Application of SNP, environmental factors and biomarker interaction in IgA nephropathy

Abstract

The application belongs to the field of biomedicine, and particularly relates to application of SNP, environmental factor and biomarker interaction in IgA nephropathy. The application provides application of SNP, environmental factor and biomarker interaction in IgA nephropathy to construct a systematic disease risk assessment of IgA nephropathy, which can effectively guide personalized management and intervention strategy of IgAN patients. Compared with single factor analysis (only analyzing SNP, environmental factor and biomarker), the application can more comprehensively evaluate genetic sensitivity of patients to environmental factors, and greatly improves accuracy of disease risk prediction and clinical application value.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to the application of SNP, environmental factors, and biomarker interactions in IgA nephropathy. Background Technology

[0002] IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide, characterized by the deposition of immunoglobulin A (IgA) in the glomeruli, ultimately leading to chronic kidney disease and even end-stage renal disease (ESRD). Recent advances in research have revealed the underlying pathogenesis of this disease, with a core "multiple-hit" model: first, elevated levels of circulating IgA1 due to galactose deficiency in the hinge region, originating from the mucosal immune system; subsequently, specific IgG and IgA antibodies bind to IgA to form immune complexes, which deposit within the glomeruli, triggering inflammatory responses, complement activation, and kidney damage, such as... Figure 1 As shown.

[0003] The etiology of IgAN is complex, influenced by multiple factors including genetics, environment, and immune regulation. Currently, renal biopsy is the gold standard for diagnosing IgAN, but it is invasive. IgAN also presents challenges such as difficulty in early diagnosis, high rate of missed diagnosis, high heterogeneity in clinical manifestations, and complex pathological subtypes.

[0004] In recent years, air pollution, especially PM2.5, has become increasingly serious. 2.5 The association between exposure to fine particulate matter (PM2.5), less than 2.5 micrometers in diameter, and the occurrence and progression of kidney disease is increasingly attracting attention. 2.5 As an environmental pollutant, PM2.5 is significantly associated with various chronic diseases, such as cardiovascular diseases, respiratory diseases, and kidney diseases. Studies have shown that long-term exposure to high concentrations of PM2.5 is detrimental. 2.5 It can lead to decreased kidney function and is closely related to the occurrence of kidney fibrosis and inflammation. PM 2.5 Exposure can damage the kidneys through mechanisms such as oxidative stress, inflammatory responses, and abnormal immune regulation. However, individual exposure to PM2.5 varies. 2.5 Significant differences exist in susceptibility to exposure, which may be related to genetic background. Current research largely focuses on PM2.5. 2.5 The study focused on the single role of genetic factors without considering their specific impact on individual disease risk.

[0005] Single nucleotide polymorphisms (SNPs), the most common genetic variations in the genome, can significantly affect gene expression, protein function, and signaling pathway activity, thereby regulating an individual's response to environmental factors. Several SNPs are associated with susceptibility to and progression of IgAN. For example, deletions in HLA regions, CFHR3, and CFHR1 genes, as well as SNPs related to the immune system, have all been shown to be associated with IgAN risk. However, most of these studies are genome-wide association studies (GWAS), focusing on genetic susceptibility without exploring how SNPs interact with environmental factors to accelerate disease progression. Therefore, exploring the relationship between SNPs and environmental factors (such as PM2.5) is crucial. 2.5 The interaction between these mechanisms can help reveal the mechanisms of IgAN occurrence and progression, and provide a scientific basis for disease prediction, prevention and personalized intervention.

[0006] In addition to traditional non-specific biomarkers for common kidney diseases, many novel biomarkers for IgAN have been studied in the past, such as: target antigen antibodies associated with disease occurrence, complement system biomarkers reflecting renal interstitial fibrosis, miRNAs for early diagnosis and long-term renal function prediction, and urinary enzymes, metabolic proteins and inflammatory molecules that can non-invasively monitor disease progression. However, the specificity and sensitivity of these biomarkers still need to be verified, and they cannot accurately predict the risk of disease progression in the early stages.

[0007] Because the clinical diagnosis and treatment of IgAN heavily relies on renal biopsy and the use of non-specific biomarkers for common kidney diseases, current technologies have the following limitations: (1) Limitations of single-factor analysis; Current research often focuses on the individual effects of genetic factors, environmental factors, and biomarkers, neglecting the combined impact of their interactions on disease progression. Previous studies have confirmed that leukemia suppressor factor (LIF) is associated with the production of galactose-deficient IgA1 and the development of renal fibrosis; LIF has become a hot topic gene in IgAN in multiple genome-wide association studies (GWAS). However, its interactions with genetic and environmental factors, and consequently its impact on IgAN risk, are rarely revealed. Furthermore, in IgAN risk assessment, univariate analysis models struggle to explain individual differences in responses to environmental factors.

[0008] (2) Lack of accurate disease risk assessment methods; Existing IgAN risk assessment methods are mainly based on traditional non-specific biomarkers of common kidney diseases, such as proteinuria and eGFR. These indicators typically change significantly in the middle and late stages of the disease, but cannot predict disease progression in the early stages. In addition, while GWAS-based data have revealed some genetic susceptibility loci, there is a lack of tools that can be directly applied to individualized risk prediction.

[0009] (3) Lack of research and application on the mechanisms of interaction between SNPs, environmental factors, and biomarkers; Although existing research has shown that environmental factors (such as PM) 2.5 Exposure to the kidneys (LIF) damages the kidneys through pathways such as oxidative stress and inflammatory responses, but its molecular interaction with specific SNPs (such as rs2412971) remains unclear. Current technologies cannot effectively integrate genotype, environmental exposure level, and biomarkers (such as LIF expression) to construct disease risk assessment models.

[0010] (4) The predictive methods lack clinical translation. Currently, most research remains at the laboratory stage, lacking systematic predictive methods for clinical application, and thus failing to effectively guide personalized management and intervention strategies for IgAN patients.

[0011] Given the aforementioned limitations of current technologies, developing and validating applications and products based on SNP, environmental factors, and biomarker interactions in IgA nephropathy is crucial for supporting clinical diagnosis and personalized treatment decisions. Summary of the Invention

[0012] To meet the needs of rapid clinical diagnosis and prognostic assessment, this invention utilizes the application of SNP, environmental factors, and biomarker interactions in IgA nephropathy to guide and predict the progression risk of IgA nephropathy.

[0013] The purpose of this invention is to provide an application of SNP, environmental factors, and biomarker interactions in IgA nephropathy to guide personalized management and intervention strategies for IgAN patients.

[0014] The objective of this invention is achieved through the following technical solution: In a first aspect, the present invention provides an application of SNP, environmental factors, and biomarker interactions in IgA nephropathy, wherein the application comprises at least one of the following: 1) Use in the preparation of products for indicating or evaluating the benefit of treatment for IgA nephropathy; 2) Application in the preparation of products for the diagnosis or auxiliary diagnosis of progression of IgA nephropathy; 3) Application in the preparation of products for predicting the risk of renal failure after treatment of IgA nephropathy; 4) Application in the preparation of products for prognostic assessment after treatment of IgA nephropathy. The environmental factors and the SNPs interact to regulate the expression of the biomarkers, thereby affecting the progression of IgA nephropathy.

