5025271, rs4278037, rs75822474, rs9373044, rs9373045, rs9399057, rs9402501, rs28405267, rsl2173440, rsl2175835, rs9373046, rs9373047, rs9402502, rs6919155, rs62430315, rs62430317, rs62430318, rs62430319, rs79623938, rs62431677, rs62431680, rs62431681, rsl336520, rs79563827, rs62428663, rs62428664, rs62428665, rsl 17808688, rs62428666, rs79021277, rs3822939, rsl7643865, rs9493650, rs73007473, rs73007475, rs73007476, rs9373060, rs9373061, rs6903968, rs9402523, rs56224918, rs2636609, rs2677813, rs2636608, rs2636607, rs2327362, rs2677820, rs2636599, rs2677822, rs2677823, rs9285475, rs77869820, rsl2205960, rsl0457609, rs2327429, rs3777891, rs7765436, rs7742626, rs7739552, rs62432752, rs61225515, rs61383594, rs58469593, rsl 1753075, rs62434185, rsl533746, rs62434223, rsl554447, rs2842977, rsl 133785, rs3818299, rs3777423, rs4709373, rs4709374, rs56015409, rs35435543, rs8191852, rs920811, rs894818, rs3798179, rsl050026, rs3777398, rsl888727, rs998203, rs614890, rs2297374, rsl91198133, rsl0945657, rs316020, rs501470, rs506823, rs73015965, rsl43079629, rs3800032, rsl0458130, rs62388352, rs6920971, rs!2208162, rsl2528812, rs6914704, rs6916153, rs3800036, rs3800037, rs3800040, rs3800043, rs3778519, rs722587, rs2015853, rs3800090, rsl3204935, rs6912444, rs3778536, rs9503028, rs9367921, rs9297015, rs9370916, rs2299064, rs2237166, rs3778554, rs7764600, rs9503077, rsl0946313, rs75705948, rs73382439, rs746720, rs9465741, rsl41351489, rsl2211466, rs62397656, rs61484729, rsl0484631, rs58332063, rs62399260, rs62399288, rs57498505, rsl6884190, rs9465877, rs7752602, rs7752788, rs9350323, rs6901380, rs6906201, rs9350324, rs6456398, rs6456400, rs6913868, rs9366382, rs9348457, rs9366383, rs9366384, rs9356769,20356242423.3Attorney Docket No. 046483-7468W01(04021) rs9350325, rs9358395, rs9368283, rs6916577, rs6937555, rs7739578, rs7739596, rs9366421, rs9356791, rs9350408, rs4711000, rs6456469, rs7768871, rs7748819, rs6922033, rs6899545, rs6904385, rs6904682, rs6911827, rs6939340, rs9358491, rs4565291, rsl772977, rsl772975, rs879097, rs6939442, rs6918573, rsl770910, rsl087289, rs9295619, rs33914824, rs9379657, rs6935659, rsl0947554, rs4713884, rs6931945, rsl0947557, rs9462097, rs2395655, rsl 1961047, rs2395668, rs262936, rs262938, rsl2214118, rs755852, rs9357301, rsl 13491720, rs9381083, rs9381084, rsl015150, rs6930504, rsl3200335, rsl3198178, rsl l759908, rs9471936, rs56935405, rsl46734164, rsl 16255295, rs77807794, rs9471969, rsl 12391291, rsl 16750300, rs73416724, rsl 11547017, rs7763350, rsl 13634553, rsl214761, rs2396050, rsl 