Inhibition of HSD17b13 in the treatment of liver disease in patients expressing the pnpla3 i148m variation

Abstract

The disclosure provides methods of identifying a human subject as a candidate for treating or inhibiting a liver disease by inhibiting HSD17B13. The disclosure also provides methods of treating a subject who is PNPLA3 Ile148Met+ by administering an inhibitor of HSD17B13. The disclosure also provides method of detecting a PNPLA3 Ile148Met variant and functional HSD17B13 in a subject. The disclosure also provides method of identifying a subject having a protective effect against liver disease. The disclosure also provides inhibitors of HSD17B13 for use in the treatment of a liver disease.

Description

[0001] Inhibition Of HSD17B13 In The Treatment Of Liver Disease In Patients

[0002] Expressing The PNPLA3 I148M Variation

[0003] Reference To A Sequence Listing

[0004] This application includes a Sequence Listing submitted electronical ly as a text file named 18923801002SEQ, created on October 10, 2018, with a size of 238 kilobytes. The Sequence Listing is incorporated by reference herein.

[0005] Field

[0006] The disclosu re relates generally to the field of precision medicine. More particularly, the disclosu re relates to methods of identifying subjects who are patatin like phospholipase domain containing 3 (PNPLA3) llel48Met positive and have a liver disease or susceptibility to liver disease, and treating such subjects with an inhibitor of hyd roxy steroid 17-beta

[0007] dehyd rogenase 13 (HSD17B13).

[0008] Background

[0009] Various references, including patents, patent applications, accession nu mbers, technical articles, and scholarly articles are cited throughout the specification. Each reference is incorporated by reference herein, in its entirety and for all pu rposes.

[0010] Chronic liver disease and cirrhosis are leading causes of morbidity and mortality in the

[0011] United States, accounting for 38,170 deaths (1.5% of total deaths) in 2014 (Kochanek et al., Nat'l. Vital Stat. Rep., 2016, 65, 1-122). The most common etiologies of cirrhosis in the U.S. are alcoholic liver disease, ch ronic hepatitis C, and nonalcoholic fatty liver disease (NAFLD), together accounting for about 80% of patients awaiting liver transplant between 2004 and 2013 (Wong et al., Gastroenterology, 2015, 148, 547-555). The estimated prevalence of NAFLD in the U.S. is between 19 and 46 percent (Browning et al., Hepatology, 2004, 40, 1387-1395; Lazo et al., Am. J. Epidemiol., 2013, 178, 38-45; and Williams et al., Gastroenterology, 2011, 140, 124- 131) and is rising over time (Younossi et al., Clin. Gastroenterol. Hepatol., 2011, 9, 524-530), likely in conjunction with increased rates of obesity, its primary risk factor (Cohen et al., Science, 2011, 332, 1519-1523). While significant advances have been made in the treatment of hepatitis C, there are cu rrently no evidence-based treatments for alcoholic or nonalcoholic liver disease and cirrhosis. Previous genome wide association studies (GWAS) have identified sequence variations associated with increased risk of chronic liver disease. The most robustly validated association is with a common missense va riant in patatin-like phospholipase domain-containing 3, encoded by the gene PNPLA3. This variant (rs738409, p.llel48Met) was initially found to be associated with an increase in hepatic triglyceride levels (Romeo et al., Nat. Genet., 2008, 40, 1461-5), and su bsequently associated with nonalcoholic steatohepatitis (NASH) (Rotman et al., Hepatology, 2010, 52, 894-903; Sookoian et al., J. Lipid Res., 2009, 50, 2111-2116) and cirrhosis (Shen et al., J. Lipid Res., 2015, 56, 167-175). A missense variant in TM6SF2, encoding transmembrane 6 su perfamily member 2, also confers increased risk of nonalcoholic fatty liver disease (NAFLD)( Kozlitina et al., Nat. Genet, 2014, 46, 352-6; Liu et al., Nat. Commun., 2014, 5, 4309; and

[0012] Sookoian et al., Hepatology, 2015, 61, 515-25). Exactly how the variants in PNPLA3 and TM6SF2 contribute to liver disease has yet to be fully elucidated (Smagris et al., J. Biol. Chem., 2016, 291, 10659-76; Mahdessian et al., Proc. Natl. Acad. Sci. USA, 2014, 111, 8913-8; Huang et al., J. Biol. Chem., 2011, 286, 37085-93; and Pirazzi et al., J. Hepatol., 2012, 57, 1276-82). To date, no genetic variants that protect from chronic liver disease have been identified.

[0013] Summary

[0014] The present disclosu re provides methods for identifying a hu man subject as a candidate for treating or inhibiting a liver disease, the method comprising: determining whether or not a sample from the subject comprises: i) a first nucleic acid encoding a patatin like phospholipase domain containing 3 (PNPLA3) protein comprising an I148M variation and a second nucleic acid encoding a functional HSD17B13 protein; and / or ii) a PN PLA3 protein comprising an I148M variation and a functional HSD17B13 protein; and identifying the subject as a candidate for treating or inhibiting a liver disease by inhibiting HSD17B13 when both the first and second nucleic acids as defined in i) and / or both of the proteins as defined in ii) are detected.

[0015] In some embodiments, the first nucleic acid molecu le comprises genomic DNA, mRNA, or a cDNA obtained from mRNA.

[0016] In some embodiments, the genomic DNA comprises an ATG codon at the positions corresponding to positions 5107 to 5109 according to SEQ ID NO:31; the mRNA comprises an AUG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:34; the mRNA comprises an AUG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:35; the cDNA comprises an ATG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:38; or the cDNA comprises an ATG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:39.

[0017] In some embodiments, the genomic DNA comprises the nucleotide sequence according to SEQ ID NO:31, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:31 and encoding a PNPLA3 protein which comprises the I148M variation; the mRNA comprises the nucleotide sequence according to SEQ ID NO:34, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:34 and encoding a PNPLA3 protein which comprises the I148M variation; the mRNA comprises the nucleotide sequence according to SEQ I D NO:35, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:35 and encoding a PNPLA3 protein which comprises the I148M variation; the cDNA comprises the nucleotide sequence according to SEQ ID NO:38, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:38 and encoding a PNPLA3 protein which comprises the I148M variation; or the cDNA comprises the nucleotide sequence according to SEQ I D NO:39, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:39 and encoding a PNPLA3 protein which comprises the I148M variation.

[0018] In some embodiments, detecting the first nucleic acid comprises: sequencing at least a portion of the first nucleic acid, wherein the portion comprises the codon which encodes the I 148M variation; or hybridizing the first nucleic acid with a probe or primer that specifical ly hybridizes to a portion of the first nucleic acid, wherein the portion comprises the codon encoding the I148M variation.

[0019] In some embodiments, the probe or primer is an al lele-specific probe or primer, and wherein the probe or primer optionally comprises a label.

[0020] In some embodiments, the methods further comprise determining whether the su bject is homozygous or heterozygous for the I148M variation.

[0021] In some embodiments, the second nucleic acid comprises genomic DNA, mRNA, or a cDNA obtained from mRNA.

[0022] In some embodiments, the genomic DNA comprises an adenine at the position corresponding to position 12,667 according to SEQ ID NO:l; the genomic DNA comprises the nucleotide sequence according to SEQ ID NO:l, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:l and encoding a functional HSD17B13 protein; the mRNA comprises the nucleotide sequence according to SEQ ID NO:3, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:3 and encoding a functional HSD17B13 protein; the mRNA comprises the nucleotide sequence according to SEQ ID NO:4 or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:4 and encoding a functional HSD17B13 protein; the mRNA comprises the nucleotide sequence according to SEQ ID NO:7 or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:7 and encoding a fu nctional HSD17B13 protein; the mRNA comprises the nucleotide sequence according to SEQ I D NO:ll or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:ll and encoding a fu nctional HSD17B13 protein; the cDNA comprises the nucleotide sequence according to SEQ ID NO:12 or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:12 and encoding a functional HSD17B13 protein; the cDNA comprises the nucleotide sequence according to SEQ ID NO: 13 or a nucleotide sequence having at least 90% sequence identity to SEQ I D NO:13 and encoding a functional HSD17B13 protein; the cDNA comprises the nucleotide sequence according to SEQ ID NO:16 or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:16 and encoding a functional HSD17B13 protein; or the cDNA comprises the nucleotide sequence according to SEQ ID NO:20 or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:20 and encoding a functional HSD17B13 protein.

[0023] In some embodiments, detecting the second nucleic acid comprises: sequencing the second nucleic acid; or hybridizing the second nucleic acid with a probe or primer that specifically hybridizes to a portion of the second nucleic acid, wherein the portion comprises the adenine at the position corresponding to position 12,667 according to SEQ ID NO:l.

[0024] In some embodiments, the probe or primer is an al lele-specific probe or primer, and wherein the probe or primer optionally comprises a label.

[0025] In some embodiments, the methods further comprise determining whether the su bject is homozygous or heterozygous for the second nucleic acid encoding a functional HSD17B13 protein in the sample.

[0026] In some embodiments, the methods further comprise ad ministering an inhibitor of HSD17B13 to the subject.

[0027] In some embodiments, the liver disease is an alcoholic liver disease. In some embodiments, the alcoholic liver disease comprises one or more of cirrhosis, steatosis, or hepatocellular carcinoma resulting from alcohol consumption.

[0028] In some embodiments, the liver disease is a non-alcoholic liver disease. In some embodiments, the non-alcoholic liver disease comprises nonalcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). In some embodiments, the non-alcoholic liver disease comprises one or more of cirrhosis, steatosis, or hepatocellular carcinoma not caused by alcohol consumption. Brief Description Of The Figures

[0029] The accompanying figu res, which are incorporated in and constitute a part of this specification, illustrate several aspects and together with the description serve to explain the principles of the present disclosure.

[0030] Figu re 1 shows baseline characteristics of sequenced Eu ropean-ancestry individuals from the discovery and replication cohorts.

[0031] Figu re 2 shows single nucleotide variants associated with serum transaminase levels at P < l.OxlO"7in the discovery cohort.

[0032] Figu re 3 shows replication and joint meta-analysis of 35 exome-wide significant single nucleotide variants from the discovery cohort in three separate European -ancestry cohorts.

[0033] Figu re 4 shows association of thirteen exome-wide significant and replicating single nucleotide variants with liver disease phenotypes in the discovery cohort.

[0034] Figu re 5 shows baseline characteristics of genotyped multi-eth nic cases and controls from the Dallas Liver and Pediatric Liver Studies.

[0035] Figu re 6 (panels A and B) shows regional association plots for alanine aminotransferase (ALT; A) and aspartate aminotransferase (AST; B) levels in the GHS discovery cohort in the region around HSD17B13.

[0036] Figu re 7 shows the expression of PNPLA3 in homozygous reference (T / T), heterozygous (T / TA), and homozygous alternate (TA / TA) carriers of the HSD17B13 rs72613567 splice variant.

[0037] Figu re 8 shows the expression difference of the 63 PNPLA3 rs738409 carriers (C / C and C / G) in the th ree HSD17B13 rs72613567 genotypes (T / T, T / TA, TA / TA).

[0038] Figu re 9 shows an analysis of the genetic interaction between PN PLA3 rs738409 (P.I148M) and HSD17B13 rs72613567.

[0039] Figu re 10 (panels A and B) shows HSD17B13 rs72613567:TA mitigates the risk of liver inju ry associated with PN PLA3 p. H48M.

[0040] Figu re 11 (panels A through F) shows raw and residualized ALT levels by PNPLA3 rs738409 (p.H48M) and HSD17B13 rs72613567 genotype. Figu re 12 (panels A through F) shows raw and residualized AST levels by PNPLA3 rs738409 (p.H48M) and HSD17B13 rs72613567 genotype.

[0041] Figu re 13 (panels A through F) show mRNA expression of fou r additional novel HSD17B13 transcripts (E-H) in homozygous reference (T / T), heterozygous (T / TA), and homozygous alternate (TA / TA) carriers of the HSD17B13 splice variant.

[0042] Figu re 14 (panels A and B) shows Manhattan plots (left) and quantile-quantile plots (right) of single nucleotide variant associations with seru m transaminase levels in the GHS discovery cohort.

[0043] Figu re 15 (panels A and B) shows HSD17B13 rs72613567:TA is associated with reduced risk of alcoholic and nonalcoholic liver disease phenotypes.

[0044] Figu re 16 (panels A and B) shows HSD17B13 rs72613567:TA mitigates the risk of liver inju ry associated with PN PLA3 p. H48M.

[0045] Figu re 17 (panels A and B) shows HSD17B13 rs72613567:TA is associated with reduced risk of progression from simple steatosis to steatohepatitis and fibrosis.

[0046] Figu re 18 (panels A through G) shows Expression, subcellular localization, and enzymatic activity of a novel HSD17B13 transcript.

[0047] Figu re 19 (panels A and B) shows HSD17B13 rs72613567:TA mitigates the risk of alcoholic and nonalcoholic liver disease associated with PNPLA3 I148M. The numbers over each bar represent controls / cases.

[0048] Additional advantages of the disclosure will be set forth in part in the description which follows, and in part wil l be apparent from the description, or can be learned by practice of the embodiments disclosed herein. The advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the fol lowing detailed description are exemplary and explanatory only and are not restrictive of the embodiments, as claimed.

[0049] Description

[0050] Various terms relating to aspects of disclosure are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art, unless otherwise indicated. Other specifically defined terms are to be construed in a manner consistent with the definition provided herein. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order.

[0051] Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is in no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0052] As used herein, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise.

[0053] As used herein, the terms "subject" and "patient" are used interchangeably. A subject may include any animal, including mammals. Mammals include, without limitation, farm animals (e.g., horse, cow, pig), companion animals (e.g., dog, cat), laboratory animals (e.g., mouse, rat, rabbits), and non-human primates. In some embodiments, the subject is a human being.

[0054] As used herein, a "nucleic acid," a "nucleic acid molecule," a "nucleic acid sequence," "polynucleotide," or "oligonucleotide" can comprise a polymeric form of nucleotides of any length, may comprise DNA and / or RNA, and can be single-stranded, double-stranded, or multiple stranded. One strand of a nucleic acid also refers to its complement.

[0055] As used herein, the phrase "corresponding to" or grammatical variations thereof when used in the context of the numbering of a given amino acid or nucleic acid sequence or position refers to the numbering of a specified reference sequence when the given amino acid or nucleic acid sequence is compared to the reference sequence (e.g., with the reference sequence herein being the nucleic acid molecule or polypeptide of (functional or transcript behaving as a functional) HSD17B13, for example). In other words, the residue (e.g., amino acid or nucleotide) number or residue (e.g., amino acid or nucleotide) position of a given polymer is designated with respect to the reference sequence rather than by the actual numerical position of the residue within the given amino acid or nucleic acid sequence. For example, a given amino acid sequence can be aligned to a reference sequence by introducing gaps to optimize residue matches between the two sequences. In these cases, although the gaps are present, the numbering of the residue in the given amino acid or nucleic acid sequence is made with respect to the reference sequence to which it has been aligned. For example, the phrase "nucleic acid molecule encoding an HSD17B13 loss-of- fu nction variant protein which comprises a thymine at the position corresponding to position 12,667 according to SEQ ID NO:2" (and similar phrases) means that, if the nucleic acid sequence of the HSD17B13 genomic DNA being examined is aligned to the nucleotide sequence according to SEQ ID NO:2, the HSD17B13 genomic DNA being examined comprises a thymine at the position that corresponds to position 12,667 of SEQ ID NO:2.

[0056] A nucleic acid molecule encoding an HSD17B13 loss-of-function variant protein which comprises a thymine at the position corresponding to position 12,667 according to SEQ ID NO:2, for example, can easily be identified by performing a sequence align ment between the given HSD17B13 protein and the nucleic acid sequence of SEQ ID NO:2. Likewise, a PNPLA3 l lel48Met protein having a methionine at a position corresponding to position 148 according to SEQ ID NO:42, or at a position corresponding to position 144 according to SEQ ID NO:43 can easily be identified by performing a sequence alignment between the given PNPLA3 protein and the amino acid sequence of SEQ ID NO:42 or SEQ ID NO:43. A variety of computational algorith ms exist that can be used for performing a sequence align ment in order to identify particu lar nucleic acid molecules and proteins having particular nucleotides or amino acids at the particular position that corresponds to a position of a particular SEQ ID NOs. For example, programs for identifying percent sequence identity can be used to perform a sequence alignment. Percent identity (or percent complementarity) between particular stretches of nucleic acid sequences within nucleic acids or amino acid sequences within polypeptides can be determined using BLAST programs (basic local align ment search tools) and PowerBLAST programs (Altschul ef al., J. Mol. Biol., 1990, 215, 403-410; Zhang and Madden, Genome Res., 1997, 7, 649-656) or CLUSTALW software (Sievers et al., 2014, Methods Mol. Biol., 1079, 105- 116) or by using the Gap program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, University Research Park, Madison Wis.), using default settings, which uses the algorithm of Smith and Waterman (Adv. Appl. Math., 1981, 2, 482-489).

[0057] However, sequences can also be aligned manually. Herein, if reference is made to percent sequence identity, the higher percentages of sequence identity are preferred over the lower ones.

[0058] The present disclosu re provides methods of identifying a hu man subject as a candidate for treating or inhibiting a liver disease by in hibiting HSD17B13; methods of treating or inhibiting liver disease comprising administering an inhibitor of HSD17B13; methods of detecting PNPLA3 llel48Met (also referred to herein as "I148M") and functional HSD17B13 in a su bject; methods of identifying a su bject having a protective effect against liver disease; and inhibitors of HSD17B13 for use in the treatment of a liver disease.

[0059] The present disclosu re provides methods of classifying a human subject as a candidate for treating or inhibiting a liver disease by in hibiting HSD17B13; methods of treating or inhibiting liver disease comprising administering an inhibitor of HSD17B13; methods of detecting PNPLA3 llel48Met (also referred to herein as "I148M") and functional HSD17B13 in a su bject; methods of classifying a subject having a protective effect against liver disease; and inhibitors of HSD17B13 for use in the treatment of a liver disease.

[0060] It has been observed in accordance with the disclosure that a splice variant

[0061] (rs72613567:TA) in HSD17B13, which encodes 17-beta hyd roxy steroid dehyd rogenase 13, a hepatic lipid droplet protein, was reproducibly associated with reduced ALT (P=4.2xl0~12) and AST (P=6.2xl0~10) levels. It was also observed that this variant was associated with reduced risk of alcoholic and nonalcoholic liver disease (by 38%, 95% confidence interval (CI) 19%-52%; and by 16%, 95% CI 9%-22%, respectively, for each rs72613567:TA allele) and cirrhosis (by 44%, 95% CI 22-59%; and by 26%, 95% CI 12%-38% for alcoholic and nonalcoholic cirrhosis, respectively, for each rs72613567:TA allele) in an al lele dosage-dependent manner. The associations were confirmed in two independent cohorts. rs72613567:TA was associated with decreased severity of histological features of nonalcoholic steatohepatitis (NASH) (23% reduction, 95% CI 10%-34% in nonalcoholic steatohepatitis (NASH) for each rs72613567:TA allele among individuals with fatty liver disease), and mitigated liver injury associated with PNPLA3 p.H48M. rs72613567:TA results in a truncated isoform deficient in enzymatic activity against steroid substrates. Thus, a loss-of-function variant in HSD17B13 was associated with reduced risk of alcoholic and nonalcoholic liver disease, and progression from steatosis to NASH. U.S. Patent Application Publication No. US2018 / 0216084 (corresponding to PCT Publication No. WO 2018 / 136702) is incorporated herein by reference in its entirety.

[0062] The present disclosu re provides methods for identifying a hu man subject as a candidate for treating or inhibiting a liver disease by inhibiting hydroxysteroid 17-beta dehyd rogenase 13 (HSD17B13), the method comprising determining whether or not a sample from the subject comprises a first nucleic acid encoding a patatin like phospholipase domain containing 3 (PNPLA3) protein comprising an I148M variation and a second nucleic acid encoding a fu nctional HSD17B13 protein, and / or a PNPLA3 protein comprising an I148M variation and a functional HSD17B13 protein, and identifying the subject as a candidate for treating or inhibiting a liver disease by inhibiting HSD17B13 when both the first and second nucleic acids are detected and / or both of the proteins are detected.

[0063] The present disclosu re also provides methods of classifying a hu man subject as a candidate for treating or inhibiting a liver disease by inhibiting HSD17B13; methods of treating or inhibiting liver disease comprising administering an inhibitor of HSD17B13; methods of detecting PNPLA3 llel48Met (also referred to herein as "I148M") and functional HSD17B13 in a su bject; methods of classifying a subject having a protective effect against liver disease; and inhibitors of HSD17B13 for use in the treatment of a liver disease.

[0064] The present disclosu re also provides methods of treating or inhibiting liver disease, comprising administering an inhibitor of hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) to a hu man liver disease patient expressing a patatin like phospholipase domain containing 3 (PNPLA3) protein comprising an I148M variation such that liver disease is treated or inhibited in the patient.

[0065] In the methods described herein, various PN PLA3 and HSD17B13 proteins, and nucleic acid molecu les (e.g., genomic DNA, mRNA, and cDNA derived from the mRNA) encoding the same are detected, expressed, or employed. These PNPLA3 and HSD17B13 proteins and nucleic acid molecu les encoding the same are described in more detail.

[0066] The amino acid sequences for two wild type PNPLA3 proteins are set forth in SEQ ID NO:40 and SEQ ID NO:41. The wild type PNPLA3 protein having SEQ ID NO:40 is 481 amino acids in length, whereas the wild type PNPLA3 protein having SEQ ID NO:41 is 477 amino acids in length. The wild type PNPLA3 protein having SEQ ID NO:40 has an isoleucine at position 148. The wild type PNPLA3 protein having SEQ ID NO:41 has an isoleucine at position 144.

[0067] In some embodiments, a variant PNPLA3 llel48Met protein comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence according to SEQ ID NO:42, and comprises a methionine at a position corresponding to position 148 according to SEQ ID NO:42. In some embodiments, the variant PNPLA3 llel48Met protein comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence according to SEQ ID NO:42, and comprises a methionine at a position corresponding to position 148 according to SEQ ID NO:42. In some embodiments, the variant PNPLA3 l lel48Met protein comprises or consists of the amino acid sequence according to SEQ ID NO:42.

[0068] In some embodiments, a variant PNPLA3 llel44Met protein comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence according to SEQ ID NO:43, and comprises a methionine at a position corresponding to position 144 according to SEQ ID NO:43. In some embodiments, the variant PNPLA3 llel44Met protein comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence according to SEQ ID NO:43, and comprises a methionine at a position corresponding to position 144 according to SEQ ID NO:43. In some embodiments, the variant PNPLA3 l lel44Met protein comprises or consists of the amino acid sequence according to SEQ ID NO:43.