[0015] In some specific embodiments of the present invention, the therapeutic benefit is manifested in at least one of the following: 1) Reduce proteinuria, where proteinuria is the ratio of urinary protein to creatinine (UPCR). 2) Reduces the risk of progression of IgA nephropathy; 3) Reduces the risk of kidney failure; 4) Improve kidney survival rate.

[0016] In some specific embodiments of the present invention, the risk allele of the SNP affects the expression level of the biomarker; further, the SNP is rs2412971; even further, the risk allele is A, i.e., the rs2412971AA genotype; the environmental factor is PM2.5. 2.5 The exposure, wherein the biomarker is LIF; the LIF is selected from one or more of renal LIF and urinary LIF, further, the renal LIF is selected from one or more of glomerular LIF and renal tubular LIF, and even further, the urinary LIF is uLCR, i.e., the ratio of urinary leukemia inhibitory factor to creatinine.

[0017] In some specific embodiments of the present invention, the rs2412971AA genotype upregulates the expression level of LIF by enhancing promoter activity.

[0018] In some specific embodiments of the present invention, the PM 2.5 Exposure will have at least one of the following effects: 1) Upregulation of its concentration can lead to an increase in LIF expression levels in IgAN patients; 2) Upregulation of its concentration significantly increases the risk of disease progression in IgAN patients carrying the rs2412971AA genotype; 3) Downregulation of its concentration will affect the decrease in LIF expression levels in IgAN patients; 4) Downregulation of its concentration reduces the risk of disease progression in IgAN patients carrying the rs2412971AA genotype.

[0019] In some specific embodiments of the present invention, the rs2412971 will perform at least one of the following functions: 1) LIF expression was significantly higher in carriers of the AA genotype than in carriers of the AG / GG genotype; 2) The risk of IgAN progression is higher in carriers of the AA genotype than in carriers of the AG / GG genotype; 3) Carriers of the rs2412971AA genotype exposed to high levels of PM2.5 have a higher risk of IgAN progression than carriers of the same genotype who are consistently exposed to low levels of PM2.5.

[0020] In some specific embodiments of the present invention, the LIF will serve at least one of the following functions: 1) Its expression level can reflect PM 2.5 Furthermore, regarding the concentration level of exposure, patients exposed to high levels of PM2.5 had significantly higher LIF expression levels than those exposed to low levels of PM2.5. 2) Upregulation of its expression can increase the risk of disease progression in IgAN patients carrying the rs2412971AA genotype; 3) Downregulation of its expression reduces the risk of disease progression in IgAN patients carrying the rs2412971AA genotype.

[0021] In some specific embodiments of the present invention, the product includes one or more of the following: reagents, reagent kits, chips, test strips, membrane strips, and detection platforms.

[0022] In some specific embodiments of the present invention, the product testing uses an indicator obtained from a patient, and the indicator is selected from one of the following: 1) The genotype of the SNP and the concentration level of the environmental factor; 2) The genotype of the SNP and the expression level of the biomarker; 3) The concentration levels of the environmental factors and the expression levels of the biomarkers; 4) The expression level of the biomarkers.

[0023] In a second aspect, the present invention provides a method for predicting the risk of progression of IgA nephropathy, the method comprising detecting a sample of indicators obtained from a patient, the method comprising: 1) Bring the sample into contact with a reagent or instrument capable of detecting the sample; 2) Obtain the detection results of the sample; 3) Predict the risk of progression of IgA nephropathy in patients based on the test results of the samples described in the test results.

[0024] In a third aspect, the present invention provides a system based on a method for predicting the risk of progression of IgA nephropathy, comprising: A detection module is used to detect the content of indicators in the sample; The analysis module is used to compare the index content of the sample obtained by the detection module with preset values. When the index content of the sample is higher than the preset value, the analysis determines it to be high-risk. The output module is used to output the above analysis results.

[0025] The technical solution provided by this invention has the following technical contributions: (1) This invention is geared towards clinical application and is the first to effectively integrate SNPs, environmental factors, and biomarkers to construct a systematic disease risk assessment for IgA nephropathy, which can effectively guide personalized management and intervention strategies for IgAN patients. Compared with single-factor analysis (which only analyzes SNPs, environmental factors, and biomarkers), this invention can more comprehensively assess the genetic sensitivity of patients to environmental factors, and significantly improve the accuracy of disease risk prediction and its clinical application value.

[0026] (2) This invention discovers through mechanism research that PM 2.5 Exposure regulates LIF gene expression through genetic background SNPs (rs2412971 genotype), thereby affecting the progression of IgAN. This discovery not only provides a new perspective for the study of the pathological mechanisms of IgAN, but also provides a reference for future research on the interaction between other environmental factors and genetics.

[0027] (3) Through mechanism research, this invention found that LIF expression in rs2412971AA genotype carriers was significantly higher than that in AG / GG genotype carriers. rs2412971AA genotype carriers exposed to high levels of PM2.5 had a higher risk of IgAN progression than genotype carriers who were continuously exposed to low levels of PM2.5, thus affecting IgAN progression.

[0028] (4) Through mechanistic studies, this invention has found that the expression level of LIF can reflect the concentration level of PM2.5 exposure. Patients exposed to high levels of PM2.5 have significantly higher LIF expression levels than patients exposed to low levels of PM2.5, which in turn affects the progression of IgAN. Compared with traditional clinical indicators (such as proteinuria, eGFR, etc.), changes in LIF levels can reflect renal function damage in the early stages of the disease, which helps to identify high-risk patients earlier and take intervention measures.

[0029] (5) This invention also found that the urine LIF concentration ratio (uLCR) can serve as an early marker of IgAN progression, and is correlated with SNP genotype and PM. 2.5 It is closely related to exposure.

[0030] (6) This invention effectively combines genetics, environmental science and clinical medicine to construct a novel disease prediction model. This model is not only applicable to IgAN, but can also be extended to risk assessment of other complex diseases involving the interaction between genetics and environment (such as chronic kidney disease, cardiovascular disease, etc.).

[0031] (7) The gene detection (such as PCR), environmental exposure assessment (based on NASA data), and urine detection (ELISA) used in this invention are all mature technologies that are easy to operate and have low cost. This method is suitable for large-scale population screening, has strong clinical translation potential, and can be widely used in the early diagnosis and management of IgAN patients.

[0032] (8) This invention combines genetic factors, environmental factors, and biomarkers to accurately stratify the risk of IgAN patients. Patients in different risk groups can receive personalized disease management advice, such as reducing PM2.5. 2.5 Exposure, enhanced follow-up monitoring, or targeted treatment are all options. This precision medicine strategy can effectively optimize treatment outcomes and reduce the socioeconomic burden of disease progression.