1965885, rs881858, rs833805, rs201691646, rs3799965, rs542444, rs3799973, rs7756472, rsl934328, rs6930053, rs6911664, rsl0485422, rs6904353, rs6915569, rsl934329, rs6458447, rs7748231, rsl0948236, rsl0948237, rsl928533, rsl2204049, rsl0948238, rsl3201287, rsl755056, rs485817, rs7764616, rs6458489, rs7760123, rs6921636, rs9472692, rs2143746, rs6940977, rs2274656, rs9472872, rs6458520, rs6903162, rsl38318676, rsl2213841, rs73736668, rs628782, rs2272903, rs2076309, rs2207136, rsl2209596, rs571503, rsl327271, rsl327282, rs2796905, rs2397046, rs2251549, rs2767729, rsl409884, rs2767730, rs9463688, rs9463689, rs6919930, rs56297668, rs28515748, rs9474014, rs9367433, rs9463690, rsl337846, rs72902108, rs9349583, rs72902111, rsl2204244, rs9474016, rs4144141, rs9463692, rs4090367, rs7741896, rs57892111, rs72902167, rs72902176, rs72902201, rs7449794, rsl414504, rs76572975, rs9395707, rs7751077, rsl2214235, rs9367447, rs9382004, rs2025747, rs6920806, rs6921803, rs7746090, rs9370043, rs9395708, rs9395709, rs9370044, rs9349593, rsl326611, rsl326610, rs932801, rs932802, rsl567215, rs4715230, rs2148460, rs9370046, rsl255999, rs2397058, rs9370047, rsl0948642, rsl507911, rsl326609, rs9395711, rs35999523, rs765525, rs986546, rs986547, rs4715231, rsl7753015, rs72899402, rsl750961, rsl326605, rs6914483, rs6914672, rs9370049, rs9395712, rs9370050, rs9382006, rs9367448, rs!326586, rsl326585, rsl0948643, rsl2055557, rs2025750, rs2025749, rs9382007, rs9395713, rs9357706, rs9395714, rs9395715, rs9349594, rsl409541, rsl2665434, rs9382011, rs9367450, rs9382012, rs966709, rs966708, rs966707, rs9382013, rs9382014, rs9382015, rs9370051, rs9382018, rs9382019, rsl42522748, rs6927544, rs9370052, rs9395716, rs3920621, rs2182508, rs9370054, rs4543373, rs4263578, rs9463715, rsl0948644, rs9474070, rsl0807430, rsl 160620, rsl 1754528, rsl 1754532, rsl326559, rsl326560, rsl326561, rsl326562, rs7765455, rs4715233,20456242423.3Attorney Docket No. 046483-7468W01(04021) rs2104522, rsl 326563, rs6900031, rs2397063, rs2894790, rsl 0948647, rsl 326567, rsl 980834, rs2148459, rsl326569, rsl326570, rs9395723, rsl326573, rs6458786, rs9382031, rs6916797, rsl326576, rs2209638, rs75059606, rs9395728, rs9395729, rs9463720, rs6917984, rs7773970, rsl3202413, rs9474100, rs7764015, rs9474105, rs6908319, rs6458797, rs4715249, rs788509, rs788510, rs809292, rsl266905, rsl266916, rsl266922, rs45517932, rsl0807443, rsl884458, rs958203, rs6423287, rs6415165, rs7745053, rs76801519, rs7755335, rs2397120, rs4144184, rs7760615, rs36175277, rs34102057, rs34576365, rs77183015, rs9296694, rs7753187, rs7753323, rs7753564, rs7757768, rs7757925, rs7739622, rsl 13873355, rs6934115, rs4715356, rs7757068, rs3125265, rsl2189637, rs9382492, rs563123784, rs9475312, rs4441954, rsl2210599, rs9382498, rs4386822, rs4546489, rs4409174, rs4275061, rs4626423, rs9296787, rs7761740, rsl2213162, rs4398739, rsl45338431, rs9392827, rs35303881, rs6922083, rs9392137, rs6925389, rs9406043, rs2327010, rs2327009, rsl 1243202, rsl2198986, rsl2194650, rsl 1243203, rs55837820, rs62386963, rsl7673852, rs72827088, rs9942510, rs72912510, rs854922, rsl6881983, rs75689585, rsl 17820411, rsl3206900, rs35387650, rsl 1982462, rsl0245459, rs6959827, rsl0249739, rs9655773, rsl0261132, rsl0231704, rsl 12699345, rsl 13605241, rs73185883, rs73185884, rsl7495210, rsl2538702, rsl38929673, rs2694157, rs2694158, rsl 