[0069] In some embodiments, the variant PN PLA3 llel48Met and variant PN PLA3 llel44Met proteins are fragments of the proteins described above, wherein the fragments comprise a methionine at a position corresponding to position 148 according to SEQ ID NO:42, or comprise a methionine at a position corresponding to position 144 according to SEQ ID NO:43. In some embodiments, the fragments comprise at least about 10, at least about 15, at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 55, at least about 60, at least about 65, at least about 70, at least about 75, at least about 80, at least about 85, at least about 90, at least about 95, at least about 100, at least about 150, or at least about 200 contiguous amino acid residues of the encoded polypeptide (such as the polypeptide having the amino acid sequence of SEQ ID NO:42 or SEQ I D NO:43). In this regard, the longer fragments are preferred over the shorter ones. In some embodiments, the fragments comprise at least about 10, at least about 15, at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 55, at least about 60, at least about 65, at least about 70, at least about 75, at least about 80, at least about 85, at least about 90, at least about 95, or at least about 100 contiguous amino acid residues of the encoded polypeptide. In this regard, the longer fragments are preferred over the shorter ones. The nucleic acid sequence for a genomic DNA molecu le encoding wild type PN PLA3 protein is set forth in SEQ ID NO:30. The wild type PN PLA3 genomic DNA molecule having SEQ I D NO:30 comprises a cytosine at position 5109. The wild type PNPLA3 genomic DNA molecu le having SEQ ID NO:30 comprises the codon ATC at the positions 5107 to 5109.

[0070] In some embodiments, the variant PN PLA3 genomic DNA molecule comprises or consists of a nucleic acid sequence that encodes a PNPLA3 llel48Met protein or a PNPLA3 l lel44Met protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ I D NO:42 or SEQ ID NO:43, respectively, and comprises a methionine at a position corresponding to position 148 according to SEQ ID NO:42 or comprises a methionine at a position corresponding to position 144 according to SEQ ID NO:43. In some embodiments, the variant PN PLA3 genomic DNA molecu le comprises or consists of a nucleic acid sequence that encodes a PNPLA3 llel48Met protein or a PNPLA3 llel44Met protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:42 or SEQ I D NO:43, respectively, and comprises a methionine at a position corresponding to position 148 according to SEQ ID NO:42 or comprises a methionine at a position corresponding to position 144 according to SEQ ID NO:43. In some embodiments, the variant PNPLA3 genomic DNA molecule comprises or consists a nucleic acid sequence that encodes a PNPLA3 l lel48Met protein or a PNPLA3 llel44Met protein that comprises or consists of an amino acid sequence according to SEQ ID NO:42 or SEQ ID NO:43, respectively.

[0071] In some embodiments, the variant PN PLA3 genomic DNA molecule encoding the variant PN PLA3 llel48Met protein or the variant PNPLA3 llel44Met protein comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:31, and comprises a guanine at a position corresponding to position 5109 according to SEQ I D NO:31, or comprises the codon ATG at the positions corresponding to positions 5107 to 5109 according to SEQ ID NO:31. In some embodiments, the variant PNPLA3 genomic DNA molecule encoding the variant PNPLA3 l lel48Met protein or the variant PNPLA3 llel44Met protein comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96% at least about 97% at least about 98°% or at least about 99% sequence identity to SEQ ID NO:31, and comprises a guanine at a position corresponding to position 5109 according to SEQ I D NO:31, or comprises the codon ATG at the positions corresponding to positions 5107 to 5109 according to SEQ ID NO:31. In some embodiments, the variant PNPLA3 genomic DNA molecule encoding the variant PNPLA3 l lel48Met protein or the variant PNPLA3 llel44Met protein comprises or consists of the nucleotide sequence according to SEQ I D NO:31.

[0072] In some embodiments, the variant PN PLA3 genomic DNA molecules comprise less than the entire genomic DNA sequence. In some embodiments, the variant PNPLA3 genomic DNA molecules comprise or consist of at least about 15, at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 200, at least about 300, at least about 400, at least about 500, at least about 600, at least about 700, at least about 800, at least about 900, at least about 1000, at least about 2000, at least about 3000, at least about 4000, at least about 5000, at least about 6000, at least about 7000, at least about 8000, at least about 9000, at least about 10000, at least about 11000, or at least about 11500 contiguous nucleotides of SEQ ID NO:31. In some embodiments, the variant PNPLA3 genomic DNA molecules comprise or consist of at least about 1000 to at least about 2000 contiguous nucleotides of SEQ ID NO:31.

[0073] In some embodiments, the variant PN PLA3 genomic DNA molecules comprise or consist of at least about 15, at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 200, at least about 300, at least about 400, at least about 500, at least about 600, at least about 700, at least about 800, at least about 900, at least about 1000, at least about 1000, at least about 1100, at least about 1200, at least about 1300, at least about 1400, at least about 1500, at least about 1600, at least about 1700, at least about 1800, at least about 1900, at least about 2000, at least about 2100, at least about 2200, at least about 2300, at least about 2400, or at least about 2500 contiguous nucleotides of SEQ ID NO:31.

[0074] The nucleic acid sequences of two wild type PNPLA3 mRNA molecules are set forth in SEQ ID NO:32 and SEQ ID NO:33. The wild type PNPLA3 mRNA molecule having SEQ ID NO:32 comprises a cytosine at position 444. The wild type PNPLA3 mRNA molecule having SEQ ID NO:32 comprises the codon AUC at the positions 442 to 444. The wild type PNPLA3 mRNA molecule having SEQ ID NO:33 comprises a cytosine at position 432. The wild type PNPLA3 mRNA molecule having SEQ ID NO:33 comprises the codon AUC at the positions 430 to 432.

[0075] In some embodiments, the variant PN PLA3 mRNA molecule comprises or consists of a nucleic acid sequence that encodes a PNPLA3 llel48Met protein or a PNPLA3 llel44Met protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ I D NO:42 or SEQ I D NO:43, respectively, and comprises a methionine at a position corresponding to position 148 according to SEQ ID NO:42 or comprises a methionine at a position corresponding to position 144 according to SEQ ID NO:43. In some embodiments, the variant PNPLA3 mRNA molecule comprises or consists of a nucleic acid sequence that encodes a PNPLA3 llel48Met protein or a PNPLA3 llel44Met protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:42 or SEQ ID NO:43, respectively, and comprises a methionine at a position corresponding to position 148 according to SEQ ID NO:42 or comprises a methionine at a position corresponding to position 144 according to SEQ ID NO:43. In some embodiments, the variant PNPLA3 mRNA molecule comprises or consists a nucleic acid sequence that encodes a PNPLA3 llel48Met protein or a PNPLA3 llel44Met protein that comprises or consists of an amino acid sequence according to SEQ ID NO:42 or SEQ ID NO:43, respectively.

[0076] In some embodiments, the variant PN PLA3 mRNA molecule encoding the variant PNPLA3 llel48Met protein comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:34, and comprises a guanine at a position corresponding to position 444 according to SEQ ID NO:34, or comprises the codon AUG at the positions corresponding to positions 442 to 444 according to SEQ ID NO:34. In some embodiments, the variant PN PLA3 mRNA molecule encoding the variant PNPLA3 llel48Met protein comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:34, and comprises a guanine at a position corresponding to position 444 according to SEQ I D NO:34, or comprises the codon AUG at the positions corresponding to positions 442 to 444 according to SEQ ID NO:34. In some embodiments, the variant PNPLA3 mRNA molecule encoding the variant PNPLA3 llel48Met protein comprises or consists of the nucleotide sequence according to SEQ I D NO:34.

[0077] In some embodiments, the variant PN PLA3 mRNA molecule encoding the variant PNPLA3 llel44Met protein comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:35, and comprises a guanine at a position corresponding to position 432 according to SEQ ID NO:35, or comprises the codon AUG at the positions corresponding to positions 430 to 432 according to SEQ ID NO:35. In some embodiments, the variant PN PLA3 mRNA molecule encoding the variant PNPLA3 llel44Met protein comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:35, and comprises a guanine at a position corresponding to position 432 according to SEQ ID NO:35, or comprises the codon AUG at the positions corresponding to positions 430 to 432 according to SEQ ID NO:35. In some embodiments, the variant PNPLA3 mRNA molecule encoding the variant PNPLA3 llel44Met protein comprises or consists of the nucleotide sequence according to SEQ I D NO:35.

[0078] In some embodiments, the variant PN PLA3 mRNA molecule comprises less nucleotides than the entire variant PNPLA3 mRNA sequence. In some embodiments, the variant PNPLA3 mRNA molecules comprise or consist of at least about 5, at least about 8, at least about 10, at least about 12, at least about 15, at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 200, at least about 300, at least about 400, at least about 500, or at least about 600 contiguous nucleotides of SEQ I D NO:34 or SEQ ID NO:35. I n some embodiments, the variant PNPLA3 mRNA molecules comprise or consist of at least about 200 to at least about 500 contiguous nucleotides of SEQ ID NO:34 or SEQ ID NO:35. In this regard, the longer mRNA molecules are preferred over the shorter ones. In some embodiments, the variant PNPLA3 mRNA molecules comprise or consist of at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 200, at least about 300, at least about 400, or at least about 500 contiguous nucleotides of SEQ ID NO:34 or SEQ ID NO:35. In this regard, the longer mRNA molecules are preferred over the shorter ones. In some embodiments, such variant PNPLA3 mRNA molecules include the codon that encodes the methionine at the position that corresponds to position 148 according to SEQ ID NO:42 or the codon that encodes the methionine at the position that corresponds to position 144 according to SEQ ID NO:43. In some embodiments, such variant PNPLA3 mRNA molecules include the guanine at the position corresponding to position 444 according to SEQ ID NO:34 or the guanine at the position corresponding to position 432 according to SEQ ID NO:35. In some embodiments, such variant PNPLA3 mRNA molecu les include the codon AUG at the positions corresponding to positions 442 to 444 according to SEQ ID NO:34, or the codon AUG at the positions corresponding to positions 430 to 432 according to SEQ ID NO:35.

[0079] The nucleic acid sequences of two wild type PNPLA3 cDNA molecules are set forth in SEQ ID NO:36 and SEQ ID NO:37. The wild type PNPLA3 cDNA molecule having SEQ ID NO:36 comprises a cytosine at position 444. The wild type PNPLA3 cDNA molecu le having SEQ ID NO:36 comprises the codon ATC at positions 442 to 444. The wild type PNPLA3 cDNA molecule having SEQ ID NO:37 comprises a cytosine at position 432. The wild type PNPLA3 cDNA molecule having SEQ ID NO:37 comprises the codon ATC at positions 430 to 432.

[0080] In some embodiments, the variant PN PLA3 cDNA molecule comprises or consists of a nucleic acid sequence that encodes a PNPLA3 llel48Met protein or a PNPLA3 llel44Met protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:42 or SEQ I D NO:43, respectively, and comprises a methionine at a position corresponding to position 148 according to SEQ ID NO:42 or comprises a methionine at a position corresponding to position 144 according to SEQ ID NO:43. In some embodiments, the variant PNPLA3 cDNA molecule comprises or consists of a nucleic acid sequence that encodes a PNPLA3 llel48Met protein or a PNPLA3 llel44Met protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:42 or SEQ ID NO:43, respectively, and comprises a methionine at a position corresponding to position 148 according to SEQ ID NO:42 or comprises a methionine at a position corresponding to position 144 according to SEQ ID NO:43. In some embodiments, the variant PNPLA3 cDNA molecule comprises or consists a nucleic acid sequence that encodes a PNPLA3 llel48Met protein or a PNPLA3 llel44Met protein that comprises or consists of an amino acid sequence according to SEQ ID NO:42 or SEQ ID NO:43, respectively.

[0081] In some embodiments, the variant PN PLA3 cDNA molecule encoding the variant PNPLA3 llel48Met protein comprises or consists of a nucleic acid sequence that has at least about 90% at least about 91% at least about 92% at least about 93% at least about 94% at least about 95% at least about 96% at least about 97% at least about 98% or at least about 99% sequence identity to SEQ ID NO:38, and comprises a guanine at a position corresponding to position 444 according to SEQ ID NO:38, or comprises the codon ATG at the positions corresponding to positions 442 to 444 according to SEQ ID NO:38. In some embodiments, the variant PN PLA3 cDNA molecule encoding the variant PNPLA3 llel48Met protein comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:38, and comprises a guanine at a position corresponding to position 444 according to SEQ ID NO:38, or comprises the codon ATG at the positions corresponding to positions 442 to 444 according to SEQ ID NO:38. In some embodiments, the variant PNPLA3 cDNA molecule encoding the variant PNPLA3 llel48Met protein comprises or consists of the nucleotide sequence according to SEQ I D NO:38.

[0082] In some embodiments, the variant PN PLA3 cDNA molecule encoding the variant PNPLA3 llel44Met protein comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:39, and comprises a guanine at a position corresponding to position 432 according to SEQ ID NO:39, or comprises the codon ATG at the positions corresponding to positions 430 to 432 according to SEQ ID NO:39. In some embodiments, the variant PN PLA3 cDNA molecule encoding the variant PNPLA3 llel44Met protein comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:39, and comprises a guanine at a position corresponding to position 432 according to SEQ ID NO:39, or comprises the codon ATG at the positions corresponding to positions 430 to 432 according to SEQ ID NO:39. In some embodiments, the variant PNPLA3 cDNA molecule encoding the variant PNPLA3 llel44Met protein comprises or consists of the nucleotide sequence according to SEQ I D NO:39. In some embodiments, the variant PN PLA3 cDNA molecule comprises less nucleotides than the entire variant PNPLA3 cDNA sequence. In some embodiments, the variant PNPLA3 cDNA molecu les comprise or consist of at least about 5, at least about 8, at least about 10, at least about 12, at least about 15, at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 200, at least about 300, at least about 400, at least about 500, or at least about 600 contiguous nucleotides of SEQ I D NO:38 or SEQ ID NO:39. I n some embodiments, the variant PNPLA3 cDNA molecu les comprise or consist of at least about 200 to at least about 500 contiguous nucleotides of SEQ ID NO:38 or SEQ ID NO:39. In this regard, the longer cDNA molecules are preferred over the shorter ones. In some embodiments, the variant PNPLA3 cDNA molecules comprise or consist of at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 200, at least about 300, at least about 400, or at least about 500 contiguous nucleotides of SEQ ID NO:38 or SEQ ID NO:39. In this regard, the longer cDNA molecules are preferred over the shorter ones. In some embodiments, such variant PNPLA3 cDNA molecu les include the codon that encodes the methionine at the position that corresponds to position 148 according to SEQ ID NO:42 or the codon that encodes the methionine at the position that corresponds to position 144 according to SEQ ID NO:43. In some embodiments, such variant PNPLA3 cDNA molecules include the guanine at the position corresponding to position 444 according to SEQ ID NO:38 or the guanine at the position corresponding to position 432 according to SEQ ID NO:39. In some embodiments, such variant PNPLA3 cDNA molecules include the codon ATG at the positions corresponding to positions 442 to 444 according to SEQ I D NO:38, or the codon ATG at the positions corresponding to positions 430 to 432 according to SEQ ID NO:39.

[0083] The amino acid sequences for fou r HSD17B13 isoform proteins associated with the fu nctional HSD17B13 protein are set forth in SEQ ID NO:21 (Isoform A), SEQ ID NO:22 (Isoform B), SEQ ID NO:25 (Isoform E), and SEQ I D NO:29 (Isoform I). The HSD17B13 protein having SEQ I D NO:21 (Isoform A) is 300 amino acids in length. The HSD17B13 protein having SEQ ID NO:22 (Isoform B) is 264 amino acids in length. The HSD17B13 protein having SEQ ID NO:25 (Isoform E) is 324 amino acids in length. The HSD17B13 protein having SEQ ID NO:29 (Isoform I) is 271 amino acids in length. In some embodiments, an HSD17B13 isoform protein associated with the functional HSD17B13 protein comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence according to SEQ ID NO:21 (Isoform A). In some embodiments, the HSD17B13 isoform protein associated with the functional HSD17B13 protein comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence according to SEQ ID NO:21 (Isoform A). In some embodiments, the HSD17B13 isoform protein associated with the functional HSD17B13 protein comprises or consists of the amino acid sequence according to SEQ ID NO:21 (Isoform A).

[0084] In some embodiments, an HSD17B13 isoform protein associated with the functional HSD17B13 protein comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence according to SEQ ID NO:22 (Isoform B). In some embodiments, the HSD17B13 isoform protein associated with the functional HSD17B13 protein comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence according to SEQ ID NO:22 (Isoform B). In some embodiments, the HSD17B13 isoform protein associated with the functional HSD17B13 protein comprises or consists of the amino acid sequence according to SEQ ID NO:22 (Isoform B).

[0085] In some embodiments, an HSD17B13 isoform protein associated with the functional HSD17B13 protein comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence according to SEQ ID NO:25 (Isoform E). In some embodiments, the HSD17B13 isoform protein associated with the functional HSD17B13 protein comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence according to SEQ ID NO:25 (Isoform E). In some embodiments, the HSD17B13 isoform protein associated with the functional HSD17B13 protein comprises or consists of the amino acid sequence according to SEQ ID NO:25 (Isoform E).

[0086] In some embodiments, an HSD17B13 isoform protein associated with the functional HSD17B13 protein comprises an amino acid sequence that has at least about 90%, at least about 91% at least about 92% at least about 93% at least about 94% at least about 95% at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence according to SEQ ID NO:29 (Isoform I). In some embodiments, the HSD17B13 isoform protein associated with the functional HSD17B13 protein comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence according to SEQ ID NO:29 (Isoform I). In some embodiments, the HSD17B13 isoform protein associated with the functional HSD17B13 protein comprises or consists of the amino acid sequence according to SEQ ID NO:29 (Isoform I).

[0087] The amino acid sequences for five HSD17B13 isoform proteins associated with the loss-of-function rs72613567 HSD17B13 protein (SEQ ID NO:2) are set forth in SEQ I D NO:23

[0088] (Isoform C), SEQ ID NO:24 (Isoform D), SEQ I D NO:26 (Isoform F), SEQ ID NO:27 (Isoform G), and SEQ ID NO:28 (Isoform H). The HSD17B13 protein having SEQ ID NO:23 (Isoform C) is 261 amino acids in length. The HSD17B13 protein having SEQ ID NO:24 (Isoform D) is 274 amino acids in length. The HSD17B13 protein having SEQ ID NO:26 (Isoform F) is 284 amino acids in length. The HSD17B13 protein having SEQ ID NO:27 (Isoform G) is 238 amino acids in length. The HSD17B13 protein having SEQ ID NO:28 (Isoform H) is 298 amino acids in length.

[0089] In some embodiments, an HSD17B13 variant protein associated with a loss-of-fu nction comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence according to SEQ ID NO:23 (Isoform C). In some embodiments, the HSD17B13 variant protein associated with a loss-of-fu nction comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence according to SEQ ID NO:23 (Isoform C). In some embodiments, the HSD17B13 variant protein associated with a loss-of-fu nction comprises or consists of the amino acid sequence according to SEQ I D NO:23 (Isoform C). In some embodiments, an HSD17B13 variant protein associated with a loss-of-fu nction comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence according to SEQ ID NO:24 (Isoform D). In some embodiments, the HSD17B13 variant protein associated with a loss-of-fu nction comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence according to SEQ ID NO:24 (Isoform D). In some embodiments, the HSD17B13 variant protein associated with a loss-of-fu nction comprises an amino acid sequence that comprises or consists of the amino acid sequence according to SEQ ID NO:24 (Isoform D).

[0090] In some embodiments, an HSD17B13 variant protein associated with a loss-of-fu nction comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence according to SEQ ID NO:26 (Isoform F). In some embodiments, the HSD17B13 variant protein associated with a loss-of-fu nction comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence according to SEQ ID NO:26 (Isoform F). In some embodiments, the HSD17B13 variant protein associated with a loss-of-fu nction comprises or consists of the amino acid sequence according to SEQ I D NO:26 (Isoform F).

[0091] In some embodiments, an HSD17B13 variant protein associated with a loss-of-fu nction comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence according to SEQ ID NO:27 (Isoform G). In some embodiments, the HSD17B13 variant protein associated with a loss-of-fu nction comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence according to SEQ ID NO:27 (Isoform G). In some embodiments, the HSD17B13 variant protein associated with a loss-of-fu nction comprises or consists of the amino acid sequence according to SEQ I D NO:27 (Isoform G). In some embodiments, an HSD17B13 variant protein associated with a loss-of-fu nction comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence according to SEQ ID NO:28 (Isoform H). In some embodiments, the HSD17B13 variant protein associated with a loss-of-fu nction comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence according to SEQ ID NO:28 (Isoform H). In some embodiments, the HSD17B13 variant protein associated with a loss-of-fu nction comprises or consists of the amino acid sequence according to SEQ I D NO:28 (Isoform H).

[0092] In some embodiments, the HSD17B13 isoform proteins associated with the functional HSD17B13 protein and the HSD17B13 variant proteins associated with a loss-of-fu nction are fragments of the proteins described above. In some embodiments, the fragments comprise at least about 10, at least about 15, at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 55, at least about 60, at least about 65, at least about 70, at least about 75, at least about 80, at least about 85, at least about 90, at least about 95, at least about 100, at least about 150, or at least about 200 contiguous amino acid residues of the encoded polypeptide (such as the polypeptides having the amino acid sequence of SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:29). In this regard, the longer fragments are preferred over the shorter ones. In some embodiments, the fragments comprise at least about 10, at least about 15, at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 55, at least about 60, at least about 65, at least about 70, at least about 75, at least about 80, at least about 85, at least about 90, at least about 95, or at least about 100 contiguous amino acid residues of the encoded polypeptide. In this rega rd, the longer fragments are preferred over the shorter ones.

[0093] A nucleic acid sequence for the functional HSD17B13 genomic DNA molecule is set forth in SEQ ID NO:l. The functional HSD17B13 genomic DNA molecule having SEQ ID NO:l comprises an adenine at position 12,667.

[0094] In some embodiments, the functional HSD17B13 genomic DNA molecule comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ I D NO:21 (Isoform A). In some embodiments, the functional HSD17B13 genomic DNA molecule comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:21 (Isoform A). In some embodiments, the functional HSD17B13 genomic DNA molecule comprises or consists a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:21 (Isoform A).

[0095] In some embodiments, the functional HSD17B13 genomic DNA molecule comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ I D NO:22 (Isoform B). In some embodiments, the functional HSD17B13 genomic DNA molecule comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:22 (Isoform B). In some embodiments, the functional HSD17B13 genomic DNA molecule comprises or consists a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:22 (Isoform B).