[0033] In summary, this invention, based on the application of SNPs, environmental factors, and biomarker interactions in IgA nephropathy, provides a clearer basis for the diagnosis and treatment of IgA nephropathy, significantly improving the accuracy of disease risk prediction and its clinical application value. Attached Figure Description

[0034] Figure 1 It is IgAN's multi-strike model.

[0035] Figure 2 It is PM 2.5 The interaction between exposure and rs2412971 genotype on IgAN progression. Figure 2 A is a forest map showing PM 2.5 The hazard ratio (HR) and 95% confidence interval (CI) of exposure to IgAN progression, including overall patients and results stratified by rs2412971 genotype. The interaction p-value represents the p-value of the association between SNP and PM2.5 exposure. Figure 2 B is the cumulative hazard function plotted based on PM2.5 exposure levels and rs2412971 genotype grouping. The cumulative hazard curves are generated based on a multivariate Cox proportional hazards model, adjusted for age, sex, baseline eGFR, proteinuria, albumin, hemoglobin, systolic and diastolic blood pressure, short-term use of steroids or immunosuppressants after renal biopsy, and use of ACE inhibitors or ARBs. The vertical axis (y-axis) represents the cumulative risk of renal failure, and the horizontal axis (x-axis) represents the follow-up time (years). Note: HR is the hazard ratio, and CI is the confidence interval.

[0036] Figure 3 This section discusses the population distribution, sequence background, and functional significance of rs2412971. Figure 3 A is the sequence background of rs2412971, indicating that it is located within a conserved genomic motif (highlighted). Figure 3 B is a sequence diagram of the shared binding motif of the relevant transcription factors, where the rs2412971 site is marked (red box). This variation may alter the binding affinity of the transcription factor at this site. Figure 3C and 3D are luciferase reporter gene assays. The results show that the rs2412971_A allele can significantly enhance ( Figure 3 C) pGL3 promoter and ( Figure 3 D) Promoter activity of the LIF promoter. Data are expressed as mean ± standard error (mean ± SEM). t-test analysis was performed, and ***P < 0.001 (indicating highly statistically significant difference) was observed.

[0037] Figure 4 Immunofluorescence staining of LIF in renal biopsies of 30 IgAN patients, grouped according to PM2.5 exposure level and rs2412971 genotype. Figure 4 A represents the LIF expression staining profile grouped by PM2.5 exposure level and rs2412971 genotype. Figure 4 B and 4C are glomeruli grouped according to PM2.5 exposure levels. Figure 4 B) and renal tubules ( Figure 4 C) LIF deposition grading. Patients exposed to high PM2.5 environments showed significantly stronger LIF expression. Figure 4 D, 4E are glomeruli grouped according to the rs2412971 genotype ( Figure 4 D) and renal tubules ( Figure 4 E) LIF deposition grading. LIF expression was significantly higher in AA genotype carriers than in AG / GG carriers. Statistical comparisons between the two groups were performed using the Mann-Whitney U test. Figure 4 F represents the urinary LIF (uLIF) level in IgAN patients exposed to different PM2.5 levels. Figure 4 G represents urinary LIF levels grouped according to the rs2412971 genotype. PM2.5 exposure categories were defined based on the annual average PM2.5 concentration before study enrollment: high exposure ≥53.6 μg / m³, low exposure <53.6 μg / m³. Scale bar: glomeruli 50 μm, renal tubules and interstitium 100 μm. Significance markers: *p<0.05, **p<0.01, ***p<0.001.

[0038] Figure 5 It is the correlation between the urinary leukemia inhibitory factor-creatinine ratio (uLCR) and the progression of renal function. Figure 5 A is the Kaplan-Meier curve of kidney survival based on uLCR grouping (low group: <0.25 μg / gCr; high group: ≥0.25 μg / gCr). Figure 5B is a forest plot: showing the uLCR hazard ratio (HR) and 95% confidence interval (CI) calculated using the Cox proportional hazards model. Model 1: Unadjusted; Model 2: Adjusted for age, sex, baseline estimated glomerular filtration rate (eGFR), proteinuria, mean arterial pressure (MAP), short-term use of glucocorticoids or immunosuppressants after renal biopsy, and use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs); Model 3: Adjusted using the Xieequation; Model 4: Further adjusted for laboratory parameters (LP) based on Model 3.

[0039] Figure 6 This is the association between renal LIF expression and uLCR levels and the histopathological features of IgAN. Figure 6 The box plot of A shows the relationship between LIF expression and OxfordMEST-CT score. Figure 6 Box plot B shows the relationship between LIF expression and interstitial inflammatory cell infiltration. Figure 6 The box plot of C shows the relationship between uLCR level and OxfordMEST-CT score. Figure 6 The box plot of D shows the relationship between uLCR levels and interstitial inflammatory cell infiltration. Detailed Implementation

[0040] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0041] Unless otherwise specified, the terms used in the following embodiments are explained as follows: In this disclosure, unless otherwise specified, the term "single nucleotide polymorphism (SNP)" primarily refers to the diversity of DNA sequences caused by variations in a single nucleotide at the genomic level. SNPs are numerous and exhibit rich polymorphism. Theoretically, each SNP site can have four different forms of variation (substitution (transition or transversion), insertion, or deletion), but in practice, only two occur: transition and transversion, with a ratio of 2:1. SNPs occur most frequently in CG sequences, and are mostly C-to-T conversions because the C in CG is often methylated, spontaneously deaminated to become thymine. Generally, an SNP refers to a single nucleotide variation with a frequency greater than 1%. Polymorphism analysis is typically performed using DnaSP software, which can be downloaded from: http: / / www.ub.edu / dnasp / .

[0042] In this disclosure, unless otherwise specified, the term “rs2412971” is the number of a specific single nucleotide polymorphism (SNP) representing a base A variation at position 22:30098382 (GRCh38) on chromosome 22.

[0043] In this disclosure, unless otherwise specified, the term "genotype" refers to the genetic makeup of an individual at a particular locus.

[0044] In this disclosure, unless otherwise specified, the term "allele" refers to a gene that controls different morphologies of the same trait at the same locus on homologous chromosomes. In this text, G and A represent two alleles at that locus. Here, AA indicates that both alleles are A, GG indicates that both alleles are G, and AG indicates two genotypes with alleles A and G. 1 / 1 indicates that both alleles are 1, 2 / 2 indicates that both alleles are 2, and 1 / 2 indicates two genotypes with alleles 1 and 2. When the genotyping result is AA or GG, it indicates that the individual's genotype is homozygous, meaning that both alleles represent the same gene; when the genotyping result is AG or 1 / 2, it indicates that the individual's genotype is heterozygous, meaning that the two alleles represent different genes.