1764413, rsl7398575, rsl2705390, rsl7477177, rs62481856, rs2392929, rs6962980, rs6963273, rsl2705912, rs7796648, rs73234873, rsl348103, rs3779526, rsl345509, rs3808061, rs322834, rs322833, rs322832, rs3757387, rsl3227214, rs6467228, rs2693730, rs3817530, rsl 1556924, rs4721388, rs3918226, rs891511, rsl3225215, rs6464124, rsl7642575, rs7787908, rs7807134, rs7788234, rsl7715460, rs76331945, rs76747376, rs28764001, rsl 12864625, rsl 11720710, rsl 13731249, rsl 13032029, rsl 11386955, rsl 12258991, rs6966231, rs74882587, rs78219774, rs80311488, rs75885547, rs73475440, rsl7643028, rs75388874, rsl 13769875, rsl 12032351, rs4726061, rs4726062, rs4726063, rs6967946, rs9801653, rs78248188, rs73478069, rs74558374, rs79937579, rs4725416, rs4726067, rs870441, rs2374230, rs73478073, rsl 11748119, rs7457260, rsl860737, rsl860736, rs73478084, rs58461640, rs4725417, rs2536084, rs56012466, rsl0265221, rs6976065, rsl881632, rs2374300, rs9691493, rs62482826, rsl2670060, rs4582430, rsl920454, rsl0256316, rsl0949743, rs34052609, rs61122188, rs58969967, rsl0224079, rsl0242491, rsl2154725, rsl0241108, rs6459914, rs6972521, rs6944698, rsl0261098, rs!0264480, rsl 11631734, rs73167161, rs2249337, rs2178428, rs3735576, rs3801906, rs!0275919,20556242423.3Attorney Docket No. 046483-7468W01(04021) rsl0226744, rsl0235856, rsl0226143, rs28431141 , rs!3222019, rs!920452, rsl920449, rs28487953, rs28472693, rsl0239683, rsl0249636, rs71536007, rsl2698317, rsl 1765009, rs28731268, rsl 1771062, rsl 1770545, rs28529313, rsl 1505217, rs4716552, rs4716908, rs28649765, rs2051939, rsl0264279, rs2108192, rsl0269841, rs9333592, rs35225900, rsl 1576047, rs288766, rsl47880513, rs200865507, rsl225381, rsl225382, rsl225383, rs!225388, rsl731836, rs!731837, rsl675569, rs!675568, rsl675567, rsl731839, rsl731840, rsl617620, rsl616634, rsl731843, rsl731844, rsl731845, rsl731846, rsl675566, rsl731847, rs34044649, rs34652818, rs62481324, rsl0247896, rs6459952, rsl2698328, rs28591492, rs28380269, rs28691751, rsl 11239279, rs34596806, rs62480403, rs28507157, rs6976733, rsl2531716, rs9654678, rs7789438, rs6977899, rs4076780, rs28479099, rs4421245, rs6964302, rs56900386, rs59018066, rsl48455601, rsl 18063067, rs78037833, rsl524430, rsl524429, rs2365285, rsl 17728856, rsl0279504, rs77081024, rs6951593, rs883870, rs2530737, rsl 1765182, rsl 1972575, rs75353505, rsl0270726, rsl0252526, rs7383874, rsl2539909, rsl0950331, rsl2536482, rs4720922, rsl0227916, rs6968554, rsl0950659, rsl0249317, rsl7655457, rsl l772776, rsl l766613, rs75104284, rs73073181, rsl2538102, rs544353322, rs3846995, rs7782974, rs2686467, rs2528806, rs3094970, rs3094971, rs2686505, rs2528812, rs917252, rsl 815051, rs939863, rs2528813, rs2686513, rs2528835, rs80301631, rsl 7152552, rs28392961, rsl0245353, rs7798130, rs41469349, rsl0282436, rsl0267498, rsl0242536, rsl0951112, rsl0262483, rs57246313, rs56005128, rsl0950803, rsl l05420, rsl0241879, rs3757657, rsl81179233, rs35355140, rs2071265, rs35042646, rsl859168, rs7777128, rsl7428471, rsl7438292, rsl7502580, rsl 1563582, rs61127279, rs57768476, rs59783209, rsl 