[0096] In some embodiments, the functional HSD17B13 genomic DNA molecule comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ I D NO:25 (Isoform E). In some embodiments, the functional HSD17B13 genomic DNA molecule comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:25 (Isoform E). In some embodiments, the functional HSD17B13 genomic DNA molecule comprises or consists a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:25 (Isoform E).

[0097] In some embodiments, the functional HSD17B13 genomic DNA molecule comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ I D NO:29 (Isoform I). In some embodiments, the functional HSD17B13 genomic DNA molecule comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:29 (Isoform I). In some embodiments, the functional HSD17B13 genomic DNA molecule comprises or consists a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:29 (Isoform I).

[0098] In some embodiments, the functional HSD17B13 genomic DNA molecule comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:l. In some embodiments, the functional HSD17B13 genomic DNA molecule comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: l. In some

[0099] embodiments, the functional HSD17B13 genomic DNA molecule comprises or consists a nucleic acid sequence according to SEQ ID NO:21.

[0100] A nucleic acid sequence for the variant HSD17B13 genomic DNA molecule encoding an HSD17B13 variant protein associated with a loss-of-fu nction is set forth in SEQ ID NO:2. The variant HSD17B13 genomic DNA molecule having SEQ ID NO:2 comprises a thymine at position 12,667.

[0101] In some embodiments, the variant HSD17B13 genomic DNA molecule comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ I D NO:23 (Isoform C). In some embodiments, the variant HSD17B13 genomic DNA molecu le comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:23 (Isoform C). In some

[0102] embodiments, the variant HSD17B13 genomic DNA molecule comprises or consists a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:23 (Isoform C).

[0103] In some embodiments, the variant HSD17B13 genomic DNA molecule comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ I D NO:24 (Isoform D). In some embodiments, the variant HSD17B13 genomic DNA molecu le comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:24 (Isoform D). In some

[0104] embodiments, the variant HSD17B13 genomic DNA molecule comprises or consists a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:24 (Isoform D).

[0105] In some embodiments, the variant HSD17B13 genomic DNA molecule comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ I D NO:26 (Isoform F). In some embodiments, the variant HSD17B13 genomic DNA molecu le comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:26 (Isoform F). I n some

[0106] embodiments, the variant HSD17B13 genomic DNA molecule comprises or consists a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:26 (Isoform F). ln some embodiments, the variant HSD17B13 genomic DNA molecule comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ I D NO:27 (Isoform G). In some embodiments, the variant HSD17B13 genomic DNA molecu le comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:27 (Isoform G). In some

[0107] embodiments, the variant HSD17B13 genomic DNA molecule comprises or consists a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:27 (Isoform G).

[0108] In some embodiments, the variant HSD17B13 genomic DNA molecule comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ I D NO:28 (Isoform H). In some embodiments, the variant HSD17B13 genomic DNA molecu le comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:28 (Isoform H). In some

[0109] embodiments, the variant HSD17B13 genomic DNA molecule comprises or consists a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:28 (Isoform H).

[0110] In some embodiments, the variant HSD17B13 genomic DNA molecule comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:2. In some embodiments, the variant HSD17B13 genomic DNA molecu le comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:2. In some embodiments, the variant HSD17B13 genomic DNA molecule comprises or consists a nucleic acid sequence according to SEQ ID NO:2.

[0111] In some embodiments, the functional HSD17B13 genomic DNA and variant HSD17B13 genomic DNA molecules comprise less than the entire genomic DNA sequence. In some embodiments, the functional HSD17B13 genomic DNA and variant HSD17B13 genomic DNA molecules comprise or consist of at least about 15, at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 200, at least about 300, at least about 400, at least about 500, at least about 600, at least about 700, at least about 800, at least about 900, at least about 1000, at least about 2000, at least about 3000, at least about 4000, at least about 5000, at least about 6000, at least about 7000, at least about 8000, at least about 9000, at least about 10000, at least about 11000, or at least about 11500 contiguous nucleotides of SEQ ID NO:l (functional HSD17B13 genomic DNA) or SEQ ID NO:2 (variant HSD17B13 genomic DNA). In some embodiments, the functional HSD17B13 genomic DNA and variant HSD17B13 genomic DNA molecu les comprise or consist of at least about 1000 to at least about 2000 contiguous nucleotides of SEQ ID NO:l (functional HSD17B13 genomic DNA) or SEQ I D NO:2 (variant HSD17B13 genomic DNA).

[0112] In some embodiments, the functional HSD17B13 genomic DNA and variant HSD17B13 genomic DNA molecules comprise or consist of at least about 15, at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 200, at least about 300, at least about 400, at least about 500, at least about 600, at least about 700, at least about 800, at least about 900, at least about 1000, at least about 1000, at least about 1100, at least about 1200, at least about 1300, at least about 1400, at least about 1500, at least about 1600, at least about 1700, at least about 1800, at least about 1900, at least about 2000, at least about 2100, at least about 2200, at least about 2300, at least about 2400, or at least about 2500 contiguous nucleotides of SEQ ID NO: l (functional HSD17B13 genomic DNA) or SEQ I D NO:2 (variant HSD17B13 genomic DNA).

[0113] The nucleic acid sequences for fou r HSD17B13 RNA transcripts encoding isoform proteins associated with the functional HSD17B13 protein are set forth in SEQ ID NO:44 (Transcript A), SEQ ID NO:45 (Transcript B), SEQ ID NO:48 (Transcript E), and SEQ ID NO:52 (Transcript I). ln some embodiments, an HSD17B13 RNA transcript encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90% at least about 91% at least about 92% at least about 93% at least about 94% at least about 95% at least about 96% at least about 97% at least about 98% or at least about 99% sequence identity to SEQ ID NO:21 (Isoform A). In some embodiments, the HSD17B13 RNA transcript encoding an isoform protein associated with the functional

[0114] HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:21 (Isoform A). In some embodiments, the HSD17B13 RNA transcript encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:21 (Isoform A).

[0115] In some embodiments, an HSD17B13 RNA transcript encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:22 (Isoform B). In some embodiments, the HSD17B13 RNA transcript encoding an isoform protein associated with the functional

[0116] HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:22 (Isoform B). In some embodiments, the HSD17B13 RNA transcript encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:22 (Isoform B).

[0117] In some embodiments, an HSD17B13 RNA transcript encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94% at least about 95% at least about 96% at least about 97% at least about 98% or at least about 99% sequence identity to SEQ ID NO:25 (Isoform E). In some embodiments, the HSD17B13 RNA transcript encoding an isoform protein associated with the functional

[0118] HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:25 (Isoform E). In some embodiments, the HSD17B13 RNA transcript encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:25 (Isoform E).

[0119] In some embodiments, an HSD17B13 RNA transcript encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:29 (Isoform I). In some embodiments, the HSD17B13 RNA transcript encoding an isoform protein associated with the functional

[0120] HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:29 (Isoform I). In some embodiments, the HSD17B13 RNA transcript encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:29 (Isoform I).

[0121] In some embodiments, an HSD17B13 RNA transcript encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:44 (Transcript A). I n some embodiments, the HSD17B13 RNA transcript encoding an isoform protein associated with the fu nctional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:44 (Transcript A). In some embodiments, the HSD17B13 RNA transcript encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence according to SEQ ID NO:44 (Transcript A).

[0122] In some embodiments, an HSD17B13 RNA transcript encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:45 (Transcript B). In some embodiments, the HSD17B13 RNA transcript encoding an isoform protein associated with the fu nctional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:45 (Transcript B). In some embodiments, the HSD17B13 RNA transcript encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence according to SEQ ID NO:45 (Transcript B).

[0123] In some embodiments, an HSD17B13 RNA transcript encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:48 (Transcript E). In some embodiments, the HSD17B13 RNA transcript encoding an isoform protein associated with the fu nctional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:48 (Transcript E). In some embodiments, the HSD17B13 RNA transcript encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence according to SEQ ID NO:48 (Transcript E).

[0124] In some embodiments, an HSD17B13 RNA transcript encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:52 (Transcript I). In some embodiments, the HSD17B13 RNA transcript encoding an isoform protein associated with the fu nctional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 95% at least about 96% at least about 97% at least about 98% or at least about 99% sequence identity to SEQ ID NO:52 (Transcript I). In some embodiments, the HSD17B13 RNA transcript encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence according to SEQ ID NO:52 (Transcript I).

[0125] The nucleic acid sequences for five HSD17B13 RNA transcripts encoding isoform proteins associated with a loss-of-function are set forth in SEQ ID NO:46 (Transcript C), SEQ ID NO:47 (Transcript D), SEQ I D NO:49 (Transcript F), SEQ I D NO:50 (Transcript G), and SEQ ID NO:51 (Transcript H).

[0126] In some embodiments, an HSD17B13 RNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90% at least about 91% at least about 92°% at least about 93% at least about 94% at least about 95% at least about 96% at least about 97% at least about 98% or at least about 99% sequence identity to SEQ ID NO:23 (Isoform C). In some embodiments, the HSD17B13 RNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:23 (Isoform C). In some embodiments, the HSD17B13 RNA transcript encoding the isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:23 (Isoform C).

[0127] In some embodiments, an HSD17B13 RNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:24 (Isoform D). In some embodiments, the HSD17B13 RNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:24 (Isoform D). In some embodiments, the HSD17B13 RNA transcript encoding the isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:24 (Isoform D).

[0128] In some embodiments, an HSD17B13 RNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90% at least about 91% at least about 92°% at least about 93% at least about 94% at least about 95% at least about 96% at least about 97% at least about 98% or at least about 99% sequence identity to SEQ ID NO:26 (Isoform F). In some embodiments, the HSD17B13 RNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:26 (Isoform F). In some embodiments, the HSD17B13 RNA transcript encoding the isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:26 (Isoform F).

[0129] In some embodiments, an HSD17B13 RNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:27 (Isoform G). In some embodiments, the HSD17B13 RNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:27 (Isoform G). In some embodiments, the HSD17B13 RNA transcript encoding the isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:27 (Isoform G). In some embodiments, an HSD17B13 RNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90% at least about 91°% at least about 92°% at least about 93°% at least about 94°% at least about 95°% at least about 96°% at least about 97°% at least about 98°% or at least about 99% sequence identity to SEQ ID NO:28 (Isoform H). In some embodiments, the HSD17B13 RNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:28 (Isoform H). In some embodiments, the HSD17B13 RNA transcript encoding the isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:28 (Isoform H).

[0130] In some embodiments, an HSD17B13 RNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:46 (Transcript C). In some embodiments, the HSD17B13 RNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:46 (Transcript C). In some embodiments, the HSD17B13 RNA transcript encoding the isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence according to SEQ ID NO:46 (Transcript C).

[0131] In some embodiments, an HSD17B13 RNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:47 (Transcript D). In some embodiments, the HSD17B13 RNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97% at least about 98°% or at least about 99% sequence identity to SEQ ID NO:47 (Transcript D). In some embodiments, the HSD17B13 RNA transcript encoding the isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence according to SEQ ID NO:47 (Transcript D).

[0132] In some embodiments, an HSD17B13 RNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 90°% at least about 91°% at least about 92°% at least about 93°% at least about 94°% at least about 95°% at least about 96°% at least about 97°% at least about 98°% or at least about 99% sequence identity to SEQ I D NO:49 (Transcript F). In some embodiments, the HSD17B13 RNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:49 (Transcript F). In some embodiments, the HSD17B13 RNA transcript encoding the isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence according to SEQ ID NO:49 (Transcript F).

[0133] In some embodiments, an HSD17B13 RNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:50 (Transcript G). I n some embodiments, the HSD17B13 RNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:50 (Transcript G). In some embodiments, the HSD17B13 RNA transcript encoding the isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence according to SEQ ID NO:50 (Transcript G).

[0134] In some embodiments, an HSD17B13 RNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:51 (Transcript H). In some embodiments, the HSD17B13 RNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:51 (Transcript H). In some embodiments, the HSD17B13 RNA transcript encoding the isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence according to SEQ ID NO:51 (Transcript H).

[0135] In some embodiments, the functional HSD17B13 RNA transcripts and variant

[0136] HSD17B13 RNA transcripts comprise less than the RNA transcript sequence. In some embodiments, the functional HSD17B13 RNA transcripts and variant HSD17B13 RNA transcripts comprise or consist of at least about 15, at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 200, at least about 300, at least about 400, at least about 500, at least about 600, at least about 700, at least about 800, at least about 900, at least about 1000, at least about 2000, or at least about 2500 contiguous nucleotides of SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:48, or SEQ ID NO:52 (functional HSD17B13 RNA transcripts) or SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:50, or SEQ I D NO:51 (variant HSD17B13 RNA transcripts). In some embodiments, the fu nctional HSD17B13 RNA transcripts and variant HSD17B13 RNA transcripts comprise less than the RNA transcript sequence. In some embodiments, the functional HSD17B13 RNA transcripts and variant HSD17B13 RNA transcripts comprise or consist of at least about 15, at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 200, at least about 300, at least about 400, or at least about 500 contiguous nucleotides of SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:48, or SEQ I D NO:52 (functional HSD17B13 RNA transcripts) or SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:50, or SEQ I D NO:51 (variant HSD17B13 RNA transcripts). In some embodiments, the fu nctional HSD17B13 RNA transcripts and variant HSD17B13 RNA transcripts comprise or consist of at least about 1000 to at least about 2000 contiguous nucleotides of SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:48, or SEQ I D NO:52 (functional HSD17B13 RNA transcripts) or SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:50, or SEQ ID NO:51 (variant HSD17B13 RNA transcripts).

[0137] The nucleic acid sequences for fou r HSD17B13 cDNA transcripts encoding isoform proteins associated with the functional HSD17B13 protein are set forth in SEQ ID NO:53 (Transcript A), SEQ ID NO:54 (Transcript B), SEQ ID NO:57 (Transcript E), and SEQ ID N0:61 (Transcript I).

[0138] In some embodiments, an HSD17B13 cDNA transcript encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90% at least about 91% at least about 92% at least about 93% at least about 94% at least about 95% at least about 96% at least about 97% at least about 98% or at least about 99% sequence identity to SEQ ID NO:21 (Isoform A). In some embodiments, the HSD17B13 cDNA transcript encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:21 (Isoform A). In some embodiments, the HSD17B13 cDNA transcript encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:21 (Isoform A).

[0139] In some embodiments, an HSD17B13 cDNA transcript encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:22 (Isoform B). In some embodiments, the HSD17B13 cDNA transcript encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:22 (Isoform B). In some embodiments, the HSD17B13 cDNA transcript encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:22 (Isoform B).

[0140] In some embodiments, an HSD17B13 cDNA transcript encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90% at least about 91% at least about 92% at least about 93% at least about 94% at least about 95% at least about 96% at least about 97% at least about 98% or at least about 99% sequence identity to SEQ ID NO:25 (Isoform E). In some embodiments, the HSD17B13 cDNA transcript encoding an isoform protein associated with the functional

[0141] HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:25 (Isoform E). In some embodiments, the HSD17B13 cDNA transcript encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:25 (Isoform E).

[0142] In some embodiments, an HSD17B13 cDNA transcript encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:29 (Isoform I). In some embodiments, the HSD17B13 cDNA transcript encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:29 (Isoform I). In some embodiments, the HSD17B13 cDNA transcript encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:29 (Isoform I).

[0143] In some embodiments, an HSD17B13 cDNA transcript encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:53 (Transcript A). I n some embodiments, the HSD17B13 cDNA transcript encoding an isoform protein associated with the fu nctional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 95% at least about 96% at least about 97% at least about 98% or at least about 99% sequence identity to SEQ ID NO:53 (Transcript A). In some embodiments, the HSD17B13 cDNA transcript encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence according to SEQ ID NO:53 (Transcript A).

[0144] In some embodiments, an HSD17B13 cDNA transcript encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:54 (Transcript B). In some embodiments, the HSD17B13 cDNA transcript encoding an isoform protein associated with the fu nctional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:54 (Transcript B). In some embodiments, the HSD17B13 cDNA transcript encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence according to SEQ ID NO:54 (Transcript B).

[0145] In some embodiments, an HSD17B13 cDNA transcript encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:57 (Transcript E). In some embodiments, the HSD17B13 cDNA transcript encoding an isoform protein associated with the fu nctional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:57 (Transcript E). In some embodiments, the HSD17B13 cDNA transcript encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence according to SEQ ID NO:57 (Transcript E).

[0146] In some embodiments, an HSD17B13 cDNA transcript encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:61 (Transcript I). In some embodiments, the HSD17B13 cDNA transcript encoding an isoform protein associated with the fu nctional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 95% at least about 96% at least about 97% at least about 98% or at least about 99% sequence identity to SEQ ID NO:61 (Transcript I). In some embodiments, the HSD17B13 cDNA transcript encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence according to SEQ ID NO:61 (Transcript I).

[0147] The nucleic acid sequences for five HSD17B13 cDNA transcripts encoding isoform proteins associated with a loss-of-function are set forth in SEQ ID NO:55 (Transcript C), SEQ ID NO:56 (Transcript D), SEQ I D NO:58 (Transcript F), SEQ I D NO:59 (Transcript G), and SEQ ID NO:60 (Transcript H).

[0148] In some embodiments, an HSD17B13 cDNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90% at least about 91% at least about 92°% at least about 93% at least about 94% at least about 95% at least about 96% at least about 97% at least about 98% or at least about 99% sequence identity to SEQ ID NO:23 (Isoform C). In some embodiments, the HSD17B13 cDNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:23 (Isoform C). In some embodiments, the HSD17B13 cDNA transcript encoding the isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:23 (Isoform C).

[0149] In some embodiments, an HSD17B13 cDNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:24 (Isoform D). In some embodiments, the HSD17B13 cDNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:24 (Isoform D). In some embodiments, the HSD17B13 cDNA transcript encoding the isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:24 (Isoform D).

[0150] In some embodiments, an HSD17B13 cDNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:26 (Isoform F). In some embodiments, the HSD17B13 cDNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:26 (Isoform F). In some embodiments, the HSD17B13 cDNA transcript encoding the isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:26 (Isoform F).

[0151] In some embodiments, an HSD17B13 cDNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:27 (Isoform G). In some embodiments, the HSD17B13 cDNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:27 (Isoform G). In some embodiments, the HSD17B13 cDNA transcript encoding the isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:27 (Isoform G).

[0152] In some embodiments, an HSD17B13 cDNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90% at least about 91°% at least about 92°% at least about 93°% at least about 94°% at least about 95°% at least about 96°% at least about 97°% at least about 98°% or at least about 99% sequence identity to SEQ ID NO:28 (Isoform H). In some embodiments, the HSD17B13 cDNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:28 (Isoform H). In some embodiments, the HSD17B13 cDNA transcript encoding the isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:28 (Isoform H).

[0153] In some embodiments, an HSD17B13 cDNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:55 (Transcript C). In some embodiments, the HSD17B13 cDNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:55 (Transcript C). In some embodiments, the HSD17B13 cDNA transcript encoding the isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence according to SEQ ID NO:55 (Transcript C).

[0154] In some embodiments, an HSD17B13 cDNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:56 (Transcript D). In some embodiments, the HSD17B13 cDNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:56 (Transcript D). In some embodiments, the HSD17B13 cDNA transcript encoding the isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence according to SEQ ID NO:56 (Transcript D).

[0155] In some embodiments, an HSD17B13 cDNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:58 (Transcript F). In some embodiments, the HSD17B13 cDNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:58 (Transcript F). In some embodiments, the HSD17B13 cDNA transcript encoding the isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence according to SEQ ID NO:58 (Transcript F).

[0156] In some embodiments, an HSD17B13 cDNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:59 (Transcript G). I n some embodiments, the HSD17B13 cDNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:59 (Transcript G). In some embodiments, the HSD17B13 cDNA transcript encoding the isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence according to SEQ ID NO:59 (Transcript G).

[0157] In some embodiments, an HSD17B13 cDNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:60 (Transcript H). In some embodiments, the HSD17B13 cDNA transcript encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:60 (Transcript H). In some embodiments, the HSD17B13 cDNA transcript encoding the isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence according to SEQ ID NO:60 (Transcript H).

[0158] In some embodiments, the HSD17B13 cDNA transcripts comprise less than the cDNA transcript sequence. In some embodiments, the HSD17B13 cDNA transcripts comprise or consist of at least about 15, at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 200, at least about 300, at least about 400, at least about 500, at least about 600, at least about 700, at least about 800, at least about 900, at least about 1000, at least about 2000, or at least about 2500 contiguous nucleotides of SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:57, or SEQ I D NO:61 or SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:59, or SEQ ID NO:60. In some embodiments, the HSD17B13 cDNA transcripts comprise less than the cDNA transcript sequence. In some embodiments, the HSD17B13 cDNA transcripts comprise or consist of at least about 15, at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 200, at least about 300, at least about 400, or at least about 500 contiguous nucleotides of SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:57, or SEQ I D NO:61 or SEQ I D NO:55, SEQ I D NO:56, SEQ I D NO:58, SEQ I D NO:59, or SEQ ID NO:60. In some embodiments, the HSD17B13 cDNA transcripts comprise or consist of at least about 1000 to at least about 2000 contiguous nucleotides of SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:57, or SEQ ID NO:61 or SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:59, or SEQ I D NO:60.

[0159] The nucleic acid sequences for fou r HSD17B13 mRNA molecules encoding isoform proteins associated with the functional HSD17B13 protein are set forth in SEQ ID NO:3

[0160] (Transcript A), SEQ ID NO:4 (Transcript B), SEQ I D NO:7 (Transcript E), and SEQ ID NO: ll (Transcript I).

[0161] In some embodiments, an HSD17B13 mRNA molecule encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90% at least about 91% at least about 92% at least about 93% at least about 94% at least about 95% at least about 96% at least about 97% at least about 98% or at least about 99% sequence identity to SEQ ID NO:21 (Isoform A). In some embodiments, the HSD17B13 mRNA molecule encoding an isoform protein associated with the functional

[0162] HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:21 (Isoform A). In some embodiments, the HSD17B13 mRNA molecu le encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:21 (Isoform A).

[0163] In some embodiments, an HSD17B13 mRNA molecule encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:22 (Isoform B). In some embodiments, the HSD17B13 mRNA molecule encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:22 (Isoform B). In some embodiments, the HSD17B13 mRNA molecu le encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:22 (Isoform B).

[0164] In some embodiments, an HSD17B13 mRNA molecule encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:25 (Isoform E). In some embodiments, the HSD17B13 mRNA molecule encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:25 (Isoform E). In some embodiments, the HSD17B13 mRNA molecu le encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:25 (Isoform E).

[0165] In some embodiments, an HSD17B13 mRNA molecule encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:29 (Isoform I). In some embodiments, the HSD17B13 mRNA molecule encoding an isoform protein associated with the functional

[0166] HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:29 (Isoform I). In some embodiments, the HSD17B13 mRNA molecule encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:29 (Isoform I).