[0045] In this disclosure, unless otherwise specified, the term "minor allele" refers to an allele that occurs at a relatively lower frequency in a specific population sample (corresponding to "major allele," which is an allele with a higher frequency). For example, if a gene locus has two alleles, A and G, and the frequency of A in the study population is 30% and the frequency of G is 70%, then A is the minor allele.

[0046] In this disclosure, unless otherwise specified, the term "effect allele" refers to an allele that is statistically associated with the phenotype of interest (such as disease risk, height, blood pressure, etc.) and is considered to have an influence on that phenotype. Typically, the results will clearly indicate which allele is the effect allele (which may be a minor or major allele).

[0047] In this disclosure, unless otherwise specified, the term "transcription factor" is a class of proteins that can bind to specific DNA sequences and regulate the process of gene transcription (from DNA to RNA).

[0048] In this disclosure, unless otherwise specified, the term "promoter" is a DNA sequence located upstream of a gene, which is the site where RNA polymerase binds and plays a key regulatory role in the initiation of gene transcription.

[0049] In this disclosure, unless otherwise specified, the term "PM" refers to... 2.5 Also known as fine particulate matter, it refers to particulate matter in ambient air with an aerodynamic equivalent diameter of less than or equal to 2.5 μm. This substance has a complex chemical composition, including organic carbon (OC), elemental carbon (EC), nitrates, sulfates, ammonium salts, and sodium salts (Na). + These substances, such as PM2.5, can remain suspended in the air for extended periods. 2.5 An increase in atmospheric concentration indicates worsening environmental pollution. In environmental science, the rise in particulate matter concentration due to human activities has become one of the main indicators of air pollution. Because PM2.5 concentrations... 2.5 Its ability to remain in the air for extended periods, coupled with its larger size than viruses but smaller than bacteria, makes it easy for it to enter the respiratory system during human respiration. It can then carry toxic substances and accumulate in the lungs or other organs, causing serious harm to human health.

[0050] In this disclosure, unless otherwise specified, the term "IgAN" is an abbreviation for IgA nephropathy, short for Immunoglobulin A Nephropathy, a common primary glomerular disease. IgA nephropathy is the most common primary glomerular disease, characterized by predominantly IgA deposition in the glomerular mesangial area, with or without the deposition of other immunoglobulins. Lesion types include focal segmental lesions, endocapillary proliferative lesions, mesangial proliferative lesions, crescentic lesions, and sclerotic lesions. Its clinical manifestations include recurrent episodes of gross or microscopic hematuria, which may be accompanied by varying degrees of proteinuria. Some patients may develop severe hypertension or renal insufficiency.

[0051] In this disclosure, unless otherwise specified, the term "proteinuria" is also known as the urinary total protein-to-creatinine ratio (UPCR), which is an important indicator for assessing the protein content in urine. It reflects the presence and extent of protein leakage in the kidneys by calculating the ratio of the concentration of total protein in urine to creatinine. It is of key significance in the early screening, disease monitoring and efficacy evaluation of kidney diseases.

[0052] In this disclosure, unless otherwise specified, the term "renal biopsy" is also known as percutaneous renal biopsy or kidney biopsy. It is a routine technique in nephrology to obtain kidney tissue samples for pathological diagnosis. It is mainly used to determine the type of kidney disease, guide treatment, and assess prognosis, and is regarded as the "gold standard" for diagnosing kidney disease.

[0053] The Oxford classification is currently the most commonly used international pathological classification standard for IgA nephropathy. The C score is an indicator in this classification for assessing the degree of intravascular proliferation in glomerular capillaries.

[0054] In this disclosure, unless otherwise specified, the term “MEST-C score” is a core indicator of the Oxford classification of IgA nephropathy, representing glomerular mesangial proliferation (M), intracapillary proliferation (E), segmental sclerosis / adhesion (S), tubular atrophy / interstitial fibrosis (T), and crescent (C), used to assess the pathological severity of the disease.

[0055] In this disclosure, unless otherwise specified, the terms "HR: hazard ratio" and "CI: confidence interval" are both commonly used statistical indicators. HR is often used in survival analysis (such as the Cox proportional hazards model) to represent the strength of the association between the exposure factor and the risk of the outcome event. CI is used to reflect the reliability of statistical results, and the 95% confidence interval is commonly used, meaning that in multiple repeated samplings, about 95% of the interval will contain the true population parameter.

[0056] In this disclosure, unless otherwise specified, the term "eGFR: estimated glomerular filtration rate" is a medical indicator used to assess kidney function and is widely used in the screening, diagnosis, and monitoring of chronic kidney disease (CKD). It is calculated by measuring serum creatinine levels in the blood and combining this with specific formulas (such as MDRD or CKD-EPI) and the patient's age, sex, and ethnicity. Creatinine is a waste product of muscle metabolism and is normally excreted through the kidneys. When kidney function declines, the rate of creatinine excretion slows, leading to an increase in its concentration in the blood, thus lowering the eGFR value. eGFR is an important tool for assessing chronic kidney disease (CKD), helping physicians to develop appropriate treatment plans by identifying stages of declining kidney function. Furthermore, eGFR is influenced by various factors such as age, physical condition, and dietary habits. Based on eGFR values, kidney health can be categorized into the following stages: Normal or high (≥90 mL / min / 1.73 m²): Normal kidney function; Mild decline (60-89 mL / min / 1.73 m²): Mild decline in kidney function; Moderate decline (30-59 mL / min / 1.73 m²): Moderate kidney impairment; Severe decline (15-29 mL / min / 1.73 m²): Severe kidney impairment; Kidney failure (<15 mL / min / 1.73 m²): Kidney failure requiring dialysis or transplantation.

[0057] In this disclosure, unless otherwise specified, the term "UPE: urinary protein excretion", also known as 24-hour urinary protein quantification or 24-hour urinary protein excretion rate, is used to measure the protein content in 24 hours by collecting all urine over 24 hours, and then calculate the total protein content in 24 hours. The protein content in normal urine is extremely low, with a normal level below 150 mg / 24h.

[0058] In this disclosure, unless otherwise specified, the term "SBP" refers to systolic blood pressure. SBP (systolic blood pressure) is the highest pressure of blood against the walls of blood vessels when the heart contracts, reflecting the heart's pumping capacity. The normal range is usually 90-120 mmHg.

[0059] In this disclosure, unless otherwise specified, the term "DBP: diastolic blood pressure" is the lowest pressure that the blood vessel walls bear when the heart is in diastole, reflecting peripheral vascular resistance, and the normal range is usually 60-80 mmHg.

[0060] In this disclosure, unless otherwise specified, the term "ACEI: angiotensin-converting enzyme inhibitors" refers to the inhibitory effect on blood pressure and the protection of target organs by inhibiting the activity of angiotensin-converting enzyme, thereby blocking the conversion of angiotensin I to angiotensin II.

[0061] In this disclosure, unless otherwise specified, the term "ARB" refers to angiotensin receptor blockers, which directly block the binding of angiotensin II to receptors on target organs (without affecting the angiotensin-converting enzyme), thereby preventing its effects of vasoconstriction, raising blood pressure, and damaging target organs, resulting in a stable and sustained reduction in blood pressure.