13269191, rs6977427, rs56897630, rsl 1763393, rs9648399, rs3088060, rs6942974, rsl0951369, rs3750117, rs4723235, rs28439161, rs2392210, rs6965942, rs4723238, rs4562213, rs4565371, rs6462450, rs4720097, rs6956397, rs7806813, rsl0280692, rsl609410, rsl0230500, rs7778958, rs7796184, rs7801701, rs7801986, rsl0486512, rs!0807866, rs4723240, rs4723241, rsl0231011, rsl0233749, rsl0951370, rsl0251079, rsl0281012, rs6948759, rsl0256717, rsl881749, rsl3228827, rsl0262141, rsl0265315, rs4454197, rs4604334, rs6951584, rsl609409, rsl0486697, rs7793162, rs6970558, rs62449449, rs62449453, rsl7714920, rs6978876, rs62452861, rs75913615, rs62452864, rs62452871, rs62452872, rs62452875, rs62452879, rsl38988531, rsl51040565, rs75603545, rsl l5762479, rs35503270, rsl 1761217, rsl 1496034, rs28852211, rs73101770, rs79291900, rsl 1766300, rsl 1764171, rsl 1765266,20656242423.3Attorney Docket No. 046483-7468W01(04021) rsl 294866, rsl 294864, rsl 294863, rsl 294861, rs700753, rs891867, rs6463354, rs6463356, rsl2702289, rs7780082, rs4724519, rs7800437, rs7804168, rsl2666798, rs34614572, rs34648469, rs28503901, rsl3242927, rsl3230300, rs7791301, rsl7540828, rs995794, rs28757789, rs67583356, rs2097880, rs2881491, rsl2668937, rsl2666569, rsl3225703, rs28616137, rsl2534770, rsl2532088, rsl2535456, rs36061487, rsl2702293, rsl2702294, rsl2702295, rsl2702296, rsl2702297, rsl2702298, rsl2702299, rsl2702300, rs6964742, rs9785020, rs9785022, rs9784985, rs6957572, rs6957879, rs6976373, rs6976393, rs73090642, rsl0277263, rsl0277420, rs6958251, rs6958583, rsl0282172, rsl3237826, rs73116822, rs73118808, rs73118816, rs2715119, rs7781924, rsl0267953, rsl43760919, rsl39824462, rsl3221342, rs9771330, rs9330365, rs9770123, rsl3241164, rsl3225240, rsl3243899, rsl3240925, rsl3229710, rs71518321, rs62432160, rs7800001, rs766333, rs7383796, rs2460432, rs313827, rs35072105, rs6978429, rs6460301, rsl3235168, rs34392598, rs34702628, rs34495733, rs79742506, rs3750170, rs6460556, rs41301394, rs2302429, rs6956241, rs2868782, rs59674745, rs60670836, rs55953411, rs73703313, rs73703314, rs7778518, rsl48783322, rs7779290, rs75504181, rsl7151202, rsl 17574221, rs74554481, rs2177993, rs2177989, rsl7151592, rs66977236, rsl0268139, rs6965245, rsl0235275, rsl0953304, rs6976611, rs6963486, rs7795371, rsl0240081, rs7801305, rsl0953349, rsl0263369, rs28605882, rs6465825, rs2057933, rs6973656, rs7786368, rs62462688, rsl0270542, rs848476, rs848483, rs848487, rs848492, rsl636665, rs848446, rs3735687, rsl38657567, rs6463533, rs35934045, rs34520461, rs60760028, rs6950388, rsl39157823, rsl3230509, rsl3230519, rs35347566, rs3824082, rs4724907, rs3735709, rs2211914, rsl3271310, rs2244648, rs6601600, rsl0101782, rs62523306, rsl2544197, rs79346194, rsl 1984773, rsl 1984866, rs7813263, rsl0955942, rs62528677, rsl0955943, rs62528692, rsl 1988434, rsl 1995536, rs6995862, rs6996081, rs9918814, rs9918815, rs4871028, rsl 1998247, rs68097758, rs!0087605, rsl0102995, rs28760377, rs55660329, rsl 