[0167] In some embodiments, an HSD17B13 mRNA molecule encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:3 (Transcript A). In some embodiments, the HSD17B13 mRNA molecule encoding an isoform protein associated with the fu nctional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:3 (Transcript A). In some embodiments, the HSD17B13 mRNA molecule encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence according to SEQ ID NO:3 (Transcript A).

[0168] In some embodiments, an HSD17B13 mRNA molecule encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:4 (Transcript B). In some embodiments, the HSD17B13 mRNA molecule encoding an isoform protein associated with the fu nctional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:4 (Transcript B). In some embodiments, the HSD17B13 mRNA molecule encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence according to SEQ ID NO:4 (Transcript B).

[0169] In some embodiments, an HSD17B13 mRNA molecule encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:7 (Transcript E). In some embodiments, the HSD17B13 mRNA molecule encoding an isoform protein associated with the fu nctional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:7 (Transcript E). In some embodiments, the HSD17B13 mRNA molecule encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence according to SEQ ID NO:7 (Transcript E).

[0170] In some embodiments, an HSD17B13 mRNA molecule encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:ll (Transcript I). In some embodiments, the HSD17B13 mRNA molecule encoding an isoform protein associated with the fu nctional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:ll (Transcript I). In some embodiments, the HSD17B13 mRNA molecule encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence according to SEQ ID NO:ll (Transcript I).

[0171] The nucleic acid sequences for five HSD17B13 mRNA molecules encoding isoform proteins associated with a loss-of-function are set forth in SEQ ID NO:5 (Transcript C), SEQ ID NO:6 (Transcript D), SEQ ID NO:8 (Transcript F), SEQ ID NO:9 (Transcript G), and SEQ I D NO:10 (Transcript H).

[0172] In some embodiments, an HSD17B13 mRNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90% at least about 91% at least about 92°% at least about 93% at least about 94% at least about 95% at least about 96% at least about 97% at least about 98% or at least about 99% sequence identity to SEQ ID NO:23 (Isoform C). In some embodiments, the HSD17B13 mRNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:23 (Isoform C). In some embodiments, the HSD17B13 mRNA molecule encoding the isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:23 (Isoform C).

[0173] In some embodiments, an HSD17B13 mRNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:24 (Isoform D). In some embodiments, the HSD17B13 mRNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:24 (Isoform D). In some embodiments, the HSD17B13 mRNA molecule encoding the isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:24 (Isoform D).

[0174] In some embodiments, an HSD17B13 mRNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90% at least about 91% at least about 92°% at least about 93% at least about 94% at least about 95% at least about 96% at least about 97% at least about 98% or at least about 99% sequence identity to SEQ ID NO:26 (Isoform F). In some embodiments, the HSD17B13 mRNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:26 (Isoform F). In some embodiments, the HSD17B13 mRNA molecule encoding the isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:26 (Isoform F).

[0175] In some embodiments, an HSD17B13 mRNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:27 (Isoform G). In some embodiments, the HSD17B13 mRNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:27 (Isoform G). In some embodiments, the HSD17B13 mRNA molecule encoding the isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:27 (Isoform G). In some embodiments, an HSD17B13 mRNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90% at least about 91°% at least about 92°% at least about 93°% at least about 94°% at least about 95°% at least about 96°% at least about 97°% at least about 98°% or at least about 99% sequence identity to SEQ ID NO:28 (Isoform H). In some embodiments, the HSD17B13 mRNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:28 (Isoform H). In some embodiments, the HSD17B13 mRNA molecule encoding the isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:28 (Isoform H).

[0176] In some embodiments, an HSD17B13 mRNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:5 (Transcript C). In some embodiments, the HSD17B13 mRNA molecule encoding an isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:5 (Transcript C). In some embodiments, the HSD17B13 mRNA molecule encoding the isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence according to SEQ ID NO:5 (Transcript C).

[0177] In some embodiments, an HSD17B13 mRNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:6 (Transcript D). In some embodiments, the HSD17B13 mRNA molecule encoding an isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97% at least about 98°% or at least about 99% sequence identity to SEQ ID NO:6 (Transcript D). In some embodiments, the HSD17B13 mRNA molecule encoding the isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence according to SEQ ID NO:6 (Transcript D).

[0178] In some embodiments, an HSD17B13 mRNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 90°% at least about 91°% at least about 92°% at least about 93°% at least about 94°% at least about 95°% at least about 96°% at least about 97°% at least about 98°% or at least about 99% sequence identity to SEQ ID NO:8 (Transcript F). In some embodiments, the HSD17B13 mRNA molecule encoding an isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:8 (Transcript F). In some embodiments, the HSD17B13 mRNA molecule encoding the isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence according to SEQ ID NO:8 (Transcript F).

[0179] In some embodiments, an HSD17B13 mRNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:9 (Transcript G). In some embodiments, the HSD17B13 mRNA molecule encoding an isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:9 (Transcript G). In some embodiments, the HSD17B13 mRNA molecule encoding the isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence according to SEQ ID NO:9 (Transcript G).

[0180] In some embodiments, an HSD17B13 mRNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:10 (Transcript H). In some embodiments, the HSD17B13 mRNA molecule encoding an isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:10 (Transcript H). In some embodiments, the HSD17B13 mRNA molecule encoding the isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence according to SEQ ID NO:10 (Transcript H).

[0181] In some embodiments, the HSD17B13 mRNA molecules comprise less nucleotides than the entire mRNA sequence. In some embodiments, the HSD17B13 mRNA molecules comprise or consist of at least about 5, at least about 8, at least about 10, at least about 12, at least about 15, at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 200, at least about 300, at least about 400, at least about 500, at least about 600, at least about 700, at least about 800, or at least about 900 contiguous nucleotides of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:7, or SEQ ID NO:ll, or SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:9, or SEQ I D NO:10. In some embodiments, the HSD17B13 mRNA molecules comprise or consist of at least about 200 to at least about 500 contiguous nucleotides of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:7, or SEQ ID NO:ll, or SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:9, or SEQ I D NO:10. In this regard, the longer mRNA molecules are preferred over the shorter ones. In some embodiments, the HSD17B13 mRNA molecules comprise or consist of at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 200, at least about 300, at least about 400, or at least about 500 contiguous nucleotides of SEQ I D NO:3, SEQ ID NO:4, SEQ I D NO:7, or SEQ ID NO:ll, or SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:9, or SEQ ID NO: 10. In this regard, the longer mRNA molecules are preferred over the shorter ones.

[0182] The nucleic acid sequences for fou r HSD17B13 cDNA molecules encoding isoform proteins associated with the functional HSD17B13 protein are set forth in SEQ ID NO:12 (Transcript A), SEQ ID NO:13 (Transcript B), SEQ ID NO:16 (Transcript E), and SEQ ID NO:20 (Transcript I).

[0183] In some embodiments, an HSD17B13 cDNA molecule encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:21 (Isoform A). In some embodiments, the HSD17B13 cDNA molecule encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:21 (Isoform A). In some embodiments, the HSD17B13 cDNA molecu le encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:21 (Isoform A).

[0184] In some embodiments, an HSD17B13 cDNA molecule encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:22 (Isoform B). In some embodiments, the HSD17B13 cDNA molecule encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:22 (Isoform B). In some embodiments, the HSD17B13 cDNA molecu le encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:22 (Isoform B).

[0185] In some embodiments, an HSD17B13 cDNA molecule encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:25 (Isoform E). In some embodiments, the HSD17B13 cDNA molecule encoding an isoform protein associated with the functional

[0186] HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:25 (Isoform E). In some embodiments, the HSD17B13 cDNA molecu le encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:25 (Isoform E).

[0187] In some embodiments, an HSD17B13 cDNA molecule encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:29 (Isoform I). In some embodiments, the HSD17B13 cDNA molecule encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:29 (Isoform I). In some embodiments, the HSD17B13 cDNA molecule encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:29 (Isoform I).

[0188] In some embodiments, an HSD17B13 cDNA molecule encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:12 (Transcript A). I n some embodiments, the HSD17B13 cDNA molecule encoding an isoform protein associated with the fu nctional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:12 (Transcript A). In some embodiments, the HSD17B13 cDNA molecule encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence according to SEQ ID NO:12 (Transcript A).

[0189] In some embodiments, an HSD17B13 cDNA molecule encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:13 (Transcript B). In some embodiments, the HSD17B13 cDNA molecule encoding an isoform protein associated with the fu nctional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:13 (Transcript B). In some embodiments, the HSD17B13 cDNA molecule encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence according to SEQ ID NO:13 (Transcript B).

[0190] In some embodiments, an HSD17B13 cDNA molecule encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:16 (Transcript E). In some embodiments, the HSD17B13 cDNA molecule encoding an isoform protein associated with the fu nctional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:16 (Transcript E). In some embodiments, the HSD17B13 cDNA molecule encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence according to SEQ ID NO:16 (Transcript E).

[0191] In some embodiments, an HSD17B13 cDNA molecule encoding an isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:20 (Transcript I). In some embodiments, the HSD17B13 cDNA molecule encoding an isoform protein associated with the fu nctional HSD17B13 protein comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:20 (Transcript I). In some embodiments, the HSD17B13 cDNA molecule encoding the isoform protein associated with the functional HSD17B13 protein comprises or consists of a nucleic acid sequence according to SEQ ID NO:20 (Transcript I). The nucleic acid sequences for five HSD17B13 cDNA molecu les encoding isoform proteins associated with a loss-of-function are set forth in SEQ ID NO:14 (Transcript C), SEQ ID NO: 15 (Transcript D), SEQ I D NO:17 (Transcript F), SEQ I D NO:18 (Transcript G), and SEQ ID NO: 19 (Transcript H).

[0192] In some embodiments, an HSD17B13 cDNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90% at least about 91% at least about 92°% at least about 93% at least about 94% at least about 95% at least about 96% at least about 97% at least about 98% or at least about 99% sequence identity to SEQ ID NO:23 (Isoform C). In some embodiments, the HSD17B13 cDNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:23 (Isoform C). In some embodiments, the HSD17B13 cDNA molecule encoding the isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:23 (Isoform C).

[0193] In some embodiments, an HSD17B13 cDNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:24 (Isoform D). In some embodiments, the HSD17B13 cDNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:24 (Isoform D). In some embodiments, the HSD17B13 cDNA molecule encoding the isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:24 (Isoform D). In some embodiments, an HSD17B13 cDNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90% at least about 91% at least about 92°% at least about 93% at least about 94% at least about 95% at least about 96% at least about 97% at least about 98% or at least about 99% sequence identity to SEQ ID NO:26 (Isoform F). In some embodiments, the HSD17B13 cDNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:26 (Isoform F). In some embodiments, the HSD17B13 cDNA molecule encoding the isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:26 (Isoform F).

[0194] In some embodiments, an HSD17B13 cDNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:27 (Isoform G). In some embodiments, the HSD17B13 cDNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:27 (Isoform G). In some embodiments, the HSD17B13 cDNA molecule encoding the isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:27 (Isoform G).

[0195] In some embodiments, an HSD17B13 cDNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95% at least about 96°% at least about 97°% at least about 98°% or at least about 99% sequence identity to SEQ ID NO:28 (Isoform H). In some embodiments, the HSD17B13 cDNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises an amino acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:28 (Isoform H). In some embodiments, the HSD17B13 cDNA molecule encoding the isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that encodes an HSD17B13 isoform protein that comprises or consists of an amino acid sequence according to SEQ ID NO:28 (Isoform H).

[0196] In some embodiments, an HSD17B13 cDNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:14 (Transcript C). In some embodiments, the HSD17B13 cDNA molecu le encoding an isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:14 (Transcript C). In some embodiments, the HSD17B13 cDNA molecule encoding the isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence according to SEQ ID NO:14 (Transcript C).

[0197] In some embodiments, an HSD17B13 cDNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ I D NO:15 (Transcript D). In some embodiments, the HSD17B13 cDNA molecu le encoding an isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:15 (Transcript D). In some embodiments, the HSD17B13 cDNA molecu le encoding the isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence according to SEQ ID NO:15 (Transcript D). In some embodiments, an HSD17B13 cDNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 90% at least about 91°% at least about 92°% at least about 93°% at least about 94°% at least about 95°% at least about 96°% at least about 97°% at least about 98°% or at least about 99% sequence identity to SEQ ID NO:17 (Transcript F). In some embodiments, the HSD17B13 cDNA molecu le encoding an isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:17 (Transcript F). In some embodiments, the HSD17B13 cDNA molecule encoding the isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence according to SEQ ID NO:17 (Transcript F).

[0198] In some embodiments, an HSD17B13 cDNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:18 (Transcript G). I n some embodiments, the HSD17B13 cDNA molecu le encoding an isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:18 (Transcript G). In some embodiments, the HSD17B13 cDNA molecu le encoding the isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence according to SEQ ID NO:18 (Transcript G).

[0199] In some embodiments, an HSD17B13 cDNA molecule encoding an isoform protein associated with a loss-of-function comprises or consists of a nucleic acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:19 (Transcript H). In some embodiments, the HSD17B13 cDNA molecu le encoding an isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence that has at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:19 (Transcript H). In some embodiments, the HSD17B13 cDNA molecu le encoding the isoform protein associated with a loss-of-fu nction comprises or consists of a nucleic acid sequence according to SEQ ID NO:19 (Transcript H).

[0200] In some embodiments, the HSD17B13 cDNA molecules comprise less nucleotides than the entire cDNA sequence. In some embodiments, the HSD17B13 cDNA molecu les comprise or consist of at least about 5, at least about 8, at least about 10, at least about 12, at least about 15, at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 200, at least about 300, at least about 400, at least about 500, at least about 600, at least about 700, at least about 800, or at least about 900 contiguous nucleotides of SEQ ID NO:12, SEQ ID NO: 13, SEQ ID NO:16, or SEQ I D NO:20 or SEQ I D NO:14, SEQ I D NO:15, SEQ I D NO:17, SEQ I D NO:18, or SEQ ID NO:19. In some embodiments, the HSD17B13 cDNA molecu les comprise or consist of at least about 200 to at least about 500 contiguous nucleotides of SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:16, or SEQ I D NO:20 or SEQ I D NO:14, SEQ I D NO:15, SEQ I D NO:17, SEQ I D NO:18, or SEQ ID NO:19. In this regard, the longer cDNA molecules are preferred over the shorter ones. In some embodiments, the

[0201] HSD17B13 cDNA molecules comprise or consist of at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 200, at least about 300, at least about 400, or at least about 500 contiguous nucleotides of SEQ I D NO:12, SEQ ID NO:13, SEQ ID NO:16, or SEQ I D NO:20 or SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:18, or SEQ I D NO:19. In this regard, the longer cDNA molecules are preferred over the shorter ones.

[0202] The probes and primers described herein can be used to hybridize to any of the fu nctional or variant PNPLA3 genomic DNA molecules, mRNA molecules, or cDNA molecules derived from mRNA molecules described herein. The primers can be used, for example, to amplify portions of any of the functional or variant PNPLA3 genomic DNA molecules, mRNA molecules, or cDNA molecu les derived from mRNA molecu les described herein, so that the amplifications products can be, for example, detected or sequenced.

[0203] For example, the probes and primers can be used to hybridize to any of the wild type PNPLA3 genomic DNA molecu les described herein, including the wild type PNPLA3 genomic DNA molecule comprising SEQ ID NO:30. The probes and primers can also be used to hybridize to any of the wild type PNPLA3 mRNA molecules described herein, including the wild type PNPLA3 mRNA molecu les comprising SEQ ID NO:32 or SEQ ID NO:33. The probes and primers can also be used to hybridize to any of the wild type PNPLA3 cDNA molecu les described herein, including the wild type PNPLA3 cDNA molecules comprising SEQ ID NO:36 or SEQ ID NO:37.

[0204] The probes and primers can also be used to hybridize to any of the variant PNPLA3 genomic DNA molecules described herein, including the variant PNPLA3 genomic DNA molecule comprising SEQ ID NO:31. The probes and primers can also be used to hybridize to any of the variant PN PLA3 mRNA molecules described herein, including the variant PNPLA3 mRNA molecules comprising SEQ ID NO:34 or SEQ ID NO:35. The probes and primers can also be used to hybridize to any of the variant PNPLA3 cDNA molecules described herein, including the variant PN PLA3 cDNA molecules comprising SEQ ID NO:38 or SEQ ID NO:39.

[0205] The probes can be used, for example, to detect any of the functional or variant

[0206] HSD17B13 genomic DNA molecules, mRNA molecules, or cDNA molecu les derived from mRNA molecules described herein. The primers can be used, for example, to amplify portions of any of the functional or variant HSD17B13 genomic DNA molecules, mRNA molecules, or cDNA molecules derived from mRNA molecules described herein, so that the amplifications products can be, for example, detected or sequenced.

[0207] For example, the probes and primers can be used to hybridize to any of the functional HSD17B13 genomic DNA molecules described herein, including the functional HSD17B13 genomic DNA molecule comprising SEQ ID NO: l. The probes and primers can also be used to hybridize to any of the functional HSD17B13 RNA transcripts described herein, including the fu nctional HSD17B13 RNA transcripts comprising SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:48, or SEQ ID NO:52. The probes and primers can also be used to hybridize to any of the functional HSD17B13 DNA transcripts described herein, including the functional HSD17B13 DNA transcripts comprising SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:57, or SEQ ID NO:61. The probes and primers can also be used to hybridize to any of the functional HSD17B13 mRNA molecules described herein, including the functional HSD17B13 mRNA molecules comprising SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:7, or SEQ ID NO:ll. The probes and primers can also be used to hybridize to any of the functional HSD17B13 cDNA molecules described herein, including the fu nctional HSD17B13 cDNA molecules comprising SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:16, or SEQ I D NO:20.

[0208] The probes and primers can also be used to hybridize to any of the variant HSD17B13 genomic DNA molecules described herein, including the variant HSD17B13 genomic DNA molecule comprising SEQ ID NO:2. The probes and primers can also be used to hybridize to any of the variant HSD17B13 RNA transcripts described herein, including the variant HSD17B13 RNA transcripts comprising SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:50, or SEQ ID NO:51. The probes and primers can also be used to hybridize to any of the variant HSD17B13 DNA transcripts described herein, including the variant HSD17B13 DNA transcripts comprising SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:59, or SEQ I D NO:60. The probes and primers can also be used to hybridize to any of the variant HSD17B13 mRNA molecules described herein, including the variant HSD17B13 mRNA molecules comprising SEQ I D NO:5, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:9, or SEQ ID NO:10. The probes and primers can also be used to hybridize to any of the HSD17B13 cDNA molecules described herein, including the HSD17B13 cDNA molecules comprising SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO: 18, or SEQ I D NO:19.

[0209] In some embodiments, the probes and / or primers described herein comprise a nucleic acid sequence that specifically hybridizes to any of the nucleic acid molecules disclosed herein, or the complement thereof. In some embodiments, the probe or primer specifical ly hybridizes to any of the nucleic acid molecules disclosed herein under stringent conditions. The present disclosu re also provides nucleic acid molecu les having nucleic acid sequences that hybridize u nder moderate conditions to any of the nucleic acid molecules disclosed herein, or the complement thereof.

[0210] Appropriate stringency conditions which promote DNA hybridization include, for example, 6X sodium chloride / sodium citrate (SSC) at about 45°C, followed by a wash of 2X SSC at 50°C (see, also Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1- 6.3.6). Typically, stringent conditions for hybridization and detection will be those in which the salt concentration is less than about 1.5 M Na ion, typically about 0.01 to 1.0 M Na ion concentration (or other salts) at pH 7.0 to 8.3 and the temperature is at least about 30°C for short probes (e.g., 10 to 50 nucleotides) and at least about 60°C for longer probes (e.g., greater than 50 nucleotides). Stringent conditions may also be achieved with the addition of destabilizing agents such as formamide. Exemplary low stringency conditions include hybridization with a buffer solution of 30 to 35% formamide, 1 M NaCI, 1% SDS (sodium dodecyl su lfate) at 37°C, and a wash in IX to 2X SSC (20X SSC = 3.0 M NaCI / 0.3 M trisodium citrate) at 50 to 55°C. Exemplary moderate stringency conditions include hybridization in 40 to 45% formamide, 1.0 M NaCI, 1% SDS at 37°C, and a wash in 0.5X to IX SSC at 55 to 60°C. Exemplary high stringency conditions include hybridization in 50% formamide, 1 M NaCI, 1% SDS at 37°C, and a wash in 0.1X SSC at 60 to 65°C. Optionally, wash buffers may comprise about 0.1% to about 1% SDS. Duration of hybridization is generally less than about 24 hours, usually about 4 to about 12 hou rs. The du ration of the wash time will be at least a length of time sufficient to reach equilibrium.

[0211] In hybridization reactions, specificity is typically the function of post-hybridization washes, the critical factors being the ionic strength and temperature of the final wash solution. For DNA-DNA hybrids, the Tmcan be approximated from the equation of Meinkoth and Wahl, Anal. Biochem., 1984, 138, 267-284: Tm= 81.5°C + 16.6 (log M) + 0.41 (% GC) - 0.61 (% form) - 500 / L; where M is the molarity of monovalent cations, %GC is the percentage of guanosine and cytosine nucleotides in the DNA, % form is the percentage of formamide in the hybridization solution, and L is the length of the hybrid in base pairs. The Tmis the temperatu re (under defined ionic strength and pH) at which 50% of a complementary target sequence hybridizes to a perfectly matched probe. Tmis reduced by about 1°C for each 1% of mismatching; thus, Tm, hybridization, and / or wash conditions can be adjusted to hybridize to sequences of the desired identity. For example, if sequences with >90% identity are sought, the Tmcan be decreased 10°C. General ly, stringent conditions are selected to be about 5°C lower than the thermal melting point (Tm) for the specific sequence and its complement at a defined ionic strength and pH. However, severely stringent conditions can utilize a hybridization and / or wash at 1°C, 2°C, 3°C, or 4°C lower than the thermal melting point (Tm); moderately stringent conditions can utilize a hybridization and / or wash at 6°C, 7°C, 8°C, 9°C, or 10°C lower than the thermal melting point (Tm); low stringency conditions can utilize a hybridization and / or wash at 11°C, 12°C, 13°C, 14°C, 15°C, or 20°C lower than the thermal melting point (Tm). Using the equation, hybridization and wash compositions, and desired Tm, those of ordinary skill will understand that variations in the stringency of hybridization and / or wash solutions are inherently described. If the desired degree of mismatching results in a Tmof less than 45°C (aqueous solution) or 32°C (formamide solution), it is optimal to increase the SSC concentration so that a higher temperatu re can be used.