[0062] In this disclosure, unless otherwise specified, the term "ESRD: end-stage renal disease" refers to the end stage of chronic kidney disease (CKD), in which patients almost completely lose their kidney function and require long-term renal replacement therapy to maintain their lives. ESRD is characterized by high disease severity, a high incidence of complications, and a heavy financial burden from treatment. Common complications in ESRD patients include renal anemia, hyperphosphatemia, hyperparathyroidism, and hyperkalemia.

[0063] In this disclosure, unless otherwise specified, the term "MAP" is an abbreviation for "mean arterial pressure," referring to MBP (mean arterial pressure), which is the average arterial blood pressure throughout the entire cardiac cycle, reflecting organ perfusion. The calculation formula is MBP = DBP + 1 / 3 (SBP). DBP), the normal range is about 70-105 mmHg.

[0064] In this disclosure, unless otherwise specified, the term "median follow-up time" refers to the median (50th percentile) of the actual follow-up duration for all subjects in a follow-up study. It describes the overall follow-up time of subjects and reflects the depth of follow-up for patients or subjects in the study. The calculation of median follow-up time takes into account factors such as subject enrollment time, occurrence of endpoint events, and voluntary withdrawal, thus enabling a more accurate assessment of disease progression and treatment efficacy.

[0065] In this disclosure, unless otherwise specified, the term "angiotensin-converting enzyme inhibitor (also known as ACE inhibitor or ACEI)" refers to medications used to lower blood pressure, "blocking the blood pressure-raising signal," and are a common treatment for diabetic patients. Representative drugs include captopril and enalapril (captopril is a short-acting drug, while enalapril is a long-acting drug, more suitable for long-term use). ACE inhibitors prevent an enzyme in the body from producing angiotensin 2 (a substance that causes blood vessels to constrict). When blood vessels constrict, the heart needs to work harder. This can lead to increased blood pressure. Angiotensin 2 also releases hormones that can raise blood pressure.

[0066] In this disclosure, unless otherwise specified, the term "ARB class drugs" refers to drugs such as valsartan, losartan, and olmesartan. ARBs selectively block angiotensin II receptors (AT1 type), thus inhibiting the vasoconstrictive, blood pressure-raising, aldosterone-promoting, sodium-water-water-retention, and sympathetic nerve-stimulating effects of angiotensin II (Ang II), producing pharmacological effects similar to angiotensin-converting enzyme inhibitors (ACEIs). On the other hand, due to the feedback increase in Ang II synthesis, Ang II levels in the blood and tissues rise, acting on AT2 to produce vasodilatory, anti-cell proliferation, and apoptosis-regulating effects.

[0067] In this disclosure, unless otherwise specified, the term "leukemia inhibitory factor (LIF)" belongs to the IL-6 family and is a pleiotropic cytokine named for its ability to inhibit the proliferation of mouse myeloid M1 leukemia cells and induce their terminal differentiation. LIF is widely involved in organ, neural development and regeneration, and immune regulation, and also plays an important role in tumor development. Contrary to its inhibitory effect on leukemia cell growth, LIF typically promotes the development of various types of solid tumors. High expression of LIF can promote tumor development, metastasis, drug resistance, and tumor immune escape, and is associated with poor patient prognosis.

[0068] In this disclosure, unless otherwise specified, the term "uLCR (urine LIF-to-creatinine ratio)" refers to the ratio of urinary leukemia inhibitory factor to creatinine, used to standardize the concentration of leukemia inhibitory factor (LIF) in urine and eliminate the influence of factors such as urine volume on the test results.

[0069] In this disclosure, unless otherwise specified, the term "repressor element 1-silencing transcription factor (REST)" refers to an important protein transcriptional negative regulator that regulates the transcription of target genes by binding to repressor element 1 on the target gene through its zinc finger structure. REST is also known as neuronal restriction silencing factor (NRSF) and plays a role in the orderly acquisition and maintenance of neuronal properties by relieving the repression of neuron-specific genes.

[0070] In this disclosure, unless otherwise specified, the term "Cox Proportional Hazards Model" refers to a semi-parametric regression model used in survival analysis, primarily to assess the impact of multiple factors on survival time. Proposed by statistician D.R. Cox in 1972, it is widely used in medical research and survival analysis. The core of this model lies in analyzing multiple covariates (independent variables) affecting survival time, and it allows for the presence of censored data.

[0071] In this disclosure, unless otherwise specified, the term "Spearman correlation analysis" or "Spearman correlation coefficient" is a nonparametric statistical method used to measure the strength of a monotonic relationship between two variables. It calculates the correlation by comparing the ranks (or rankings) of the variables and is suitable for nonlinear relationships or non-normally distributed data.

[0072] In this disclosure, unless otherwise specified, the term "Kaplan-Meier curve" is a commonly used survival analysis method used to visually demonstrate differences in survival time among different groups.

[0073] In this disclosure, unless otherwise specified, the term "dual-luciferase reporter gene assay" is a commonly used molecular biology technique primarily used to detect gene expression. Its basic principle is to simultaneously express firefly luciferase and Renilla luciferase in cells, and to assess the expression level of the target gene by measuring the activities of the two luciferases.

[0074] The following description is based on specific embodiments.

[0075] I. Research Methods 1.1 Enrollment of IgAN patients A total of 1219 patients with IgA nephropathy (IgAN) were included. The mean age at renal biopsy was 36.2 ± 12.2 years, the eGFR was 78.3 (52.3, 103.4) mL / min / 1.73 m², and the median 24-hour urinary protein excretion (UPE) was 1.37 (0.68, 2.58) g / 24h. Patient characteristics are detailed in Table 1. During a median follow-up of 3.24 years, 164 patients progressed to end-stage renal disease (ESRD). PM levels before and after enrollment were also included. 2.5 The mean exposure levels were 53.7 ± 18.5 μg / m³ and 52.5 ± 15.9 μg / m³, respectively.

[0076] Table 1. Clinical characteristics of IgA nephropathy (IgAN) patients in this study eGFR: estimated glomerular filtration rate; UPE: urinary protein excretion; SBP: systolic blood pressure; DBP: diastolic blood pressure; ACEI: angiotensin-converting enzyme inhibitors; ARB: angiotensin receptor blockers; ESRD: end-stage renal disease. *Oxford classification data were available for 1050 patients with IgA nephropathy (IgAN), of whom C-score data were available for 1045 patients.

[0077] 1.2 PM 2.5 Major impacts on IgAN progress After adjusting for factors such as age, sex, baseline eGFR, proteinuria, albumin, hemoglobin, mean arterial pressure (MAP), short-term use of steroids or immunosuppressants after renal biopsy, and use of ACE inhibitors or ARBs, the cumulative risk function method was used to analyze the main impact of PM2.5 on the progression of IgAN.