106482, rsl0086797, rs60497698, rs58466445, rs28464637, rs9656934, rsl7822044, rs72673678, rsl0087551, rsl2546902, rsl2547479, rs4871718, rs67282053, rsl 1986346, rsl973732, rs7813041, rsl 1996625, rs4871825, rs7817522, rsl2386849, rsl401811, rsl2542032, rs66608823, rs77629956, rs7820543, rs7843503, rs7830028, rsl2545676, rs960887, rs60717250, rs7824793, rs7829101, rsl0955948, rsl 1780912, rs67872361, rs28530768, rs73315941, rs66614869, rsl 12290548, rsl0095205, rsl0095532, rsl2548273, rsl519808,20756242423.3Attorney Docket No. 046483-7468W01(04021) rsl 1995866, rs6469894, rs78291 16, rsl 519813, rs6469895, rs7822662, rs7822927, rsl 0808506, rs66490854, rs7812488, rsl 15420097, rs7817016, rsl2543907, rs7821947, rs6469897, rs66507952, rsl0505376, rsl6893478, rs60754245, rs6993924, rsl 12611453, rs7016816, rsl2542895, rsl 112236, rs955293, rs2875931, rs7004815, rs7005228, rs2875928, rsl0090001, rs7013298, rsl2114445, rs2056304, rs6998730, rsl0101620, rsl 1780985, rsl0101943, rs57868486, rsl0955951, rsl6893517, rsl0095303, rs2292946, rs72675741, rsl 1780844, rs7833073, rs7007998, rsl7226296, rsl 12094354, rsl 1787175, rsl 1787250, rs6981402, rs6986231, rsl 120223, rsl0109558, rs62526967, rs3030310, rs57604049, rs79774420, rs77497750, rs76209931, rs7844497, rs2954017, rs28601761, rsl 12875651, rs7826703, rs7826864, rsl519847, rsl519842, rsl519841, rsl401826, rsl2541441, rs59017966, rs60883838, rs4733662, rsl2548036, rs7814497, rsl 1776164, rsl2681691, rs4736697, rs6471147, rs6984022, rs67935034, rs6982146, rsl2549256, rs28579238, rs76510996, rsl49539397, rs4398863, rs76072125, rs6990186, rsl0102728, rsl0103731, rs2304279, rs4961256, rs4437700, rs4874439, rs73373197, rsl 1786896, rs4074678, rs7838717, rs4977200, rs4977217, rs3757974, rs3757972, rs3757971, rs2306645, rsl7088488, rs4872526, rs76856898, rs7005025, rs75277916, rsl0448071, rs73214835, rsl 13629854, rs34861762, rsl0109414, rsl705690, rs73214850, rsl7724881, rsl7786924, rs73214858, rsl 1135910, rs71517871, rs7011265, rs6557878, rs6557879, rs57222145, rs62501771, rs62501776, rsl7241553, rs62501780, rsl7819816, rsl0104004, rsl3439370, rs62501972, rs4458838, rsl50979637, rsl 84561571, rs2978286, rs34535252, rs4733503, rsl0503900, rs4633020, rsl0104033, rsl3253981, rs4733361, rs2466077, rs2466075, rsl0102889, rs58705931, rs4311627, rs76571516, rsl89529202, rs72634862, rs28374316, rsl0092449, rs66783138, rs72636310, rsl 16938314, rs900240, rs6983178, rs7827453, rs9643523, rs7834395, rs4403445, rs7007434, rsl0102740, rsl3257359, rs9298039, rsl0435601, rsl 1777673, rsl 1777706, rsl 1996592, rs2875973, rsl0957145, rsl0808710, rsl0957151, rs586377, rs608401, rs35735391, rsl7077419, rsl0808747, rsl 1557049, rs6472227, rs35165944, rs2173579, rs2936682, rs7003219, rs6995394, rsl2678260, rsl2680737, rs7011927, rs75505314, rsl2682220, rs62523461, rsl399562, rs2922785, rs60878530, rs58494441, rsl6939150, rs2921093, rs62498670, rsl7520086, rs2976841, rs2979163, rs2976846, rsl3270194, rs6601703, rs7827182, rs7823056, rs6995407, rsl3270194, rs7009054, rs6601703, rs7827182, rs7817376, rs7823056, rs6995407, rsl 