[0212] The probes described herein can be lin ked or fused to a label to aid in detection. The label can be directly detectable (e.g., fluorophore) or indirectly detectable (e.g., hapten, enzyme, or fluorophore quencher). Such labels can be detectable by spectroscopic,

[0213] photochemical, biochemical, immunochemical, or chemical means. Such labels include, for example, radiolabels that can be measured with radiation-counting devices; pigments, dyes or other chromogens that can be visually observed or measured with a spectrophotometer; spin labels that can be measured with a spin label analyzer; and fluorescent labels (e.g.,

[0214] fluorophores), where the output signal is generated by the excitation of a suitable molecular adduct and that can be visualized by excitation with light that is absorbed by the dye or can be measured with standard fluorometers or imaging systems. The label can also be, for example, a chemiluminescent substance, where the output signal is generated by chemical modification of the signal compound; a metal-containing substance; or an enzyme, where there occurs an enzyme-dependent secondary generation of signal, such as the formation of a colored product from a colorless substrate. The term "label" can also refer to a "tag" or hapten that can bind selectively to a conjugated molecule such that the conjugated molecule, when added subsequently along with a substrate, is used to generate a detectable signal. For example, one can use biotin as a tag and then use an avidin or streptavidin conjugate of horseradish peroxidate (HRP) to bind to the tag, and then use a calorimetric substrate (e.g.,

[0215] tetramethylbenzidine (TMB)) or a fluorogenic substrate to detect the presence of HRP.

[0216] Exemplary labels that can be used as tags to facilitate purification include, but are not limited to, myc, HA, FLAG or 3XFLAG, 6XHis or polyhistidine, glutathione-S-transferase (GST), maltose binding protein, an epitope tag, or the Fc portion of immunoglobulin. Numerous labels include, for example, particles, fluorophores, haptens, enzymes and their calorimetric, fluorogenic and chemiluminescent substrates and other labels.

[0217] The probe or primer can comprise any suitable length, non-limiting examples of which include at least about 5, at least about 8, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, or at least about 25 nucleotides in length. In some embodiments, the probe or primer comprises at least about 18 nucleotides in length to about 25 nucleotides in length. The probe or primer can comprise from about 10 to about 35, from about 10 to about 30, from about 10 to about 25, from about 12 to about 30, from about 12 to about 28, from about 12 to about 24, from about 15 to about 30, from about 15 to about 25, from about 18 to about 30, from about 18 to about 25, from about 18 to about 24, or from about 18 to about 22 nucleotides in length. In some embodiments, the probe or primer is from about 18 to about 30 nucleotides in length. Alternately, in some embodiments, the probe comprises or consists of at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 55, at least about 60, at least about 65, at least about 70, at least about 75, at least about 80, at least about 85, at least about 90, at least about 95, or at least about 100 nucleotides.

[0218] In some embodiments, the probes and / or primers can hybridize to at least about 15 contiguous nucleotides of a nucleic acid molecule that is at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to any of the wild type PNPLA3 or HSD17B13 nucleic acid molecules or variant PNPLA3 or HSD17B13 nucleic acid molecules described herein.

[0219] In some embodiments, the probe or primer comprises DNA. In some embodiments, the probe or primer comprises RNA.

[0220] The probes and primers described herein can also be alteration-specific probes and alteration-specific primers. The alteration-specific probe or alteration-specific primer can comprise a nucleic acid sequence which is complementary to and / or hybridizes, or specifically hybridizes, to a nucleic acid sequence encoding a variant PNPLA3 protein but which is not complementary to and / or hybridizes, or specifically hybridizes, to a nucleic acid sequence encoding a wild type PNPLA3 protein. In this context, "specifically hybridizes" means that the probe or primer (e.g., the alteration-specific probe or alteration-specific primer) does not hybridize to a nucleic acid molecule encoding a wild type PNPLA3 protein. Herein, the term "specifically hybridizes" means that the probe or primer exclusively hybridizes to the indicated nucleic acid molecule and not to another nucleic acid molecule. Accordingly, a probe or primer which specifically hybridizes to a nucleic acid molecule encoding a PNPLA3 protein comprising the I148M variation does not hybridize to a nucleic acid molecule encoding a PNPLA3 protein which does not comprise the I148M variation. The alteration-specific probe or alteration- specific primer can also comprise a nucleic acid sequence which is complementary to and / or hybridizes, or specifically hybridizes, to a nucleic acid sequence encoding a wild type PNPLA3 protein but which is not complementary to and / or hybridizes, or specifically hybridizes, to a nucleic acid sequence encoding a variant PNPLA3 protein. In this context, "specifically hybridizes" means that the probe or primer (e.g., the alteration-specific probe or alteration- specific primer) does not hybridize to a nucleic acid molecule encoding a variant PNPLA3 protein. The alteration-specific probe or alteration-specific primer can also comprise a nucleic acid sequence which is complementary to and / or hybridizes, or specifically hybridizes, to a nucleic acid sequence encoding a variant HSD17B13 protein but which is not complementary to and / or hybridizes, or specifically hybridizes, to a nucleic acid sequence encoding a functional HSD17B13 protein. In this context, "specifically hybridizes" means that the probe or primer (e.g., the alteration-specific probe or alteration-specific primer) does not hybridize to a nucleic acid molecule encoding a functional HSD17B13 protein. For example, in this context

[0221] "specifically hybridizes" means that the probe or primer does not hybridize to a nucleic acid molecule encoding a non-active / loss of function HSD17B13 protein. The alteration-specific probe or alteration-specific primer can also comprise a nucleic acid sequence which is complementary to and / or hybridizes, or specifically hybridizes, to a nucleic acid sequence encoding a functional HSD17B13 protein but which is not complementary to and / or hybridizes, or specifically hybridizes, to a nucleic acid sequence encoding a variant HSD17B13 protein. In this context, "specifically hybridizes" means that the probe or primer (e.g., the alteration- specific probe or alteration-specific primer) does not hybridize to a nucleic acid molecule encoding a variant HSD17B13 protein.

[0222] In some embodiments, the alteration-specific probe or alteration-specific primer comprises a nucleic acid sequence which is complementary to and / or hybridizes, or specifically hybridizes, to a portion of a PNPLA3 nucleic acid sequence that comprises a methionine at a position corresponding to position 148 according to SEQ ID NO:42, or comprises a methionine at a position corresponding to position 144 according to SEQ ID NO:43. In some embodiments, the alteration-specific probe or alteration-specific primer comprises a nucleic acid sequence which is complementary to and / or hybridizes, or specifically hybridizes, to the portion of the variant PNPLA3 genomic DNA that comprises an ATG codon at the positions corresponding to positions 5107 to 5109 according to SEQ ID NO:31. In some embodiments, the alteration- specific probe or alteration-specific primer comprises a nucleic acid sequence which is complementary to and / or hybridizes, or specifically hybridizes, to the portion of the variant PNPLA3 mRNA that comprises an AUG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:34. In some embodiments, the alteration-specific probe or alteration-specific primer comprises a nucleic acid sequence which is complementary to and / or hybridizes, or specifically hybridizes, to the portion of the variant PNPLA3 mRNA that comprises an AUG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:35. In some embodiments, the alteration-specific probe or alteration-specific primer comprises a nucleic acid sequence which is complementary to and / or hybridizes, or specifically hybridizes, to the portion of the variant PNPLA3 cDNA that comprises an ATG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:38. In some embodiments, the alteration-specific probe or alteration-specific primer comprises a nucleic acid sequence which is complementary to and / or hybridizes, or specifically hybridizes, to the portion of the variant PNPLA3 cDNA that comprises an ATG codon at the positions

[0223] corresponding to positions 430 to 432 according to SEQ ID NO:39.

[0224] In some embodiments, the alteration-specific probe or alteration-specific primer comprises a nucleic acid sequence which is complementary to and / or hybridizes, or specifically hybridizes, to the portion of the HSD17B13 genomic DNA that comprises an adenine at a position corresponding to position 12,667 according to SEQ I D NO:l. In some embodiments, the alteration-specific probe or alteration-specific primer comprises a nucleic acid sequence which is complementary to and / or hybridizes, or specifically hybridizes, to the portion of the

[0225] HSD17B13 genomic DNA that comprises a thymine at a position corresponding to position 12,667 according to SEQ ID NO:2.

[0226] In some embodiments, the portion of the nucleic acid molecu le to which the probe or primer is hybridized comprises from about 10 to about 200, from about 10 to about 150, from about 10 to about 100, from about 10 to about 50, from about 10 to about 40, from about 10 to about 30, or from about 10 to about 20 nucleotides, and comprises the codon corresponding to the position containing codon encoding the particular variation (e.g., I148M of PN PLA3 or the portion of the variant HSD17B13 protein that is different from the corresponding wild type HSD17B13 protein). In some preferred embodiments, the portion of the nucleic acid molecule to which the probe or primer is hybridized comprises from about 10 to about 50, from about 10 to about 40, from about 10 to about 30, or from about 10 to about 20 nucleotides, and comprises the codon corresponding to the position containing codon encoding the particular variation (e.g., I148M of PNPLA3 or the portion of the variant HSD17B13 protein that is different from the corresponding wild type HSD17B13 protein).

[0227] The kits described herein can comprise detection and / or amplification assay reagents that can be used for detecting and / or amplifying any of the wild type PNPLA3 and / or HSD17B13 nucleic acid molecules described herein and / or any of the variant PN PLA3 and / or HSD17B13 nucleic acid molecules described herein. In some embodiments, the kits for such detection and / or amplification can contain any of the reagents (e.g., probes and primers) described herein. In some embodiments, a basic kit can comprise a container having at least one probe or primer or at least two probes or primers, such as alteration-specific probes or alteration- specific primers, for a locus in any of the nucleic acid molecules disclosed herein. A kit can also optionally comprise instructions for use. A kit can also comprise other optional kit components, such as, for example, one or more of an allelic ladder directed to each of the loci amplified, a sufficient quantity of enzyme for amplification, amplification buffer to facilitate the

[0228] amplification, divalent cation solution to facilitate enzyme activity, dNTPs for strand extension during amplification, loading solution for preparation of the amplified material for

[0229] electrophoresis, genomic DNA as a template control, a size marker to insure that materials migrate as anticipated in the separation medium, and a protocol and manual to educate the user and limit error in use. The amounts of the various reagents in the kits also can be varied depending upon a number of factors, such as the optimum sensitivity of the process. It is within the scope of these teachings to provide test kits for use in manual applications or test kits for use with automated sample preparation, reaction set-up, detectors or analyzers. In some embodiments, the kits comprise at least one labeled probe (e.g., alteration-specific probe) for detection. In some embodiments, any of the kits disclosed herein can further comprise products and reagents required to carry out an annealing reaction, and instructions.

[0230] The present disclosure provides methods for detecting the presence of any of the wild type PNPLA3 proteins described herein. The present disclosure also provides methods for detecting the presence of any of the variant PNPLA3 proteins described herein. The present disclosure also provides methods for detecting the presence of any of the wild type PNPLA3 nucleic acid molecules described herein (e.g., genomic DNA molecules, mRNA molecules, and cDNA molecules) described herein. The present disclosure also provides methods for detecting the presence of any of the variant PNPLA3 nucleic acid molecules described herein (e.g., genomic DNA molecules, mRNA molecules, and cDNA molecules) described herein.

[0231] The present disclosure also provides methods for detecting the presence of any of the functional HSD17B13 proteins described herein. The present disclosure also provides methods for detecting the presence of any of the variant HSD17B13 proteins described herein. The present disclosure also provides methods for detecting the presence of any of the functional HSD17B13 nucleic acid molecules described herein (e.g., genomic DNA molecules, RNA transcripts, cDNA transcripts, mRNA molecules, and cDNA molecules) described herein. The present disclosu re also provides methods for detecting the presence of any of the variant HSD17B13 nucleic acid molecules described herein (e.g., genomic DNA molecu les, RNA transcripts, cDNA transcripts, mRNA molecu les, and cDNA molecules) described herein.

[0232] In some embodiments of any of the methods described herein, a fu nctional HSD17B13 protein, or nucleic acid molecu le encoding the same, is detected or sought to be detected in a su bject or patient. In some embodiments, the subject or patient comprises a functional HSD17B13 protein. In some embodiments, the functional HSD17B13 protein is one of the fu nctional HSD17B13 proteins described herein (which can be encoded by any of the nucleic acid molecu les described herein encoding the same). In some embodiments, a fu nctional HSD17B13 protein has at least 90%, at least 80%, at least 70%, at least 60%, at least 50%, at least 40%, at least 30%, at least 20%, at least 10%, at least 5%, or at least 1% of the biological activity of the HSD17B13 protein having the amino acid sequence according to SEQ ID NO:40. In some embodiments, a functional HSD17B13 protein has at least 90%, at least 80%, at least 70%, at least 60%, or at least 50% of the biological activity of the HSD17B13 protein having the amino acid sequence according to SEQ ID NO:40. In some embodiments, a functional HSD17B13 protein has at least 90%, at least 80%, at least 70%, at least 60%, at least 50%, at least 40%, at least 30%, at least 20%, at least 10%, at least 5%, or at least 1% of the biological activity of HSD17B13 protein having SEQ ID NO:40. In some embodiments, a functional HSD17B13 protein has at least 70%, at least 60%, at least 50%, at least 40%, at least 30%, at least 20%, at least 10%, at least 5%, or at least 1% of the biological activity of HSD17B13 protein having SEQ ID

[0233] NO:40. In some embodiments, a functional HSD17B13 protein has at least 50%, at least 40%, at least 30%, at least 20%, at least 10%, at least 5%, or at least 1% of the biological activity of HSD17B13 protein having SEQ ID NO:40. In some embodiments, a functional HSD17B13 protein has at least 30%, at least 20%, at least 10%, at least 5%, or at least 1% of the biological activity of HSD17B13 protein having SEQ ID NO:40. In some embodiments, a functional HSD17B13 protein has at least 90% of the biological activity of HSD17B13 protein having SEQ ID NO:40. In some embodiments, a functional HSD17B13 protein has at least 80% of the biological activity of HSD17B13 protein having SEQ ID NO:40. In some embodiments, a functional HSD17B13 protein has at least 70% of the biological activity of HSD17B13 protein having SEQ ID NO:40. In some embodiments, a functional HSD17B13 protein has at least 60% of the biological activity of

[0234] HSD17B13 protein having SEQ ID NO:40. In some embodiments, a functional HSD17B13 protein has at least 50% of the biological activity of HSD17B13 protein having SEQ ID NO:40. In some embodiments, a functional HSD17B13 protein has at least 40% of the biological activity of HSD17B13 protein having SEQ ID NO:40. In some embodiments, a functional HSD17B13 protein has at least 30% of the biological activity of HSD17B13 protein having SEQ ID NO:40. In some embodiments, a functional HSD17B13 protein has at least 20% of the biological activity of HSD17B13 protein having SEQ ID NO:40. In some embodiments, a functional HSD17B13 protein has at least 10% of the biological activity of HSD17B13 protein having SEQ ID NO:40. In some embodiments, a functional HSD17B13 protein has at least 5% of the biological activity of HSD17B13 protein having SEQ ID NO:40. In some embodiments, a functional HSD17B13 protein has at least 1% of the biological activity of HSD17B13 protein having SEQ ID NO:40. In some embodiments, the activity of an HSD17B13 protein (e.g., functionality) can be determined by, for example, performing an oxidoreductase activity assay.

[0235] It is understood that gene sequences within a population and mRNAs and proteins encoded by such genes can vary due to polymorphisms such as single-nucleotide

[0236] polymorphisms. The sequences provided herein are only exemplary sequences. Other sequences for the variant PNPLA3 and HSD17B13 genomic DNA, mRNA, cDNA, and polypeptide are also possible.

[0237] The biological sample can be derived from any cell, tissue, or biological fluid from the subject. The sample may comprise any clinically relevant tissue, such as a bone marrow sample, a tumor biopsy, a fine needle aspirate, or a sample of bodily fluid, such as blood, gingival crevicular fluid, plasma, serum, lymph, ascitic fluid, cystic fluid, or urine. In some embodiments, the sample comprises a buccal swab. The sample used in the methods disclosed herein will vary based on the assay format, nature of the detection method, and the tissues, cells, or extracts that are used as the sample. A biological sample can be processed differently depending on the assay being employed. For example, when detecting a variant PNPLA3 nucleic acid molecule, preliminary processing designed to isolate or enrich the sample for the genomic DNA can be employed. A variety of techniques can be used for this purpose. When detecting the level of variant PNPLA3 mRNA, different techniques can be used enrich the biological sample with mRNA. Various methods to detect the presence or level of an mRNA or the presence of a particular variant genomic DNA locus can be used.

[0238] In some embodiments, the presence or absence of a particular PNPLA3 protein or

[0239] HSD17B13 protein (e.g., functional or variant) is detected by sequencing at least a portion of the protein to determine whether the protein comprises an amino acid sequence encoding any of the variant PNPLA3 proteins or HSD17B13 proteins (e.g., functional or variant) described herein. In some embodiments, the presence or absence of a particular PNPLA3 protein or HSD17B13 protein (e.g., functional or variant) is detected by performing an immunoassay, such as an ELISA, to determine whether any of the variant PNPLA3 proteins or HSD17B13 proteins (e.g., functional or variant) described herein are present in the sample.

[0240] In some embodiments, the portion of the protein sequenced comprises from about 5 to about 100, from about 5 to about 50, from about 5 to about 40, from about 5 to about 30, from about 5 to about 20, or from about 5 to about 10 amino acids, and comprises the position corresponding to the position containing the variation (e.g., I148M of PNPLA3 or the portion of the variant HSD17B13 protein that is different from the corresponding wild type HSD17B13 protein). In some preferred embodiments, the portion of the protein sequenced comprises from about 5 to about 20, or from about 5 to about 10 amino acids, and comprises the position corresponding to the position containing the variation (e.g., I148M of PNPLA3 or the portion of the variant HSD17B13 protein that is different from the corresponding wild type HSD17B13 protein).

[0241] Illustrative non-limiting examples of protein sequencing techniques include, but are not limited to, mass spectrometry and Edman degradation. Illustrative examples of immunoassays include, but are not limited to, immunoprecipitation, Western blot, immunohistochemistry, ELISA, immunocytochemistry, flow cytometry, and immuno-PCR. Polyclonal or monoclonal antibodies detectably labeled using various techniques (e.g., calorimetric, fluorescent, chemiluminescent, or radioactive) are suitable for use in the immunoassays.

[0242] In some embodiments, the presence or absence of a particular PNPLA3 nucleic acid molecule or HSD17B13 nucleic acid molecule (e.g., functional or variant genomic DNA, mRNA, cDNA, RNA transcript, or cDNA transcript) is detected by sequencing at least a portion of the nucleic acid molecule to determine whether the nucleic acid molecule comprises a nucleic acid sequence according to any of the variant PNPLA3 nucleic acid molecules or HSD17B13 nucleic acid molecules (e.g., functional or variant) described herein.

[0243] In some embodiments, the portion of the nucleic acid molecule sequenced comprises from about 10 to about 200, from about 10 to about 150, from about 10 to about 100, from about 10 to about 50, from about 10 to about 40, from about 10 to about 30, or from about 10 to about 20 nucleotides, and comprises the codon corresponding to the position containing codon encoding the particular variation (e.g., I148M of PN PLA3 or the portion of the variant HSD17B13 protein that is different from the corresponding wild type HSD17B13 protein). In some preferred embodiments, the portion of the nucleic acid molecule sequenced comprises from about 10 to about 50, from about 10 to about 40, from about 10 to about 30, or from about 10 to about 20 nucleotides, and comprises the codon corresponding to the position containing codon encoding the particular variation (e.g., I148M of PNPLA3 or the portion of the variant HSD17B13 protein that is different from the corresponding wild type HSD17B13 protein).

[0244] In some embodiments, the methods of detecting the presence or absence of any of the particular PNPLA3 nucleic acid molecules or HSD17B13 nucleic acid molecules (e.g., any of the functional or variant genomic DNA molecu les, mRNA molecu les, cDNA molecules, RNA transcripts, or cDNA transcripts) described herein in a subject, comprise: performing an assay on a biological sample obtained from the subject, which assay determines whether a nucleic acid molecu le in the biological sample comprises any of the particular PNPLA3 nucleic acid molecules or HSD17B13 nucleic acid molecu les (e.g., any of the functional or variant genomic DNA molecules, mRNA molecules, cDNA molecu les, RNA transcripts, or cDNA transcripts) described herein. In some embodiments, the biological sample comprises a cel l or cell lysate. Such methods can further comprise, for example, obtaining a biological sample from the su bject, optionally reverse transcribing the mRNA into cDNA, and performing the assay. Such assays can comprise, for example, determining the identity of particular positions of the particu lar nucleic acid molecules described herein.

[0245] For example, the assay can comprise the use of alteration-specific probes or alteration- specific primers that comprise a nucleic acid sequence which is complementary to and / or hybridizes, or specifically hybridizes, to a portion of a PNPLA3 nucleic acid sequence that comprises a methionine at a position corresponding to position 148 according to SEQ ID NO:42, or comprises a methionine at a position corresponding to position 144 according to SEQ ID NO:43, or a portion adjacent thereto. In some embodiments, the assay can comprise the use of alteration-specific probes or alteration-specific primers that comprise a nucleic acid sequence which is complementary to and / or hybridizes, or specifically hybridizes, to the portion of the variant PN PLA3 genomic DNA that comprises an ATG codon at the positions corresponding to positions 5107 to 5109 according to SEQ I D NO:31, or a portion adjacent thereto. In some embodiments, the assay can comprise the use of alteration-specific probes or alteration- specific primers that comprise a nucleic acid sequence which is complementary to and / or hybridizes, or specifically hybridizes, to the portion of the variant PNPLA3 mRNA that comprises an AUG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:34, or a portion adjacent thereto. In some embodiments, the assay can comprise the use of alteration-specific probes or alteration-specific primers that comprise a nucleic acid sequence which is complementary to and / or hybridizes, or specifically hybridizes, to the portion of the variant PN PLA3 mRNA that comprises an AUG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:35, or a portion adjacent thereto. In some embodiments, the assay can comprise the use of alteration-specific probes or alteration- specific primers that comprise a nucleic acid sequence which is complementary to and / or hybridizes, or specifically hybridizes, to the portion of the variant PNPLA3 cDNA that comprises an ATG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:38, or a portion adjacent thereto. In some embodiments, the assay can comprise the use of alteration-specific probes or alteration-specific primers that comprise a nucleic acid sequence which is complementary to and / or hybridizes, or specifically hybridizes, to the portion of the variant PN PLA3 cDNA that comprises an ATG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:39, or a portion adjacent thereto.