[0078] 1.3 Gene-environment interaction between PM2.5 and SNPs To systematically evaluate gene-environment interactions, we first screened 31 candidate SNPs previously thought to be associated with susceptibility to IgAN and chronic kidney disease (CKD) to analyze their association with disease progression and their potential interaction with PM2.5 exposure.

[0079] Based on the selected candidate SNP-rs2412971, and after adjusting for PM2.5 exposure category, age, sex, baseline eGFR, proteinuria, albumin, hemoglobin, mean arterial pressure (MAP), use of steroids or immunosuppressants, and use of ACE inhibitors or ARBs, the cumulative risk function method was used to determine the gene-environment interaction between PM2.5 and candidate SNP-rs2412971.

[0080] 1.4 Effects of rs2412971 on LIF gene regulation and its influence on renal expression and urinary levels A allele frequency differences were investigated across global regions, and preliminary clinical data revealed the rs2412971 locus and PM. 2.5 Exposure interactions suggest that the rs2412971 site itself may be a biologically functional regulatory site. Different alleles (A or G) of this SNP may affect the expression of a certain protein. Through literature and database analysis, chromosome 22 signals may be related to the biological function of the LIF gene.

[0081] First, primers were designed and synthesized, with sequence numbers as shown in SEQ ID NO: 1-4, to amplify the target fragment. Then, the fragment was ligated into the enzyme-digested vector. The ligation product was transformed into prepared bacterial competent cells, and the resulting single-clone colonies were sent to a sequencing company for sequencing. The clones that matched correctly were considered successfully constructed vectors. The rs2412971G vector, rs2412971A vector, rs2412971G-H-LIFPromoter vector, and rs2412971A-H-LIFPromoter vector were constructed respectively.

[0082] Table 2. Primer gene sequences Note: The addition of XhoI or NheI to the end of a nucleotide sequence is an artificial modification of the restriction enzyme site used in molecular cloning to achieve directed cloning, vector construction, and fragment splicing. The underlined part indicates the recognition sequence of NheI or XhoI.

[0083] The constructed reporter gene plasmid was transfected into target cells, and a dual-luciferase reporter assay was performed to evaluate the relationship between the rs2412971A or G site and LIF promoter activity.

[0084] 1.5 Association between rs2412971, PM2.5 exposure and LIF expression in renal biopsy tissue Thirty IgAN patients were selected from 1219 patients based on genotype and PM2.5 levels. Immunofluorescence staining of LIF was performed on renal biopsy specimens from these 30 IgAN patients to analyze the association between rs2412971, PM2.5 exposure, and LIF expression in renal biopsy tissues. The 30 IgAN patients were classified as follows: PM2.5 exposure is categorized into high exposure and low exposure, based on the annual average PM2.5 concentration before enrollment: high exposure ≥ 53.6 μg / m³, low exposure < 53.6 μg / m³.

[0085] According to genotype, they are classified as AA genotype carriers, AG genotype carriers, and GG genotype carriers.

[0086] Based on the location, LIFs are also divided into glomerular LIFs and tubular LIFs.

[0087] 1.6 Association between rs2412971, PM2.5 exposure and urinary LIF levels As a secreted protein, changes in LIF expression in kidney tissue may affect urinary LIF concentration. The urinary LIF concentration ratio (uLCR) reflects renal LIF expression. This study analyzed the association between rs2412971, PM2.5 exposure, and urinary LIF levels in 30 IgAN patients.

[0088] 1.7 Correlation between renal LIF expression and pathological features We analyzed renal LIF expression using RNA-seq data from 30 IgAN patients and assessed its correlation with pathological parameters. Clinical data are detailed in Table 3.

[0089] Table 3. Association between LIF mRNA expression level and Oxford MEST-C pathological scores in 30 IgAN patients II. Research Results 2.1 PM2.5 is a driver of adverse outcomes in IgAN patients. like Figure 2 As shown in Figure A, the risk of disease progression was significantly higher in patients with high PM2.5 exposure than in those with low PM2.5 exposure (hazard ratio [HR] 1.79; 95% confidence interval [CI] 1.27–2.53; P = 0.001). This result indicates that PM2.5 exposure is a risk factor for predicting the progression of IgAN, suggesting that environmental pollution can independently lead to adverse outcomes in IgAN.

[0090] 2.2 Gene-environment interaction between PM2.5 and SNPs The gene-environment interaction between PM2.5 and SNPs is shown in Table 4-7 below.

[0091] Table 4. Based on the genotype model, the Cox proportional hazards model was used to analyze the association between single nucleotide polymorphisms (SNPs) and end-stage renal disease (ESRD), and the results were adjusted for clinical characteristics and fine particulate matter (PM2.5) exposure. HR: hazard ratio; CI: confidence interval. HR represents the risk ratio associated with each single nucleotide polymorphism (SNP) and end-stage renal disease (ESRD). All models were adjusted for age, sex, estimated glomerular filtration rate (eGFR), 24-hour urinary protein excretion (24-hour UPE), hemoglobin, albumin, mean arterial pressure (MAP), and fine particulate matter (PM2.5) exposure levels (high exposure group vs. low exposure group).

[0092] *After Bonferroni correction, the p-value of the hazard ratio (HR) was statistically significant (P<0.00161).

[0093] None of the subjects carrying the rs80282103TT genotype progressed to end-stage renal disease (ESRD).

[0094] Table 5. Single nucleotide polymorphism (SNP) × fine particulate matter (PM2.5) in the Cox proportional hazards model P-value of the interaction between exposure groups (high exposure group vs. low exposure group) AD: Dominant model; AR: Recessive model.

[0095] The interaction p-value refers to the p-value associated with a single nucleotide polymorphism (SNP) and time-varying fine particulate matter (PM2.5) exposure.

[0096] Table 6. Fine particulate matter (PM2.5) exposure and rs2412971 genotype and IgA nephropathy (IgAN) Association with the risk of progression of renal function in patients HR: Hazard ratio; CI: Confidence interval The Cox proportional hazards model corrects for age, sex, baseline estimated glomerular filtration rate (eGFR), proteinuria, albumin, hemoglobin, mean arterial pressure (MAP), short-term use of glucocorticoids or immunosuppressants after renal biopsy, and use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs).

[0097] Table 7. Association between fine particulate matter (PM2.5) exposure and rs2412971 genotype and the risk of progression of IgA nephropathy (IgAN) in a fully adjusted model incorporating the Oxford MEST-C score. HR: Hazard ratio; CI: Confidence interval The Cox proportional hazards model corrected for age, sex, baseline estimated glomerular filtration rate (eGFR), proteinuria, albumin, hemoglobin, mean arterial pressure (MAP), short-term use of glucocorticoids or immunosuppressants after renal biopsy, use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), and OXFORDMEST-C pathology score.