1787146, rs7012814, rsl461729, rsl073788, rs4566, rs9969643,20856242423.3Attorney Docket No. 046483-7468W01(04021) rsl 0095352, rs2307075, rs2953516, rs2976178, rs2033074, rs2033075, rsl 2550043, rs4596617, rs4481558, rs4348460, rs4348461, rsl2543404, rsl2545684, rs2068005, rsl2677519, rs6471457, rs7814803, rs66477120, rsl2544778, rs2052720, rs3864655, rs7017996, rsl49180731, rsl l2123474, rs59515090, rsl2678709, rsl2676890, rsl2678729, rsl2676908, rsl2677807, rsl2677830, rs55890917, rs55716822, rsl2675372, rsl2678311, rsl2545296, rs72676935, rsl2543514, rs7832022, rs7813657, rs7814238, rs7836949, rs7833363, rs57653937, rs4008177, rs7017752, rs2554401, rs4639480, rs6471460, rsl2546263, rsl2545776, rsl2546282, rs7842400, rs7812489, rs7388010, rsl7645441, rsl046163, rs6471467, rs7462810, rs7460444, rs7462846, rs6471469, rs6471470, rs6471471, rs2554397, rs55663086, rs2722883, rs2722884, rsl3266255, rsl3254184, rs4735324, rs7844431, rs7826057, rs7835379, rsl226590, rs2780955, rs4743684, rs3818625, rsl0820599, rsl0820600, rs546232214, rsl0979879, rs2274786, rs557871513, rs2796035, rs787299, rs700122, rsl0733594, rsl0739373, rsl2350531, rs76674453, rs3827675, rsl0817564, rsl0982050, rsl2378445, rs28616789, rsl0982054, rsl864721, rsl0982063, rs7853169, rs6478062, rs9697050, rsl0983126, rs6478237, rsl040850, rs34976241, rs34430369, rsl3292335, rs34140540, rsl2156498, rs56147233, rsl2005639, rsl3284925, rs56329744, rs62575433, rsl2377406, rs34804463, rs34513895, rs4836752, rsl0983234, rs62576082, rs62576093, rs35316886, rsl0817918, rs60847503, rsl0983295, rsl0983300, rsl0983301, rs35891915, rs62574187, rsl0983308, rs60203546, rsl441748, rsl2981, rsl3284547, rs6478585, rs624108, rs618275, rsl0818775, rs7870270, rsl0760265, rsl6912523, rs2275510, rs700069, rs700074, rsl2686096, rs700080, rs700082, rs700089, rsl0818799, rsl2344903, rs4838038, rsl0985922, rsl0760271, rsl2238669, rsl3289976, rs7389288, rsl0819045, rsl0986700, rsl0819046, rs2841332, rsl0986724, rsl0760395, rsl0986759, rs4837129, rsl0987559, rsl0760476, rsl0819268, rsl0819269, rs4837197, rs3824528, rs2274426, rsl0217290, rs7038077, rs6478915, rs73672505, rs74872096, rs!82912225, rs!034022, rs62584850, rs62584851, rs62584852, rs72755265, rs72755266, rs7852266, rs7852271, rs7852436, rs7852995, rs7028152, rs7028745, rs7045022, rs56262993, rs62584858, rs62584859, rs62586260, rsl 13141778, rsl l l903950, rs62586262, rs62586264, rs62586265, rs4302946, rs2005351, rs62586266, rs4545195, rs4480218, rs4323577, rs4545196, rs2417149, rs4644354, rs62586267, rs7027714, rsl6931489, rs62586269, rsl l5154450, rs72755277, rs55711781, rs56335269, rs62586273, rs72755282, rs72755283, rs72755284, rsl6931493, rs72755285, rs72755286,20956242423.3Attorney Docket No. 046483-7468W01(04021) rs62586274, rs62586275, rs62586276, rsl 1999367, rs62583561 , rs62583562, rsl 0123409, rs4836675, rs913318, rs913322, rsl l08535, rsl