[0246] In some embodiments, the assay can comprise the use of alteration-specific probes or alteration-specific primers that comprise a nucleic acid sequence which is complementary to and / or hybridizes, or specifically hybridizes, to the portion of the HSD17B13 genomic DNA that comprises an adenine at a position corresponding to position 12,667 according to SEQ ID NO:l, or a portion adjacent thereto. In some embodiments, the assay can comprise the use of alteration-specific probes or alteration-specific primers that comprise a nucleic acid sequence which is complementary to and / or hybridizes, or specifically hybridizes, to the portion of the HSD17B13 genomic DNA that comprises a thymine at a position corresponding to position 12,667 according to SEQ ID NO:2, or a portion adjacent thereto.

[0247] In some embodiments, the assay comprises: sequencing at least a portion of the nucleic acid molecules described herein present in the biological sample from the subject, wherein the portion sequenced includes the positions disclosed herein. For example, the portion sequenced can be a portion of a PNPLA3 nucleic acid sequence that comprises a methionine at a position corresponding to position 148 according to SEQ ID NO:42, or comprises a methionine at a position corresponding to position 144 according to SEQ ID NO:43. I n some embodiments, the portion sequenced can be portion of the variant PNPLA3 genomic DNA that comprises an ATG codon at the positions corresponding to positions 5107 to 5109 according to SEQ ID NO:31. In some embodiments, the portion sequenced can be a portion of the variant PNPLA3 mRNA that comprises an AUG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:34. In some embodiments, the portion sequenced can be a portion of the variant PNPLA3 mRNA that comprises an AUG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:35. In some embodiments, the portion sequenced can be a portion of the variant PN PLA3 cDNA that comprises an ATG codon at the positions corresponding to positions 442 to 444 according to SEQ I D NO:38. In some embodiments, the portion sequenced can be a portion of the variant PNPLA3 cDNA that comprises an ATG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:39.

[0248] In some embodiments, the portion sequenced can be a portion of the HSD17B13 genomic DNA that comprises an adenine at a position corresponding to position 12,667 according to SEQ ID NO:l. In some embodiments, the portion sequenced can be a portion of the HSD17B13 genomic DNA that comprises a thymine at a position corresponding to position 12,667 according to SEQ ID NO:2.

[0249] In some embodiments, the assay comprises: a) contacting the biological sample with a primer (or alteration-specific primer) hybridizing to the regions adjacent to the portions of the nucleic acid molecules identified herein (e.g., adjacent to a portion of a PNPLA3 nucleic acid sequence that comprises a methionine at a position corresponding to position 148 according to SEQ ID NO:42, or comprises a methionine at a position corresponding to position 144 according to SEQ ID NO:43; adjacent to a portion of the variant PNPLA3 genomic DNA that comprises an ATG codon at the positions corresponding to positions 5107 to 5109 according to SEQ I D NO:31; adjacent to a portion of the variant PNPLA3 mRNA that comprises an AUG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:34; adjacent to a portion of the variant PNPLA3 mRNA that comprises an AUG codon at the positions

[0250] corresponding to positions 430 to 432 according to SEQ ID NO:35; adjacent to a portion of the variant PN PLA3 cDNA that comprises an ATG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:38; adjacent to a portion of the variant PNPLA3 cDNA that comprises an ATG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:39; adjacent to a portion of the HSD17B13 genomic DNA that comprises an adenine at a position corresponding to position 12,667 according to SEQ ID NO:l; or adjacent to a portion of the HSD17B13 genomic DNA that comprises a thymine at a position corresponding to position 12,667 according to SEQ I D NO:2); b) extending the primer at least th rough the position of the nucleic acid molecules corresponding to nucleotide positions beyond the altered site (e.g., the portion of a PNPLA3 nucleic acid sequence that comprises a methionine at a position corresponding to position 148 according to SEQ ID NO:42, or comprises a methionine at a position corresponding to position 144 according to SEQ ID NO:43; the portion of the variant PN PLA3 genomic DNA that comprises an ATG codon at the positions corresponding to positions 5107 to 5109 according to SEQ I D NO:31; the portion of the variant PNPLA3 mRNA that comprises an AUG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:34; the portion of the variant PNPLA3 mRNA that comprises an AUG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:35; the portion of the variant PN PLA3 cDNA that comprises an ATG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:38; the portion of the variant PNPLA3 cDNA that comprises an ATG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:39; the portion of the HSD17B13 genomic DNA that comprises an adenine at a position corresponding to position 12,667 according to SEQ ID NO:l; or the portion of the HSD17B13 genomic DNA that comprises a thymine at a position corresponding to position 12,667 according to SEQ ID NO:2); and c) determining whether the extension product of the primer comprises the nucleic acid sequence of any of the variant or wild type PNPLA3 or HSD17B13 nucleic acid molecules described herein.

[0251] In some embodiments, on ly PNPLA3 genomic DNA is analyzed. In some embodiments, only PNPLA3 mRNA is analyzed. In some embodiments, only PNPLA3 cDNA obtained from PNPLA3 mRNA is analyzed. In some embodiments, only HSD17B13 genomic DNA is analyzed. In some embodiments, only HSD17B13 mRNA is analyzed. In some embodiments, only HSD17B13 cDNA obtained from HSD17B13 mRNA is analyzed. In some embodiments, only HSD17B13 RNA transcripts is analyzed. In some embodiments, only HSD17B13 cDNA obtained from HSD17B13 RNA transcripts is analyzed.

[0252] In some embodiments, the assay comprises contacting the biological sample with a primer or probe that specifically hybridizes to any of the particular variant PNPLA3 nucleic acid molecules or variant HSD17B13 nucleic acid molecules (e.g., any of the variant genomic DNA molecules, mRNA molecules, cDNA molecules, RNA transcripts, or cDNA transcripts) described herein and not the corresponding functional nucleic acid molecu les under stringent conditions, and determining whether hybridization has occurred.

[0253] In some embodiments, the assay comprises contacting the biological sample with a primer or probe that specifically hybridizes to any of the particu lar variant PNPLA3 nucleic acid molecules (e.g., any of the variant genomic DNA molecules, mRNA molecu les, cDNA molecu les, RNA transcripts, or cDNA transcripts) or nucleic acid molecules encoding a functional HSD17B13 protein (e.g., any of the genomic DNA molecu les, mRNA molecu les, cDNA molecules, RNA transcripts, or cDNA transcripts encoding a functional HSD17B13 protein) described herein and not to the corresponding nucleic acid molecules encoding wild type PNPLA3 or variant

[0254] HSD17B13, respectively, under stringent conditions, and determining whether hybridization has occu rred.

[0255] In some embodiments, the assay comprises RNA sequencing (RNA-Seq). In some embodiments, the assays also comprise reverse transcribing mRNA into cDNA via the reverse transcriptase polymerase chain reaction (RT-PCR).

[0256] Such probes and primers can hybridize specifically to a target sequence under high stringency hybridization conditions. Probes and primers may have complete nucleic acid sequence identity of contiguous nucleotides with the target sequence, although probes differing from the target nucleic acid sequence and that retain the ability to specifically detect and / or identify a target nucleic acid sequence may be designed by conventional methods. Accordingly, probes and primers can share at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% sequence identity or complementarity to the target nucleic acid molecule.

[0257] When a probe is hybridized with a nucleic acid molecu le in a biological sample under conditions that allow for the binding of the probe to the nucleic acid molecu le, this binding can be detected and allow for an indication of the presence of the particu lar variant or wild type PNPLA3 or variant or functional HSD17B13 locus or the presence or the level of the particular variant or wild type PNPLA3 or variant or functional HSD17B13 mRNA or cDNA in the biological sample. Such identification of a bound probe has been described. The specific probe may comprise a sequence of at least about 80%, from about 80% to about 85%, from about 85% to about 90%, from about 90% to about 95%, and from about 95% to about 100% identical (or complementary) to a specific region of a variant or wild type PN PLA3 or variant or functional HSD17B13 gene. The specific probe may comprise a sequence of at least about 80%, from about 80% to about 85%, from about 85% to about 90%, from about 90% to about 95%, and from about 95% to about 100% identical (or complementary) to a specific region of a variant or wild type PNPLA3 or variant or functional HSD17B13 mRNA. The specific probe may comprise a sequence of at least about 80%, from about 80% to about 85%, from about 85% to about 90%, from about 90% to about 95%, and from about 95% to about 100% identical (or

[0258] complementary) to a specific region of a variant or wild type PN PLA3 or variant or functional HSD17B13 cDNA.

[0259] In some embodiments, to determine whether a particular nucleic acid complement of a biological sample comprises a nucleic acid sequence encoding a particular functional or variant PN PLA3 protein or HSD17B13 protein, the biological sample may be subjected to a nucleic acid amplification method using a primer pair that includes a first primer derived from the 5' flanking sequence adjacent to positions encoding a site of interest (e.g., any of the positions described herein), and a second primer derived from the 3' flanking sequence adjacent to positions encoding the same site of interest, to produce an amplicon that is diagnostic for the presence of the particular functional or variant PNPLA3 protein or HSD17B13 protein. For example, with regard to PNPLA3 the amplicon may comprise a nucleotide sequence encoding the position which corresponds to position 148 according to SEQ ID NO: 42. With regard to HSD17B13 the amplicon may comprise a nucleotide sequence which corresponds to positions 5107 to 5109 according to SEQ ID NO: 31. In some embodiments, the amplicon may range in length from the combined length of the primer pairs plus one nucleotide base pair to any length of amplicon producible by a DNA amplification protocol. This distance can range from one nucleotide base pair up to the limits of the amplification reaction, or about twenty thousand nucleotide base pairs. Optionally, the primer pair flan ks a region including positions encoding the site of interest and at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more nucleotides on each side of positions encoding the site of interest. Similar amplicons can be generated from the mRNA and / or cDNA sequences.

[0260] Representative methods for preparing and using probes and primers are described, for example, in Molecular Cloning: A Laboratory Manual, 2nd Ed., Vol. 1-3, ed. Sambrook ef al., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. 1989 (hereinafter, "Sambrook ef al., 1989"); Current Protocols in Molecular Biology, ed. Ausubel ef al., Greene Pu blishing and Wiley-lnterscience, New York, 1992 (with periodic updates) (hereinafter, "Ausubel ef al., 1992"); and I nnis ef al., PCR Protocols: A Guide to Methods and Applications, Academic Press: San Diego, 1990). PCR primer pairs can be derived from a known sequence, for example, by using computer programs intended for that purpose, such as the PCR primer analysis tool in Vector NTI version 10 (Informax Inc., Bethesda Md.); PrimerSelect (DNASTAR Inc., Madison, Wis.); and Primer3 (Version 0.4.0.COPYRGT., 1991, Whitehead Institute for Biomedical

[0261] Research, Cambridge, Mass.). Additionally, the sequence can be visually scanned and primers manually identified using guidelines.

[0262] Any nucleic acid hybridization or amplification or sequencing method can be used to specifically detect the presence of the functional or variant PNPLA3 or HSD17B13 gene locus and / or the level of functional or variant PNPLA3 or HSD17B13 mRNA or cDNA produced from mRNA. In some embodiments, the nucleic acid molecu le can be used either as a primer to amplify a region of the fu nctional or variant PNPLA3 or HSD17B13 nucleic acid or the nucleic acid molecu le can be used as a probe that specifically hybridizes, for example, under stringent conditions, to a nucleic acid molecule comprising the functional or variant PNPLA3 or

[0263] HSD17B13 gene locus or a nucleic acid molecule comprising a functional or variant PNPLA3 or HSD17B13 mRNA or cDNA produced from mRNA.

[0264] A variety of techniques are available in the art including, for example, nucleic acid sequencing, nucleic acid hybridization, and nucleic acid amplification. Il lustrative examples of nucleic acid sequencing techniques include, but are not limited to, chain terminator (Sanger) sequencing and dye terminator sequencing.

[0265] Other methods involve nucleic acid hybridization methods other than sequencing, including using labeled primers or probes directed against purified DNA, amplified DNA, and fixed cell preparations (fluorescence in situ hybridization (FISH)). In some methods, a target nucleic acid may be amplified prior to or simultaneous with detection. Illustrative examples of nucleic acid amplification techniques include, but are not limited to, polymerase chain reaction (PCR), ligase chain reaction (LCR), strand displacement amplification (SDA), and nucleic acid sequence based amplification (NASBA). Other methods include, but are not limited to, ligase chain reaction, strand displacement amplification, and thermophilic SDA (tSDA).

[0266] Any method can be used for detecting either the non-amplified or amplified polynucleotides including, for example, Hybridization Protection Assay (HPA), quantitative evaluation of the amplification process in real-time, and determining the quantity of target sequence initially present in a sample, but which is not based on a real-time amplification. Also provided are methods for identifying nucleic acids which do not necessarily require sequence amplification and are based on, for example, the methods of Southern (DNA:DNA) blot hybridizations, in situ hybridization (ISH), and fluorescence in situ hybridization (FISH) of chromosomal material. Southern blotting can be used to detect specific nucleic acid sequences. In such methods, nucleic acid that is extracted from a sample is fragmented, electrophoretically separated on a matrix gel, and transferred to a membrane filter. The filter bound nucleic acid is subject to hybridization with a labeled probe complementary to the sequence of interest. Hybridized probe bound to the filter is detected. In any such methods, the process can include hybridization using any of the probes described or exemplified herein.

[0267] In hybridization techniques, stringent conditions can be employed such that a probe or primer will specifically hybridize to its target. In some embodiments, a polynucleotide primer or probe under stringent conditions will hybridize to its target sequence (e.g., the functional or variant PN PLA3 or HSD17B13 locus, functional or variant PNPLA3 or HSD17B13 mRNA, or fu nctional or variant PNPLA3 or HSD17B13 cDNA) to a detectably greater degree than to other sequences (e.g., the corresponding functional or variant PNPLA3 or HSD17B13 locus, functional or variant PNPLA3 or HSD17B13 mRNA, or functional or variant PNPLA3 or HSD17B13 cDNA), such as, at least 2-fold, at least 3-fold, at least 4-fold, or more over background, including over 10-fold over background. In some embodiments, a polynucleotide primer or probe under stringent conditions wil l hybridize to its target sequence to a detectably greater degree than to other sequences by at least 2-fold. In some embodiments, a polynucleotide primer or probe u nder stringent conditions will hybridize to its target sequence to a detectably greater degree than to other sequences by at least 3-fold. In some embodiments, a polynucleotide primer or probe under stringent conditions will hybridize to its target sequence to a detectably greater degree than to other sequences by at least 4-fold. In some embodiments, a polynucleotide primer or probe under stringent conditions will hybridize to its target sequence to a detectably greater degree than to other sequences by over 10-fold over backgrou nd. Stringent conditions are sequence-dependent and will be different in different circu mstances. By controlling the stringency of the hybridization and / or washing conditions, target sequences that are 100% complementary to the probe can be identified (homologous probing). Alternately, stringency conditions can be adjusted to al low some mismatching in sequences so that lower degrees of identity are detected (heterologous probing). In some embodiments, the detecting step comprises: amplifying at least a portion of the nucleic acid molecu le that encodes a site of interest (e.g., any of the positions described herein); labeling the nucleic acid molecule with a detectable label; contacting the labeled nucleic acid with a support comprising a probe, wherein the probe comprises a nucleic acid sequence which hybridizes under stringent conditions to a nucleic acid sequence encoding the a site of interest (e.g., any of the positions described herein); and detecting the detectable label.

[0268] In some embodiments, the detecting step comprises: amplifying at least a portion of the nucleic acid molecu le that encodes a PNPLA3 or HSD17B13 protein, wherein the amplified nucleic acid molecule encodes an amino acid sequence which comprises a site of interest (e.g., any of the positions described herein); labeling the nucleic acid molecu le with a detectable label; contacting the labeled nucleic acid with a support comprising a probe, wherein the probe comprises a nucleic acid sequence which hybridizes under stringent conditions to a nucleic acid sequence encoding a site of interest (e.g., any of the positions described herein); and detecting the detectable label. Any of the nucleic acid molecules disclosed herein can be amplified. For example, any of the genomic DNA, cDNA, or mRNA molecu les disclosed herein can be amplified. I n some embodiments, the nucleic acid molecule is mRNA and the method further comprises reverse-transcribing the mRNA into a cDNA prior to the amplifying step.

[0269] In some embodiments, the detecting step comprises: contacting the nucleic acid molecule that encodes a PNPLA3 or HSD17B13 protein with a probe comprising a detectable label, wherein the probe comprises a nucleic acid sequence which hybridizes under stringent conditions to a nucleic acid sequence encoding the variant PNPLA3 or HSD17B13 protein, and detecting the detectable label. I n some embodiments, the detecting step comprises: contacting the nucleic acid molecu le that encodes a PNPLA3 or HSD17B13 protein with a probe comprising a detectable label, wherein the probe comprises a nucleic acid sequence which hybridizes u nder stringent conditions to a nucleic acid sequence encoding a site of interest (e.g., any of the positions described herein), and detecting the detectable label. In some embodiments, the nucleic acid molecule is present within a cell obtained from the hu man subject, such that the detection is according to an in situ hybridization technique.

[0270] Other assays that can be used in the methods disclosed herein include, for example, reverse transcription polymerase chain reaction (RT-PCR) or quantitative RT-PCR (qRT-PCR). Yet other assays that can be used in the methods disclosed herein include, for example, RNA sequencing (RNA-Seq) followed by detection of the presence and quantity of variant mRNA or cDNA in the biological sample.

[0271] In some embodiments, the detecting step comprises amplifying at least a portion of the nucleic acid molecu le that encodes a particu lar PNPLA3 or HSD17B13 protein, labeling the amplified nucleic acid molecule with a detectable label, contacting the labeled nucleic acid molecule with a support comprising a probe, wherein the probe comprises a nucleic acid sequence which specifically hybridizes, including, for example, under stringent conditions, to a nucleic acid sequence encoding the particular PNPLA3 or HSD17B13 protein, and detecting the detectable label. In some embodiments, the detecting step comprises amplifying at least a portion of the nucleic acid molecu le that encodes a particular PNPLA3 or HSD17B13 protein, labeling the amplified nucleic acid molecule with a detectable label, contacting the labeled nucleic acid molecule with a su pport comprising a probe, wherein the probe comprises a nucleic acid sequence which specifically hybridizes, including, for example, under stringent conditions, to a nucleic acid sequence encoding a site of interest (e.g., the portion of a PNPLA3 nucleic acid sequence that encodes a methionine at a position corresponding to position 148 according to SEQ ID NO:42, or encodes a methionine at a position corresponding to position 144 according to SEQ ID NO:43; the portion of the variant PNPLA3 genomic DNA that comprises an ATG codon at the positions corresponding to positions 5107 to 5109 according to SEQ ID NO:31; the portion of the variant PNPLA3 mRNA that comprises an AUG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:34; the portion of the variant

[0272] PNPLA3 mRNA that comprises an AUG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:35; the portion of the variant PNPLA3 cDNA that comprises an ATG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:38; the portion of the variant PNPLA3 cDNA that comprises an ATG codon at the positions

[0273] corresponding to positions 430 to 432 according to SEQ ID NO:39; the portion of the HSD17B13 genomic DNA that comprises an adenine at a position corresponding to position 12,667 according to SEQ ID NO:l; or the portion of the HSD17B13 genomic DNA that comprises a thymine at a position corresponding to position 12,667 according to SEQ I D NO:2), and detecting the detectable label. If the nucleic acid includes mRNA, the method may further comprise reverse-transcribing the mRNA into a cDNA prior to the amplifying step. In some embodiments, the determining step comprises contacting the nucleic acid molecule that encodes a particu lar PNPLA3 or HSD17B13 protein with a probe comprising a detectable label and detecting the detectable label.

[0274] The disclosu re provides methods for identifying a human subject as a candidate for treating or inhibiting a liver disease by inhibiting hyd roxysteroid 17-beta dehydrogenase 13 (HSD17B13), the method comprising determining whether or not a sample from the subject comprises a first nucleic acid encoding a patatin like phospholipase domain containing 3 (PNPLA3) protein comprising an I148M variation and a second nucleic acid encoding a fu nctional HSD17B13 protein, and / or a PNPLA3 protein comprising an I148M variation and a fu nctional HSD17B13 protein, and identifying the subject as a candidate for treating or inhibiting a liver disease by inhibiting HSD17B13 when both the first and second nucleic acids are detected and / or both of the proteins are detected. In some embodiments, the su bject is obese. In some embodiments, the subject has a fatty liver. In some embodiments, the first nucleic acid molecule comprises genomic DNA. In some embodiments, the genomic DNA comprises an ATG codon at the positions corresponding to positions 5107 to 5109 according to SEQ ID NO:31. In some embodiments, the genomic DNA comprises the nucleotide sequence according to SEQ ID NO:31. In some embodiments, the first nucleic acid molecule comprises mRNA. In some embodiments, the mRNA comprises an AUG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:34. In some embodiments, the mRNA comprises the nucleotide sequence according to SEQ ID NO:34. I n some embodiments, the mRNA comprises an AUG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:35. In some embodiments, the mRNA comprises the nucleotide sequence according to SEQ ID NO:35. In some embodiments, the first nucleic acid molecule comprises a cDNA obtained from mRNA. In some embodiments, the cDNA comprises an ATG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:38. In some embodiments, the cDNA comprises the nucleotide sequence according to SEQ I D NO:38. I n some embodiments, the cDNA comprises an ATG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:39. In some embodiments, the cDNA comprises the nucleotide sequence according to SEQ ID NO:39. In some embodiments, detecting the first nucleic acid comprises sequencing at least a portion of the first nucleic acid and the portion comprises the codon which encodes the I148M variation. In some embodiments, detecting the first nucleic acid comprises hybridizing the first nucleic acid with a probe or primer that specifically hybridizes to a portion of the first nucleic acid, wherein the portion comprises the codon encoding the I148M variation. In some embodiments, the probe or primer is an al lele- specific probe or primer. In some embodiments, the probe or primer comprises a label. I n some embodiments, the methods further comprise determining whether the subject is homozygous or heterozygous for the I148M variation.

[0275] In some embodiments, the second nucleic acid comprises genomic DNA. In some embodiments, the genomic DNA comprises an adenine at a position corresponding to position 12,667 according to SEQ ID NO:l. In some embodiments, the genomic DNA comprises SEQ ID NO: l. In some embodiments, the second nucleic acid molecule comprises mRNA. In some embodiments, the mRNA comprises SEQ ID NO:3. In some embodiments, the mRNA comprises SEQ ID NO:4. In some embodiments, the mRNA comprises SEQ I D NO:7. In some embodiments, the mRNA comprises SEQ ID NO: ll. In some embodiments, the second nucleic acid molecule comprises cDNA obtained from mRNA. In some embodiments, the cDNA comprises SEQ ID NO: 12. In some embodiments, the cDNA comprises SEQ ID NO:13. In some embodiments, the cDNA comprises SEQ ID NO:16. In some embodiments, the cDNA comprises SEQ ID NO:20. In some embodiments, detecting the second nucleic acid comprises sequencing the second nucleic acid. In some embodiments, detecting the second nucleic acid comprises hybridizing the second nucleic acid with a probe or primer that specifically hybridizes to the second nucleic acid. In some embodiments, the probe or primer is an allele-specific probe or primer. In some embodiments, the probe or primer comprises a label. In some embodiments, the methods fu rther comprise determining whether the subject is homozygous or heterozygous for the second nucleic acid encoding a functional HSD17B13 protein in the sample.