[0098] The results showed that only rs2412971 (the latent model) was significantly associated with an increased risk of IgAN progression (Table 3), and a statistically significant interaction was observed between rs2412971 and PM2.5 exposure (interaction P-value = 0.026, Table 4). Therefore, rs2412971 was selected as the only SNP showing a significant interaction for subsequent analysis.

[0099] After adjusting for PM2.5 exposure category, age, sex, baseline eGFR, proteinuria, albumin, hemoglobin, mean arterial pressure (MAP), use of steroids or immunosuppressants, and use of ACE inhibitors or ARBs, we analyzed the relationship between PM2.5 exposure and the risk of IgAN progression in patients with different genotypes.

[0100] The results showed that in individuals with the AG or GG genotype (N=1,137), high PM2.5 exposure still significantly increased health risk, with a hazard ratio (HR) of 1.68 (95% CI: 1.17–2.42), P=0.0054. In individuals with the AA genotype (N=82), the health risk from high PM2.5 exposure increased dramatically, with an HR as high as 10.59 (95% CI: 1.78–62.99), P=0.0095. This indicates that individuals with the AA genotype are extremely sensitive to the harmful effects of PM2.5 exposure compared to those with the AG / GG genotype, with a 10.59-fold increased risk. Figure 2 A).

[0101] Furthermore, compared with patients with low PM2.5 exposure and the AG / GG genotype, patients with high PM2.5 exposure and the AA genotype had a 6.75-fold increased risk of kidney disease progression (95% CI: 3.50–13.02, P=1.2E-08, Table 4). Figure 2 B). In the fully adjusted model including pathological scores, the results of the PM2.5 and rs2412971 interaction grouping were consistent with those described above (Table 6). The results suggest that PM2.5 exposure may significantly increase the risk of disease progression in IgAN patients carrying the rs2412971AA genotype, suggesting a potential gene-environment interaction.

[0102] 2.3 Gene regulation of LIF by rs2412971 and its effects on renal expression and urinary levels The results of dual-luciferase reporter gene assays determined the regulatory role of rs2412971. The results showed that the rs2412971_A allele significantly enhanced the pGL3 promoter (P<0.001). Figure 3 C) and the activity of the LIF promoter construct (P<0.001, Figure 3 D). These results indicate that rs2412971 can upregulate LIF expression in a genotype-dependent manner by enhancing promoter activity.

[0103] According to the Regulome DB database, rs2412971 may affect LIF expression by regulating the activity of the transcription factor REST (a RE1 repressor element silencing transcription factor). Figure 3 A and Figure 3 B).

[0104] 2.4 Association between rs2412971 and PM2.5 exposure and LIF expression in renal biopsy tissue like Figure 4 As shown in Figure A, the results of LIF immunofluorescence staining of renal biopsy specimens from 30 IgAN patients showed: (1) Glomerular LIF expression: 4 patients (13.3%) showed no expression, 14 patients (46.7%) showed mild expression (1+), 9 patients (30.0%) showed moderate expression (2+), and 3 patients (10.0%) showed strong expression (3+).

[0105] (2) LIF expression in renal tubules: 5 patients (16.7%) showed no expression, 9 patients (30.0%) showed mild expression, 9 patients (30.0%) showed moderate expression, and 7 patients (23.3%) showed strong expression.

[0106] Analysis showed that glomerular LIF expression was significantly correlated with tubulointerstitial LIF expression (Spearman correlation coefficient rho=0.78, P<0.001).

[0107] Furthermore, compared with patients with low PM2.5 exposure, patients with high PM2.5 exposure showed stronger LIF expression in the glomeruli and renal tubules. Figure 4 B and 4C). Similarly, AA genotype carriers showed significantly higher LIF expression in the glomeruli and tubules than AG / GG carriers, suggesting a potential association between PM2.5 exposure, genetic background, and upregulation of renal LIF. Figure 4 (D and 4E).

[0108] 2.5 Association between rs2412971, PM2.5 exposure and urinary LIF levels As a secreted protein, changes in LIF expression in kidney tissue may affect urinary LIF concentration. When grouped by PM2.5 exposure level, patients exposed to high PM2.5 levels had a significantly higher urinary LIF concentration ratio (uLCR) than those exposed to low PM2.5 levels (median 0.32 µg / g Cr vs. 0.25 µg / g Cr, P=0.006, n=163, see...). Figure 4 E).

[0109] Furthermore, urinary LIF levels were positively correlated with the number of rs2412971A alleles (r=0.162, P=0.039). In pairwise comparisons, urinary LIF levels were significantly higher in carriers of the AG genotype than in carriers of the GG genotype (P=0.041). Figure 4F). However, no significant differences were observed between AG and AA carriers (P=0.93) and between GG and AA carriers (P=0.24), which may be due to the limited number of AA carriers (n=11).

[0110] In the linear regression model, when analyzing the relationship between rs2412971, PM2.5 exposure, and uLCR, both the rs2412971 risk allele (A) and PM2.5 exposure were independently associated with elevated uLCR (rs2412971, β=0.12, P=0.028; high PM2.5 exposure, β=0.21, P=0.004). The results of the urinary LIF study were consistent with the renal biopsy data, indicating that urinary LIF levels may partially reflect renal LIF expression and reveal the combined effects of genetic background and environmental exposure on kidney damage.

[0111] 2.6 Association between urinary LIF and IgAN progression The urinary LIF concentration ratio (uLCR) was significantly positively correlated with proteinuria (r=0.40, P<0.001) and microalbuminuria (r=0.62, P<0.001), and significantly negatively correlated with eGFR levels (r=-0.29, P<0.001). However, no significant correlation was observed between uLCR and serum IgA (r=-0.08, P=0.359, n=140) or Gd-IgA1 (Pearson's r=-0.10, P=0.295, n=105).

[0112] Patients with higher uLCR (≥0.25µg / gCr) and Gd-IgA1 (≥26.04U / mL) had more severe proteinuria [1.35 (0.79–2.35) g / d], compared to [0.96 (0.60–1.75) g / d; P=0.041] in patients with lower uLCR.

[0113] During a median follow-up of 33 months, 22 patients (10.8%) experienced a 30% decrease in eGFR. The risk of progression was 2.88 times higher in patients with high uLCR compared to those with low uLCR (95% CI: 1.17–7.12, P=0.022, log-rank P=0.017, see [link to relevant documentation]). Figure 5 A). uLCR was significantly associated with renal function progression (hazard ratio [HR] 8.51, 95% CI: 2.69–26.93, P = 2.70E-04). This association remained robust after adjusting for clinical variables, CLIN-PATHXie score, and the international Predict-Risk tool (see [link to relevant documentation]). Figure 5 B).