l08532, rsl l08533, rs62583579, rs3780705, rs62583584, rs62583603, rsl47706265, rs76588272, rs72757235, rs62583606, rs76796731, rs61314466, rs79639102, rs76540153, rs41367050, rs78867009, rs78377535, rsl0739767, rsl0988553, rs60541956, rs79746999, rs76891739, rsl7519156, rs78526807, rs77998122, rs78058713, rsl 1793982, rs76701800, rs77693339, rsl0793962, rsl 137827, rs550057, rsl39032120, rsl0993909, rs75318400, rs7021188, rsl0821551, rs80203447, rsl48384572, rsl 1103387, rsl475259, rsl0122824, rs28711320, rs!0810652, rsl0810655, rs537176512, rsl0121943, rsl0964603, rsl537373, rsl333042, rs6475611, rs7047414, rsl0971361, rs3780490, rs3780489, rsl0758192, rsl0124479, rsl0813954, rs2209948, rsl0971424, rs7864705, rs7865745, rs7868781, rsl0813955, rs7873182, rs7873077, rs7036812, rsl3288380, rs7019647, rs9802431, rsl0738919, rsl570777, rs7865742, rs307669, rs307684, rs4272470, rs307700, rsl3300356, rs61237993, rs7033145, rs7853437, rsl331260, rs4740743, rsl0122183, rsl373850, rsl0758779, rs2297442, rs59699173, rs77979581, rsl 17451470, rs6560203, rsl3302081, rs4745093, rsl 1142922, rsl 1142926, rs4744712, rsl 1144066, rs4745353, rs7851923, rs4745366, rs4237270, rs6560419, rs7043133, rs7043242, rs7043868, rs58302882, rs60864427, rsl 1142563, rs4744612, rs6560150, rsl0868884, rsl0868885, rsl328148, rs7045063, rs7861859, rsl0868898, rsl7470958, rs4877691, rsl888327, rs80020015, rsl3290278, rs35103886, rsl3299917, rsl411662, rs4877233, rs35559314, rs955975, rsl 17355062, rs7847758, rs7040995, rs870151, rs4877118, rs6559369, rsl 1265853, rsl2346653, rs3858097, rsl l521657, rs7020638, rsl l27851, rs2275848, rsl2342200, rs73524733, rs7867526, rs781649, rs2460138, rs2945799, rs28369681, and rs!2236906.

24. The method of any one of claims 21-23, which comprises detecting a risk allele at rs4924525 at the CHAC 1 locus, and / or CpG cg05124934.

25. The method of any one of claims 21-24, wherein the kidney disease causes a reduction in a filtration capacity of the kidney in the subject as compared to a healthy control subject.

26. The method of any one of claims 21-25, wherein the subject is a human.21056242423.3Attorney Docket No. 046483-7468W01(04021)27. A method of identifying a causal kidney disease gene, the method comprising: performing a genome-wide association study (GWAS) of kidney function in a population; performing a fine-mapping credible sets of variants from the GWAS; integrating the fine-mapped variants with kidney-specific molecular data selected from the group consisting of expression quantitative trait loci (eQTL), allele-specific expression (ASE), bulk allele-specific chromatin accessibility (bASA), single-nucleus allele-specific chromatin accessibility (snASA), methylation quantitative trait loci (meQTL), and single-cell multiome peak-to-gene mapping (Open4Gene); and prioritizing one or more causal variants, genes, or regulatory elements associated with kidney disease.21156242423.3

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