[0276] The present disclosu re provides methods of identifying a subject who is a candidate for HSD17B13 in hibition, the method comprising determining whether or not a sample from the su bject comprises a nucleic acid encoding a PNPLA3 llel48Met variant or PNPLA3 llel44Met variant. The present disclosure also provides methods for identifying a hu man subject as a candidate for treating or inhibiting a liver disease by inhibiting HSD17B13, the method comprising determining whether or not a sample from the subject comprises a first nucleic acid encoding a PNPLA3 protein comprising an I148M variation and a second nucleic acid encoding a fu nctional HSD17B13 protein, and / or a PNPLA3 protein comprising an I148M variation and a fu nctional HSD17B13 protein, and identifying the subject as a candidate for treating or inhibiting a liver disease by inhibiting HSD17B13 when both the first and second nucleic acids are detected and / or when both proteins are detected. The present disclosure also provides methods of classifying a subject who is a candidate for HSD17B13 inhibition, the method comprising determining whether or not a sample from the subject comprises a nucleic acid encoding a PNPLA3 llel48Met variant or PNPLA3 llel44Met variant. The present disclosure also provides methods for classifying a human subject as a candidate for treating or inhibiting a liver disease by inhibiting HSD17B13, the method comprising determining whether or not a sample from the subject comprises a first nucleic acid encoding a PNPLA3 protein comprising an I148M variation and a second nucleic acid encoding a functional HSD17B13 protein, and / or a PNPLA3 protein comprising an I148M variation and a functional HSD17B13 protein, and classifying the subject as a candidate for treating or inhibiting a liver disease by inhibiting HSD17B13 when both the first and second nucleic acids are detected and / or when both proteins are detected.

[0277] The variant PNPLA3 llel48Met variant or PNPLA3 llel44Met variant can be any of the variant PNPLA3 llel48Met variants and PNPLA3 llel44Met variants described herein. The variant PNPLA3 llel48Met variant or PNPLA3 llel44Met variant can be detected by any of the methods described herein. In some embodiments, the methods further comprise determining whether the subject is homozygous or heterozygous for the variant PNPLA3 llel48Met variant or PNPLA3 llel44Met variant. In some embodiments, the subject is homozygous for the variant PNPLA3 llel48Met variant or PNPLA3 llel44Met variant. In some embodiments, the subject is heterozygous for the variant PNPLA3 llel48Met variant or PNPLA3 llel44Met variant. In some embodiments, the subject is homozygous for the variant PNPLA3 llel48Met variant. In some embodiments, the subject is heterozygous for the variant PNPLA3 llel48Met variant. In some embodiments, the subject is homozygous for the variant PNPLA3 llel44Met variant. In some embodiments, the subject is heterozygous for the variant PNPLA3 llel44Met variant.

[0278] In preferred embodiments, the subject does not comprise any genes encoding loss of function variations in the HSD17B13 protein. It is believed that loss of function variations in the HSD17B13 protein, including those described or exemplified herein, confer a liver disease- protective effect and it is further believed that this protective effect is enhanced in the presence of the variant PNPLA3 llel48M variation. Thus, it is believed that subjects (e.g., subjects comprising the I148M variation in PNPLA3) in whom both copies of the genes (from each chromosome) encoding the HSD17B13 protein encode a loss of function variation are unlikely to benefit from HSD17B13 inhibition therapy. Nevertheless, it is believed that subjects who express at least a partially functional HSD17B13 protein will benefit from HSD17B13 inhibition therapy. Thus, the methods may comprise classifying the status of the gene (in one or both chromosomes) encoding HSD17B13, including whether the gene encodes a loss of fu nction variation in the HSD17B13 protein, as well as whether the subject is homozygous or heterozygous.

[0279] In some embodiments, the methods further comprise detecting the presence of a nucleic acid molecule or gene encoding a functional HSD17B13 protein in a sample from the su bject. The nucleic acid molecule can encode any of the functional HSD17B13 proteins described herein. The HSD17B13 nucleic acid molecule can be detected by any of the methods described herein. In some embodiments, the methods further comprise determining whether the subject is homozygous or heterozygous for a gene encoding a functional HSD17B13 protein. I n some embodiments, the subject is homozygous for a gene encoding a functional HSD17B13 protein. In some embodiments, the subject is heterozygous for a gene encoding a functional HSD17B13.

[0280] The present disclosu re also provides supports comprising a substrate to which any one or more of the probes disclosed herein is attached. Solid supports are solid-state su bstrates or su pports with which molecules, such as any of the probes disclosed herein, can be associated. A form of solid support is an array. Another form of solid support is an array detector. An array detector is a solid support to which multiple different probes have been coupled in an array, grid, or other organized pattern.

[0281] Solid-state substrates for use in solid supports can include any solid material to which molecules can be coupled. This includes materials such as acrylamide, agarose, cellulose, nitrocellulose, glass, polystyrene, polyethylene vinyl acetate, polypropylene, polymethacrylate, polyethylene, polyethylene oxide, polysilicates, polycarbonates, teflon, fluorocarbons, nylon, silicon rubber, polyanhyd rides, polyglycolic acid, polylactic acid, polyorthoesters,

[0282] polypropylfu merate, collagen, glycosaminoglycans, and polyamino acids. Solid-state substrates can have any useful form including thin film, membrane, bottles, dishes, fibers, woven fibers, shaped polymers, particles, beads, microparticles, or a combination. Solid-state substrates and solid supports can be porous or non-porous. A form for a solid-state substrate is a microtiter dish, such as a standard 96-well type. In some embodiments, a multi-wel l glass slide can be employed that normally contain one array per well. This feature al lows for greater control of assay reproducibility, increased th rough put and sample handling, and ease of automation. In some embodiments, the support is a microarray. In some embodiments, the methods further comprises determining whether the su bject is obese. In some embodiments, a subject is obese if their body mass index (BMI) is over 30 kg / m2. Obesity is can be a characteristic of a subject having or at risk of developing a liver disease. In some embodiments, the methods further comprises determining whether the su bject has a fatty liver. A fatty liver can be a characteristic of a subject having or at risk of developing a liver disease. In some embodiments, the methods further comprises determining whether the su bject is obese and has a fatty liver.

[0283] In some embodiments, the methods further comprise ad ministering an inhibitor of HSD17B13 to the subject. Methods of ad ministering an inhibitor of HSD17B13 to the subject are described herein.

[0284] In some embodiments, the nucleic acid molecule encoding the variant PNPLA3 l lel48Met protein or PNPLA3 llel44Met protein is any of the nucleic acid molecu les described herein. In some embodiments, the nucleic acid molecu le encoding the variant PNPLA3 l lel48Met protein or PNPLA3 llel44Met protein is genomic DNA. In some embodiments, the genomic DNA encoding the variant PNPLA3 llel48Met protein or PNPLA3 llel44Met protein is any of the genomic DNA molecules described herein. In some embodiments, the nucleic acid molecule encoding the variant PNPLA3 l lel48Met protein is genomic DNA. In some

[0285] embodiments, the genomic DNA comprises an ATG codon at the positions corresponding to positions 5107 to 5109 according to SEQ I D NO:31. In some embodiments, the genomic DNA comprises the nucleotide sequence according to SEQ ID NO:31. In some embodiments, the genomic DNA encoding the variant PNPLA3 protein is detected by nucleic acid sequencing or hybridization of a probe, as described herein. In some embodiments, the genomic DNA encoding the variant PNPLA3 protein that comprises the ATG codon is detected by nucleic acid sequencing or hybridization of a probe, as described herein.

[0286] In some embodiments, the nucleic acid molecule encoding the variant PNPLA3 l lel48Met protein or PNPLA3 llel44Met protein is mRNA. In some embodiments, the mRNA encoding the variant PNPLA3 l lel48Met protein or PNPLA3 llel44Met protein is any of the mRNA molecules described herein. In some embodiments, the nucleic acid molecu le encoding the variant PNPLA3 llel48Met protein is mRNA. In some embodiments, the mRNA comprises an AUG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:34. I n some embodiments, the mRNA comprises the nucleotide sequence according to SEQ I D NO:34. In some embodiments, the mRNA comprises an AUG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:35. In some embodiments, the mRNA comprises the nucleotide sequence according to SEQ ID NO:35. I n some embodiments, the mRNA encoding the variant PNPLA3 protein is detected by nucleic acid sequencing or hybridization of a probe, as described herein. In some embodiments, the mRNA encoding the variant PN PLA3 protein that comprises the AUG codon is identified by nucleic acid sequencing or hybridization of a probe, as described herein.

[0287] In some embodiments, the nucleic acid molecule encoding the variant PNPLA3 l lel48Met protein or PNPLA3 llel44Met protein is cDNA. In some embodiments, the cDNA encoding the variant PNPLA3 llel48Met protein or PN PLA3 llel44Met protein is any of the cDNA molecu les described herein. In some embodiments, the nucleic acid molecule encoding a PNPLA3 llel48Met protein is cDNA. In some embodiments, the cDNA comprises an ATG codon at the positions corresponding to positions 442 to 444 according to SEQ I D NO:38. In some embodiments, the cDNA comprises the nucleotide sequence according to SEQ ID NO:38. In some embodiments, the cDNA comprises an ATG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:39. In some embodiments, the cDNA comprises the nucleotide sequence according to SEQ ID NO:39. In some embodiments, the cDNA encoding the variant PNPLA3 protein is identified by nucleic acid sequencing or hybridization of a probe. I n some embodiments, the cDNA encoding the variant PNPLA3 protein that comprises the ATG codon is identified by nucleic acid sequencing or hybridization of a probe, as described herein.

[0288] In some embodiments, the nucleic acid molecule encoding the functional HSD17B13 protein is any of the nucleic acid molecules described herein. I n some embodiments, the nucleic acid molecule encoding the functional HSD17B13 protein is genomic DNA. In some embodiments, the genomic DNA encoding the functional HSD17B13 protein is any of the genomic DNA molecules described herein. In some embodiments, the genomic DNA comprises an adenine at a position corresponding to position 12,667 according to SEQ ID NO:l. In some embodiments, the genomic DNA comprises SEQ ID NO:l. In some embodiments, the presence of the functional HSD17B13 genomic DNA is determined by nucleic acid sequencing or hybridization of a probe, as described herein.

[0289] In some embodiments, the nucleic acid molecule encoding the functional HSD17B13 protein is mRNA. In some embodiments, the mRNA encoding the functional HSD17B13 protein is any of the mRNA molecules described herein. In some embodiments, the fu nctional HSD17B13 nucleic acid molecule is mRNA. In some embodiments, the mRNA comprises SEQ ID NO:3. In some embodiments, the mRNA comprises SEQ ID NO:4. In some embodiments, the mRNA comprises SEQ I D NO:7. In some embodiments, the mRNA comprises SEQ ID NO:ll. In some embodiments, the presence of the functional HSD17B13 mRNA is determined by nucleic acid sequencing or hybridization of a probe, as described herein.

[0290] In some embodiments, the nucleic acid molecule encoding the functional HSD17B13 protein is cDNA. In some embodiments, the cDNA encoding the functional HSD17B13 protein is any of the cDNA molecules described herein. In some embodiments, the cDNA comprises SEQ I D NO:12. In some embodiments, the cDNA comprises SEQ I D NO:13. In some embodiments, the cDNA comprises SEQ ID NO:16. In some embodiments, the cDNA comprises SEQ ID NO:20. I n some embodiments, the presence of the functional HSD17B13 cDNA is determined by nucleic acid sequencing or hybridization of a probe, as described herein.

[0291] In some embodiments, the methods further comprising obtaining the sample from the su bject. In some embodiments, the su bject who is a candidate for HSD17B13 inhibition has a liver disease or is susceptible to developing a liver disease. In some embodiments, the liver disease is a chronic liver disease. In some preferred embodiments, the chronic liver disease is nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), non-alcoholic

[0292] steatohepatitis (NASH), cirrhosis, steatosis, or hepatocellu lar carcinoma. In some preferred embodiments, the chronic liver disease is nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), non-alcoholic steatohepatitis (NASH), cirrhosis, or steatosis. In some embodiments, the liver disease is an alcoholic liver disease. I n some embodiments, the alcoholic liver disease comprises one or more of cirrhosis, steatosis, or hepatocellu lar carcinoma resu lting from alcohol consumption. In some embodiments, the liver disease is a non-alcoholic liver disease. In some embodiments, the non-alcoholic liver disease comprises nonalcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). In some embodiments, the non-alcoholic liver disease comprises one or more of cirrhosis, steatosis, or hepatocellular carcinoma not caused by alcohol consumption.

[0293] The present disclosu re also provides methods of detecting a PNPLA3 llel48Met variant, or a PNPLA3 llel44Met variant, and functional HSD17B13 in a subject comprising: detecting the presence of a PNPLA3 llel48Met protein, or a nucleic acid molecule encoding a PNPLA3 llel48Met protein, in a sample from the su bject, or detecting the presence of a PN PLA3 l lel44Met protein, or a nucleic acid molecule encoding a PNPLA3 llel44Met protein, in a sample from the subject; and detecting the presence of a functional HSD17B13 protein, or a nucleic acid molecule encoding a functional HSD17B13 protein, in a sample from the subject. The variant PNPLA3 llel48Met variant protein or nucleic acid molecule can be any of the variant PN PLA3 llel48Met variant proteins or nucleic acid molecules described herein. The variant PN PLA3 llel44Met variant protein or nucleic acid molecule can be any of the variant PNPLA3 llel44Met variant proteins or nucleic acid molecu les described herein. The functional HSD17B13 protein or nucleic acid molecule can be any of the functional HSD17B13 proteins or nucleic acid molecules described herein.

[0294] In some embodiments, the methods further comprise determining whether the su bject is homozygous or heterozygous for the variant PNPLA3 llel48Met variant or PNPLA3 l lel44Met variant. In some embodiments, the subject is homozygous for the variant PNPLA3 l lel48Met variant or PNPLA3 llel44Met variant. In some embodiments, the subject is heterozygous for the variant PNPLA3 llel48Met variant or PNPLA3 llel44Met variant. In some embodiments, the subject is homozygous for the variant PNPLA3 llel48Met variant. In some embodiments, the subject is heterozygous for the variant PNPLA3 llel48Met variant. In some embodiments, the subject is homozygous for the variant PNPLA3 llel44Met variant. In some embodiments, the subject is heterozygous for the variant PNPLA3 llel44Met variant.

[0295] In some embodiments, the methods further comprise determining whether the su bject is homozygous or heterozygous for functional HSD17B13. I n some embodiments, the su bject is homozygous for functional HSD17B13. In some embodiments, the subject is heterozygous for functional HSD17B13.

[0296] In some embodiments, the presence of a functional HSD17B13 protein is detected in the sample. The fu nctional HSD17B13 protein can be any of the functional HSD17B13 proteins described herein. In some embodiments, the functional HSD17B13 protein comprises an amino acid sequence according to SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:25, or SEQ ID NO:29. In some embodiments, the functional HSD17B13 protein is detected by amino acid sequencing or immunoassay, as described herein.

[0297] In some embodiments, the presence of a functional HSD17B13 nucleic acid molecu le is detected in the sample. The functional HSD17B13 nucleic acid molecule can be any of the fu nctional HSD17B13 nucleic acid molecules described herein. In some embodiments, the fu nctional HSD17B13 nucleic acid molecule is genomic DNA. The fu nctional HSD17B13 genomic DNA molecule can be any of the functional HSD17B13 genomic DNA molecu les described herein. In some embodiments, the genomic DNA comprises an adenine at a position corresponding to position 12,667 according to SEQ ID NO:l. In some embodiments, the genomic DNA comprises SEQ I D NO:l. In some embodiments, the genomic DNA is detected by nucleic acid sequencing or hybridization of a probe, as described herein.

[0298] In some embodiments, the functional HSD17B13 nucleic acid molecu le is mRNA. The fu nctional HSD17B13 mRNA molecule can be any of the functional HSD17B13 mRNA molecules described herein. In some embodiments, the mRNA comprises SEQ ID NO:3. In some embodiments, the mRNA comprises SEQ ID NO:4. In some embodiments, the mRNA comprises SEQ ID NO:7. In some embodiments, the mRNA comprises SEQ I D NO:ll. In some

[0299] embodiments, the mRNA is detected by nucleic acid sequencing or hybridization of a probe, as described herein.

[0300] In some embodiments, the functional HSD17B13 nucleic acid molecu le is cDNA. The fu nctional HSD17B13 cDNA molecule can be any of the functional HSD17B13 cDNA molecules described herein. In some embodiments, the cDNA comprises SEQ ID NO:12. In some embodiments, the cDNA comprises SEQ ID NO:13. In some embodiments, the cDNA comprises SEQ ID NO:16. In some embodiments, the cDNA comprises SEQ ID NO:20. In some

[0301] embodiments, the cDNA is detected by nucleic acid sequencing or hybridization of a probe, as described herein.

[0302] In some embodiments, the presence of a PNPLA3 llel48Met protein or PNPLA3 l lel44Met protein is detected in the sample. The variant PNPLA3 llel48Met protein or PNPLA3 l lel44Met protein can be any of the variant PNPLA3 l lel48Met proteins or PNPLA3 llel44Met proteins described herein. In some embodiments, the variant PNPLA3 llel48Met protein comprises a methionine at a position corresponding to position 148 according to SEQ ID NO:42, or comprises a methionine at a position corresponding to position 144 according to SEQ ID NO:43. In some embodiments, the variant PNPLA3 llel48Met protein comprises a methionine at a position corresponding to position 148 according to SEQ ID NO:42. In some embodiments, the variant PNPLA3 protein in the sample comprises the amino acid sequence according to SEQ I D NO:42. In some embodiments, the variant PNPLA3 llel48Met protein comprises a methionine at a position corresponding to position 144 according to SEQ ID NO:43. In some embodiments, the variant PNPLA3 protein in the sample comprises the amino acid sequence according to SEQ ID NO:43. In some embodiments, the variant PNPLA3 llel48Met protein or PNPLA3 llel44Met protein is detected by amino acid sequencing or immunoassay, as described herein. In some embodiments, the presence of a nucleic acid molecule encoding a PNPLA3 l lel48Met protein or PNPLA3 llel48Met protein is detected in the sample. The nucleic acid molecule encoding a PNPLA3 llel48Met protein or PNPLA3 llel48Met protein can be any of the nucleic acid molecules encoding a PNPLA3 llel48Met protein or PN PLA3 llel48Met protein described herein.

[0303] In some embodiments, the nucleic acid molecule encoding a PNPLA3 llel48Met protein or PNPLA3 llel44Met protein is genomic DNA. The genomic DNA encoding a PNPLA3 l lel48Met protein or PNPLA3 llel44Met protein can be any of the genomic DNA molecules described herein. In some embodiments, the genomic DNA comprises an ATG codon at the positions corresponding to positions 5107 to 5109 according to SEQ ID NO:31. In some embodiments, the genomic DNA comprises the nucleotide sequence according to SEQ ID NO:31. In some embodiments, the genomic DNA encoding the variant PNPLA3 protein that comprises the ATG codon is detected by nucleic acid sequencing or hybridization of a probe, as described herein.

[0304] In some embodiments, the nucleic acid molecule encoding a PNPLA3 llel48Met protein or PNPLA3 llel48Met protein is mRNA. The mRNA molecule encoding a PNPLA3 l lel48Met protein or PNPLA3 llel48Met protein can be any of the mRNA molecules described herein. In some embodiments, the mRNA comprises an AUG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:34. In some embodiments, the mRNA comprises the nucleotide sequence according to SEQ ID NO:34. I n some embodiments, the mRNA comprises an AUG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:35. In some embodiments, the mRNA comprises the nucleotide sequence according to SEQ ID NO:35. In some embodiments, the mRNA encoding the variant PNPLA3 protein that comprises the AUG codon is identified by nucleic acid sequencing or hybridization of a probe, as described herein.

[0305] In some embodiments, nucleic acid molecule encoding a PNPLA3 llel48Met protein or PNPLA3 llel44Met protein is cDNA. The cDNA encoding a PNPLA3 llel48Met protein or PNPLA3 l lel44Met protein can be any of the cDNA molecules described herein. I n some embodiments, the cDNA comprises an ATG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:38. In some embodiments, the cDNA comprises the nucleotide sequence according to SEQ ID NO:38. In some embodiments, the cDNA comprises an ATG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:39. In some embodiments, the cDNA comprises the nucleotide sequence according to SEQ I D NO:39. I n some embodiments, the cDNA encoding the variant PNPLA3 protein that comprises the ATG codon is identified by nucleic acid sequencing or hybridization of a probe, as described herein.

[0306] In some embodiments, the method further comprises obtaining the sample from the su bject.

[0307] The present disclosure also provides methods of identifying a subject having a protective effect against liver disease, comprising: detecting the presence of a PNPLA3 l lel48Met variant or PNPLA3 llel44Met variant in a sample from the subject; and detecting the presence of an HSD17B13 loss-of-fu nction variant in a sample from the subject. The present disclosu re also provides methods of classifying a subject having a protective effect against liver disease, comprising: detecting the presence of a PN PLA3 llel48Met variant or PNPLA3 l lel44Met variant in a sample from the subject; and detecting the presence of an HSD17B13 loss-of-function variant in a sample from the subject. The variant PNPLA3 llel48Met variant and PNPLA3 llel44Met variant can be any of the variant PNPLA3 l lel48Met variants and PNPLA3 l lel44Met variants described herein. The HSD17B13 loss-of-fu nction variant can be any of the HSD17B13 loss-of-function variants described herein.

[0308] In some embodiments, the methods further comprise determining whether the su bject is homozygous or heterozygous for the variant PNPLA3 llel48Met variant or PNPLA3 l lel44Met variant. In some embodiments, the subject is homozygous for the variant PNPLA3 l lel48Met variant or PNPLA3 llel44Met variant. In some embodiments, the subject is heterozygous for the variant PNPLA3 llel48Met variant or PNPLA3 llel44Met variant. In some embodiments, the subject is homozygous for the variant PNPLA3 llel48Met variant. In some embodiments, the subject is heterozygous for the variant PNPLA3 llel48Met variant. In some embodiments, the subject is homozygous for the variant PNPLA3 llel44Met variant. In some embodiments, the subject is heterozygous for the variant PNPLA3 llel44Met variant.