[0114] 2.7 Correlation between renal LIF expression and pathological features We analyzed renal LIF expression using RNA-seq data from 30 IgAN patients, and the results are as follows: (1) Spearman correlation analysis showed that LIF expression was significantly correlated with the following pathological features: (1) Renal tubulointerstitial injury (rho=0.45, p=0.013) (2) Interstitial inflammatory cell infiltration (rho=0.39, p=0.032) LIF expression was significantly higher in patients with T1 / 2 lesions than in patients with T0 lesions (p=0.0161). Figure 6 A). Furthermore, LIF expression was significantly higher in tissues with moderate to severe inflammatory cell infiltration compared to tissues with no or minimal inflammatory cell infiltration (p=0.046). Figure 6 B).

[0115] (2) The urine LIF concentration ratio (uLCR) level is associated with the following pathological features: (1) T score (r=0.17, p=0.017) (2) Inflammatory cell infiltration (r=0.20, p=0.004) Patients with T=1 or 2 lesions had significantly higher uLCR levels than patients with T=0 lesions (p=0.016). Figure 6 C). Similarly, patients with moderate to severe inflammatory cell infiltration had significantly higher uLCR levels than those with mild inflammatory cell infiltration (p=0.001). Figure 6 D).

[0116] 2.8 PM 2.5 Exposure to and rs2412971 can improve the predictive ability of clinical indicators for IgAN progression. We progressively added environmental exposure factors (PM2.5 exposure level) and genetic factors (rs2412971 genotype) to the basic model containing only clinical parameters to assess their impact on the model's discriminative performance. The discriminative performance indices for each model are shown in Table 8.

[0117] Table 8. Discrimination Indicators for Each Model Model 1 includes age, sex, estimated glomerular filtration rate (eGFR), 24-hour urinary protein, serum albumin, hemoglobin, mean arterial pressure, history of short-term hormone use after renal biopsy, and ACEI / ARB treatment.

[0118] The highest discrimination was achieved when both models were included (Model 4) (C=0.8686, D=0.7372). Compared to Model 1 (the base model), Model 4 showed an average improvement of 0.0097% in discrimination for predicting ESRD risk (IDI=9.71×10⁻⁶).-5 95% CI [6.31×10] -5 –1.31×10 -4 [P<0.001], which is statistically significant, suggesting that combining environmental and genetic factors can further improve the discriminative ability of the end-stage renal disease risk prediction model.

[0119] Conclusion: These research results indicate that PM 2.5 Exposure and rs2412971 interact, potentially upregulating renal LIF expression and mediating IgAN progression through tubulointerstitial injury and inflammation. PM... 2.5 Incorporating exposure and rs2412971 into the clinical parameter model can improve the predictive value for IgAN progression.

[0120] The above specific embodiments are merely illustrative of the invention and do not represent a limitation thereof. Those skilled in the art will recognize that other variations of the specific structure of this invention are possible.

Claims

1. An application of SNP, environmental factors, and biomarker interactions in IgA nephropathy, characterized in that, The application is at least one of the following: 1) Use in the preparation of products for indicating or evaluating the benefit of treatment for IgA nephropathy; 2) Application in the preparation of products for the diagnosis or auxiliary diagnosis of progression of IgA nephropathy; 3) Application in the preparation of products for predicting the risk of renal failure after treatment of IgA nephropathy; 4) Application in the preparation of products for prognostic assessment after treatment of IgA nephropathy; The environmental factors interact with the SNP to regulate the expression of the biomarker, thereby affecting the progression of IgA nephropathy.

2. The application according to claim 1, characterized in that, The therapeutic benefit is manifested in at least one of the following: 1) Reduce proteinuria, where proteinuria is the ratio of urinary protein to creatinine (UPCR). 2) Reduces the risk of progression of IgA nephropathy; 3) Reduces the risk of kidney failure; 4) Improve kidney survival rate.

3. The application according to claim 1 or 2, characterized in that, The risk allele of the SNP affects the expression level of the biomarker. Further, the SNP is rs2412971, and even further, the risk allele is A, i.e., the rs2412971AA genotype. The environmental factor is PM. 2.5 Exposure; The biomarker is LIF, which is selected from one or more of renal LIF and urinary LIF. Further, the renal LIF is selected from one or more of glomerular LIF and renal tubular LIF. Even further, the urinary LIF is uLCR, which is the ratio of urinary leukemia inhibitory factor to creatinine.

4. The application according to claim 3, characterized in that, The rs2412971AA genotype upregulates the expression level of LIF by enhancing promoter activity.

5. The application according to claim 3 or 4, characterized in that, The PM 2.5 Exposure will have at least one of the following effects: 1) Upregulation of its concentration can lead to an increase in LIF expression levels in IgAN patients; 2) Upregulation of its concentration significantly increases the risk of disease progression in IgAN patients carrying the rs2412971AA genotype; 3) Downregulation of its concentration will affect the decrease in LIF expression levels in IgAN patients; 4) Downregulation of its concentration reduces the risk of disease progression in IgAN patients carrying the rs2412971AA genotype.

6. The application according to claim 3 or 4, characterized in that, The rs2412971 will perform at least one of the following functions: 1) LIF expression was significantly higher in carriers of the AA genotype than in carriers of the AG / GG genotype; 2) The risk of IgAN progression is higher in carriers of the AA genotype than in carriers of the AG / GG genotype; 3) Carriers of the rs2412971AA genotype exposed to high levels of PM2.5 have a higher risk of IgAN progression than carriers of the same genotype who are consistently exposed to low levels of PM2.

5.

7. The application according to claim 3 or 4, characterized in that, The LIF will serve at least one of the following functions: 1) Its expression level can reflect PM 2.5 Furthermore, regarding the concentration level of exposure, patients exposed to high levels of PM2.5 had significantly higher LIF expression levels than those exposed to low levels of PM2.

5. 2) Upregulation of its expression can increase the risk of disease progression in IgAN patients carrying the rs2412971AA genotype; 3) Downregulation of its expression reduces the risk of disease progression in IgAN patients carrying the rs2412971AA genotype.

8. The application according to any one of claims 1-7, characterized in that, The products include one or more of the following: reagents, reagent kits, chips, test strips, membrane strips, and detection platforms.

9. The application according to claim 8, characterized in that, The product testing indicators obtained from patients include one of the following: 1) The genotype of the SNP and the concentration level of the environmental factor; 2) The genotype of the SNP and the expression level of the biomarker; 3) The concentration levels of the environmental factors and the expression levels of the biomarkers; 4) The expression level of the biomarkers.

10. A method for predicting the risk of progression of IgA nephropathy, the method comprising detecting a sample of the indicator of claim 9 obtained from a patient, the method comprising: 1) Bring the sample into contact with a reagent or instrument capable of detecting the sample; 2) Obtain the detection results of the sample; 3) Predict the risk of progression of IgA nephropathy in patients based on the test results of the samples described in the test results.

11. A system based on the method for predicting the risk of progression of IgA nephropathy according to claim 10, characterized in that, include: A detection module is used to detect the content of indicators in the sample; The analysis module is used to compare the index content of the sample obtained by the detection module with preset values. When the index content of the sample is higher than the preset value, the analysis determines it to be high-risk. The output module is used to output the above analysis results.

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