[0309] In some embodiments, the methods further comprise determining whether the su bject is homozygous or heterozygous for functional HSD17B13. I n some embodiments, the su bject is homozygous for functional HSD17B13. In some embodiments, the subject is heterozygous for functional HSD17B13.

[0310] In some embodiments, the variant PN PLA3 llel48Met variant or PN PLA3 llel44Met variant is detected in the subject by detecting a PNPLA3 llel48Met protein, or a nucleic acid molecule encoding a PNPLA3 llel48Met protein, in a sample from the subject, or detecting a PNPLA3 llel44Met protein, or a nucleic acid molecule encoding a PNPLA3 llel44Met protein, in a sample from the subject; and the HSD17B13 loss-of-function is detected in the subject by detecting an HSD17B13 loss-of-fu nction variant protein, or a nucleic acid molecule encoding an HSD17B13 loss-of-function variant protein, in a sample from the subject. In some

[0311] embodiments, the variant PNPLA3 llel48Met variant or PNPLA3 llel44Met variant is detected in the subject by detecting a PNPLA3 llel48Met protein, or a nucleic acid molecule encoding a PNPLA3 llel48Met protein, in a sample from the su bject; and the HSD17B13 loss-of-function is detected in the subject by detecting an HSD17B13 loss-of-function variant protein, or a nucleic acid molecu le encoding an HSD17B13 loss-of-function variant protein, in a sample from the su bject.

[0312] In some embodiments, the presence of a PNPLA3 llel48Met protein or PNPLA3 l lel44Met protein is detected in the sample. The variant PNPLA3 llel48Met protein and PNPLA3 llel44Met protein can be any of the variant PNPLA3 llel48Met proteins and PNPLA3 l lel44Met proteins described herein. In some embodiments, the variant PNPLA3 llel48Met protein comprises a methionine at a position corresponding to position 148 according to SEQ ID NO:42, or comprises a methionine at a position corresponding to position 144 according to SEQ I D NO:43. In some embodiments, the variant PNPLA3 llel48Met protein comprises a methionine at a position corresponding to position 148 according to SEQ ID NO:42. In some embodiments, the variant PNPLA3 protein in the sample comprises the amino acid sequence according to SEQ ID NO:42. In some embodiments, the variant PNPLA3 llel48Met protein comprises a methionine at a position corresponding to position 144 according to SEQ ID NO:43. I n some embodiments, the variant PNPLA3 protein in the sample comprises the amino acid sequence according to SEQ ID NO:43. In some embodiments, the variant PNPLA3 l lel48Met protein is detected by amino acid sequencing or immunoassay, as described herein.

[0313] In some embodiments, the presence of a nucleic acid molecule encoding a PNPLA3 l lel48Met protein or PNPLA3 llel44Met protein is detected in the sample. The nucleic acid molecule encoding the variant PNPLA3 l lel48Met protein or PNPLA3 llel44Met protein can be any of the nucleic acid molecules encoding the variant PNPLA3 llel48Met proteins and PN PLA3 l lel44Met proteins described herein.

[0314] In some embodiments, wherein the nucleic acid molecu le encoding a PNPLA3 l lel48Met protein or PNPLA3 llel44Met protein is genomic DNA. The genomic DNA encoding the variant PNPLA3 llel48Met protein or PNPLA3 llel44Met protein can be any of the variant PNPLA3 llel48Met proteins and PNPLA3 llel44Met proteins described herein. In some embodiments, the genomic DNA comprises an ATG codon at the positions corresponding to positions 5107 to 5109 according to SEQ I D NO:31. In some embodiments, the genomic DNA comprises the nucleotide sequence according to SEQ ID NO:31. In some embodiments, the genomic DNA encoding the variant PNPLA3 protein that comprises the ATG codon is detected by nucleic acid sequencing or hybridization of a probe.

[0315] In some embodiments, the nucleic acid molecule encoding the variant PNPLA3 l lel48Met protein or PNPLA3 llel44Met protein is mRNA. The mRNA molecule encoding the variant PN PLA3 llel48Met proteins and PNPLA3 llel44Met proteins can be any of the variant PNPLA3 llel48Met proteins and PNPLA3 llel44Met proteins described herein. In some embodiments, the mRNA comprises an AUG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:34. In some embodiments, the mRNA comprises the nucleotide sequence according to SEQ ID NO:34. In some embodiments, the mRNA comprises an AUG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:35. In some embodiments, the mRNA comprises the nucleotide sequence according to SEQ I D NO:35. In some embodiments, the mRNA encoding the variant PNPLA3 protein that comprises the AUG codon is identified by nucleic acid sequencing or hybridization of a probe, as described herein.

[0316] In some embodiments, the nucleic acid molecule encoding a PNPLA3 llel48Met protein or PNPLA3 llel48Met protein is cDNA. The cDNA encoding the variant PN PLA3 l lel48Met protein and PNPLA3 llel48Met protein can be any of the variant PNPLA3 llel48Met proteins and PNPLA3 llel48Met proteins described herein. In some embodiments, the cDNA comprises an ATG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:38. In some embodiments, the cDNA comprises the nucleotide sequence according to SEQ ID NO:38. In some embodiments, the cDNA comprises an ATG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:39. In some embodiments, the cDNA comprises the nucleotide sequence according to SEQ ID NO:39. In some embodiments, the cDNA encoding the variant PNPLA3 protein that comprises the ATG codon is identified by nucleic acid sequencing or hybridization of a probe, as described herein.

[0317] In some embodiments, the presence of an HSD17B13 loss-of-fu nction variant protein is detected in the sample. The HSD17B13 loss-of-fu nction variant can be any of the HSD17B13 loss-of-function variant proteins described herein. In some embodiments, the HSD17B13 loss- of-function variant protein comprises an amino acid sequence according to SEQ ID NO:23. In some embodiments, the HSD17B13 loss-of-function variant protein comprises an amino acid sequence according to SEQ ID NO:24. In some embodiments, the HSD17B13 loss-of-fu nction variant protein comprises an amino acid sequence according to SEQ ID NO:26. In some embodiments, the HSD17B13 loss-of-function variant protein comprises an amino acid sequence according to SEQ ID NO:27. In some embodiments, the HSD17B13 loss-of-fu nction variant protein comprises an amino acid sequence according to SEQ ID NO:28. In some embodiments, the HSD17B13 loss-of-function variant protein is detected by amino acid sequencing or immunoassay, as described herein.

[0318] In some embodiments, the presence of a nucleic acid molecule encoding an HSD17B13 loss-of-function variant protein is detected in the sample. The nucleic acid molecule encoding an HSD17B13 loss-of-fu nction variant protein can be any of the nucleic acid molecules encoding the HSD17B13 loss-of-fu nction variant protein described herein.

[0319] In some embodiments, the nucleic acid molecule encoding the HSD17B13 loss-of- fu nction variant protein is genomic DNA. The genomic DNA molecu le encoding the HSD17B13 loss-of-function variant protein can be any of the HSD17B13 loss-of-function variant proteins described herein. In some embodiments, the genomic DNA encoding an HSD17B13 loss-of- fu nction variant protein which comprises a thymine at a position corresponding to position 12,667 according to SEQ ID NO:2. In some embodiments, the genomic DNA encoding an HSD17B13 loss-of-function variant protein comprises SEQ ID NO:2. In some embodiments, the genomic DNA encoding the HSD17B13 loss-of-fu nction variant protein is detected by nucleic acid sequencing or hybridization of a probe, as described herein.

[0320] In some embodiments, the nucleic acid molecule encoding the HSD17B13 loss-of- fu nction variant protein is mRNA. The mRNA molecule encoding the HSD17B13 loss-of-function variant protein can be any of the mRNA molecules encoding the HSD17B13 loss-of-fu nction variant proteins described herein. In some embodiments, the mRNA encoding an HSD17B13 loss-of-function variant protein comprises SEQ ID NO:5. In some embodiments, the mRNA encoding an HSD17B13 loss-of-fu nction variant protein comprises SEQ ID NO:6. In some embodiments, the mRNA encoding an HSD17B13 loss-of-function variant protein comprises SEQ ID NO:8. In some embodiments, the mRNA encoding an HSD17B13 loss-of-fu nction variant protein comprises SEQ ID NO:9. In some embodiments, the mRNA encoding an HSD17B13 loss- of-function variant protein comprises SEQ ID NO:10. In some embodiments, the mRNA encoding the HSD17B13 loss-of-fu nction variant protein is detected by nucleic acid sequencing or hybridization of a probe, as described herein.

[0321] In some embodiments, the nucleic acid molecule encoding the HSD17B13 loss-of- fu nction variant protein is cDNA. The cDNA molecules encoding the HSD17B13 loss-of-fu nction variant protein can be any of the cDNA molecules encoding the HSD17B13 loss-of-fu nction variant protein described herein. In some embodiments, the cDNA encoding an HSD17B13 loss- of-function variant protein comprises SEQ ID NO:5. In some embodiments, the cDNA encoding an HSD17B13 loss-of-fu nction variant protein comprises SEQ ID NO:6. In some embodiments, the cDNA encoding an HSD17B13 loss-of-fu nction variant protein comprises SEQ ID NO:8. In some embodiments, the cDNA encoding an HSD17B13 loss-of-function variant protein comprises SEQ ID NO:9. In some embodiments, the cDNA encoding an HSD17B13 loss-of- fu nction variant protein comprises SEQ ID NO:10. In some embodiments, the cDNA encoding the HSD17B13 loss-of-fu nction variant protein is detected by nucleic acid sequencing or hybridization of a probe, as described herein.

[0322] In some embodiments, the methods further comprises obtaining the sample from the su bject. In some embodiments, the liver disease is a chronic liver disease. In some

[0323] embodiments, the chronic liver disease is nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), non-alcoholic steatohepatitis (NASH), cirrhosis, steatosis, or hepatocellu lar carcinoma. In some embodiments, the liver disease is an alcoholic liver disease. In some embodiments, the alcoholic liver disease comprises one or more of cirrhosis, steatosis, or hepatocellular carcinoma resulting from alcohol consumption. In some embodiments, the liver disease is a non-alcoholic liver disease. I n some embodiments, the non-alcoholic liver disease comprises nonalcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). In some embodiments, the non-alcoholic liver disease comprises one or more of cirrhosis, steatosis, or hepatocel lular carcinoma not caused by alcohol consumption.

[0324] The present disclosu re also provides any of the methods described herein fu rther comprising administering to the subject an inhibitor of HSD17B13. In some embodiments, the inhibitor of HSD17B13 comprises a fu nctional polypeptide, an antisense DNA, RNA, an siRNA, or an shRNA that hybridizes to the endogenous HSD17B13 genomic DNA or mRNA and decreases expression of HSD17B13 polypeptide in a cell in the subject. In some embodiments, the HSD17B13 in hibitor can also inhibit one or more additional members of the short-chain dehyd rogenases / reductases (SDR) family, of which HSD17B13 is a member. Such other members include, but are not limited to, HSD17B1, HSD17B2, HSD17B3, HSD17B4, HSD17B6, HSD17B7, HSD17B8, HSD17B10, HSD17B11, HSD17B12, HSD17B13, HSD17B14, HSD11B1, HSD11B2, HSD3B1, HSD3B2, and HSD3B7, as well as close homologs dehydrogenase / reductase 3 (DHRS3) and retinol dehyd rogenase 10 (RDH10). In some embodiments, the inhibitor of HSD17B13 is administered to inhibit liver disease in the subject. In some embodiments, the inhibitor of HSD17B13 is administered to treat liver disease in the subject. In some

[0325] embodiments, the liver disease is a chronic liver disease. In some embodiments, the chronic liver disease is one or more of nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), non-alcoholic steatohepatitis (NASH), cirrhosis, steatosis, or hepatocel lular carcinoma. I n some embodiments, the liver disease is an alcoholic liver disease. In some embodiments, the alcoholic liver disease comprises one or more of cirrhosis, steatosis, or hepatocellu lar carcinoma resu lting from alcohol consumption. In some embodiments, the liver disease is a non-alcoholic liver disease. In some embodiments, the non-alcoholic liver disease comprises nonalcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). In some embodiments, the non-alcoholic liver disease comprises one or more of cirrhosis, steatosis, or hepatocellular carcinoma not caused by alcohol consumption. In some embodiments, the su bject is homozygous for the gene encoding the I148M variation. In some embodiments, the su bject is heterozygous for the gene encoding the I148M variation. In some embodiments, the su bject further is homozygous for the gene encoding the functional HSD17B13 protein. In some embodiments, the subject further is heterozygous for the gene encoding the functional HSD17B13 protein and a gene encoding a loss of function variant of HSD17B13.

[0326] The disclosu re also provides methods of treating or inhibiting liver disease, comprising administering an inhibitor of hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) to a human liver disease patient expressing a patatin like phospholipase domain containing 3 (PNPLA3) protein comprising an I148M variation such that liver disease is treated or inhibited in the patient. In some embodiments, the liver disease is a ch ronic liver disease. In some embodiments, the liver disease is one or more of nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), non-alcoholic steatohepatitis (NASH), cirrhosis, steatosis, or hepatocellular carcinoma. In some embodiments, the liver disease is an alcoholic liver disease. I n some embodiments, the alcoholic liver disease comprises one or more of cirrhosis, steatosis, or hepatocellular carcinoma resulting from alcohol consu mption. In some embodiments, the liver disease is a non-alcoholic liver disease. In some embodiments, the non-alcoholic liver disease comprises nonalcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). In some embodiments, the non-alcoholic liver disease comprises one or more of cirrhosis, steatosis, or hepatocellular carcinoma not caused by alcohol consumption. In some embodiments, the patient is obese. In some embodiments, the patient has a fatty liver. In some embodiments, the patient has been determined to express the variant PNPLA3 protein (e.g., a PNPLA3 protein comprising the I148M or I144M variation) by detection of the variant PNPLA3 protein in a sample from the subject. In some embodiments, the variant PNPLA3 protein comprises a methionine at a position corresponding to position 148 according to SEQ ID NO:42. In some embodiments, the variant PNPLA3 protein in the sample comprises the amino acid sequence according to SEQ ID NO:42. In some embodiments, the variant PNPLA3 protein is detected by amino acid sequencing or by an immunoassay. In some embodiments, the subject has been determined to express the variant PNPLA3 protein by detection of a nucleic acid molecule encoding the variant PNPLA3 protein (e.g., a variant PNPLA3 nucleic acid molecule encoding a PNPLA3 protein comprising the I148M or I144M variation) in a sample from the subject. In some embodiments, the variant PNPLA3 protein comprises a methionine at a position corresponding to position 148 according to SEQ ID NO:42. In some embodiments, the variant PNPLA3 protein comprises the amino acid sequence according to SEQ ID NO:42. In some embodiments, the nucleic acid molecule encoding the variant PNPLA3 protein comprises genomic DNA, mRNA, or cDNA obtained from mRNA. In some embodiments, the nucleic acid molecule comprises genomic DNA comprising an ATG codon at the positions corresponding to positions 5107 to 5109 according to SEQ ID NO:31. In some embodiments, the genomic DNA comprises the nucleotide sequence according to SEQ ID NO:31. In some embodiments, the nucleic acid molecule comprises mRNA comprising an AUG codon at the positions

[0327] corresponding to positions 442 to 444 according to SEQ ID NO:34. In some embodiments, the mRNA comprises the nucleotide sequence according to SEQ ID NO:34. In some embodiments, the nucleic acid molecule comprises mRNA comprising an AUG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:35. In some embodiments, the mRNA comprises the nucleotide sequence according to SEQ ID NO:35. In some embodiments, the nucleic acid molecule comprises cDNA obtained from mRNA, the cDNA comprising an ATG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:38. In some embodiments, the cDNA comprises the nucleotide sequence according to SEQ ID NO:38. In some embodiments, the nucleic acid molecule comprises cDNA obtained from mRNA, the cDNA comprising an ATG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:39. In some embodiments, the cDNA comprises the nucleotide sequence according to SEQ ID NO:39. In some embodiments, the nucleic acid is detected by sequencing at least a portion of the nucleic acid, the portion encoding the I148M variation. In some embodiments, the nucleic acid is detected by hybridization of a probe or primer that specifically hybridizes to a portion of the nucleic acid, wherein the portion comprises the codon encoding the I148M variation. In some embodiments, the probe or primer is an allele-specific probe or primer. In some embodiments, the probe or primer comprises a label. In some embodiments, the patient is homozygous for a gene encoding the variant PNPLA3 protein. In some embodiments, the patient is heterozygous for a gene encoding the variant PNPLA3 protein. In some embodiments, patient is homozygous for a gene encoding a functional HSD17B13 protein. In some embodiments, the patient is heterozygous for a gene encoding a fu nctional HSD17B13 protein. In some embodiments, the patient is heterozygous for the gene encoding the functional HSD17B13 protein and a gene encoding a loss of fu nction variant of HSD17B13.

[0328] Inhibitors of HSD17B13 can be used as described herein for treatment of a liver disease in a human subject having a PNPLA3 protein comprising an I148M variation and having a fu nctional HSD17B13 protein. In some embodiments, the hu man subject has been tested positive for a PNPLA3 protein comprising an I148M variation and for a functional HSD17B13 protein. In some embodiments, the treatment comprises determining whether or not the human subject has a PNPLA3 protein comprising an I148M variation and a functional HSD17B13 protein. In some embodiments, the human subject has been identified as being a candidate for treating or inhibiting a liver disease by inhibiting HSD17B13 by using any of the method as defined herein. In some embodiments, the variant PNPLA3 protein comprises a methionine at the position corresponding to position 148 according to SEQ I D NO:42. In some embodiments, the variant PNPLA3 protein comprises the amino acid sequence according to SEQ ID NO:42, or an amino acid sequence having at least 90% sequence identity to SEQ ID NO:42 and comprising the I148M variation. In some embodiments, the variant PN PLA3 protein comprises a methionine at the position corresponding to position 144 according to SEQ I D NO:43. In some embodiments, the variant PNPLA3 protein comprises the amino acid sequence according to SEQ ID NO:43, or an amino acid sequence having at least 90% sequence identity to SEQ ID NO:43 and comprising the I144M variation. In some embodiments, the nucleic acid molecu le encoding the variant PNPLA3 protein is genomic DNA. In some embodiments, the genomic DNA comprises an ATG codon at the positions corresponding to positions 5107 to 5109 according to SEQ ID NO:31. In some embodiments, the genomic DNA comprises the nucleotide sequence according to SEQ ID NO:31, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:31 and encoding a PNPLA3 protein which comprises the I148M variation. In some embodiments, the nucleic acid molecule encoding the variant PNPLA3 protein is mRNA. In some embodiments, the mRNA comprises an AUG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:34. In some embodiments, the mRNA comprises the nucleotide sequence according to SEQ ID NO:34, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:34 and encoding a PNPLA3 protein which comprises the I 148M variation. In some embodiments, the mRNA comprises an AUG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:35. In some embodiments, the mRNA comprises the nucleotide sequence according to SEQ ID NO:35, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:35 and encoding a PNPLA3 protein which comprises the I144M variation. In some embodiments, the nucleic acid molecule encoding the variant PN PLA3 protein is cDNA. In some embodiments, the cDNA comprises an ATG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:38. In some embodiments, the cDNA comprises the nucleotide sequence according to SEQ ID NO:38, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:38 and encoding a PNPLA3 protein which comprises the I148M variation. In some embodiments, the cDNA comprises an ATG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:39. In some embodiments, the cDNA comprises the nucleotide sequence according to SEQ ID NO:39, or a nucleotide sequence having at least 90% sequence identity to SEQ I D NO:39 and encoding a PNPLA3 protein which comprises the I144M variation. In some embodiments, the liver disease is a chronic liver disease. In some embodiments, the chronic liver disease is nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), nonalcoholic steatohepatitis (NASH), cirrhosis, steatosis, or hepatocellular carcinoma. In some embodiments, the liver disease is an alcoholic liver disease. I n some embodiments, the alcoholic liver disease comprises one or more of cirrhosis, steatosis, or hepatocellu lar carcinoma resu lting from alcohol consumption. In some embodiments, the liver disease is a non-alcoholic liver disease. In some embodiments, the non-alcoholic liver disease comprises nonalcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). In some embodiments, the non-alcoholic liver disease comprises one or more of cirrhosis, steatosis, or hepatocellular carcinoma not caused by alcohol consumption. In some embodiments, the human subject is homozygous or heterozygous for functional HSD17B13.

[0329] In some embodiments, in hibitors of HSD17B13 reduce or inhibit HSD17B13 gene expression or the function of HSD17B13 protein. Inhibitors of HSD17B13 include, but are not limited to, naturally occu rring and synthetic ligands, antagonists, agonists, antibodies, peptides, cyclic peptides, nucleic acids, functional polynucleotides, small organic molecu les, and the like. Functional polynucleotides are nucleic acid molecules that have a specific function, such as binding a target molecule or catalyzing a specific reaction. Examples of functional

[0330] polynucleotides include, but are not limited to, antisense molecules, aptamers, ribozymes, and triplex forming molecules. The functional polynucleotides can act as inhibitors of a specific activity possessed by a target molecule. Antisense molecu les are designed to interact with a target nucleic acid molecule through either canonical or non-canonical base pairing. The interaction of the antisense molecule and the target molecule is designed to promote the destruction of the target molecu le through, for example, RNase-H-mediated RNA-DNA hybrid degradation. Alternately, the antisense molecule is designed to interrupt a processing function that normally wou ld take place on the target molecule, such as transcription or replication. Antisense molecules can be designed based on the sequence of the target molecule. Numerous methods for optimization of antisense efficiency by identifying the most accessible regions of the target molecule exist. Exemplary methods include, but are not limited to, in vitro selection experiments and DNA modification studies using DMS and DEPC. Antisense molecules generally bind the target molecule with a dissociation constant (kd) less than or equal to about 10-6, less than or equal to about 10-8, less than or equal to about 10-10, or less than or equal to about 10-12. A representative sample of methods and techniques which aid in the design and use of antisense molecules, and antisense molecu les, can be found in the following non-limiting list of U.S. Patents and applications: 5,135,917; 5,294,533; 5,627,158; 5,641,754; 5,691,317;

[0331] 5,780,607; 5,786,138; 5,849,903; 5,856,103; 5,919,772; 5,955,590; 5,990,088; 5,994,320;

[0332] 5,998,602; 6,005,095; 6,007,995; 6,013,522; 6,017,898; 6,018,042; 6,025,198; 6,033,910;

[0333] 6,040,296; 6,046,004; 6,046,319; 6,057,437; and U.S. Serial No. 62 / 645,941 filed March 21, 2018, each of which is incorporated herein by reference in its entirety. Examples of antisense molecules include, but are not limited to, antisense RNAs, small interfering RNAs (siRNAs), and short hairpin RNAs (shRNAs). For example, the antisense RNAs, siRNAs, or shRNAs can be designed to target a region unique of the HSD17B13 genomic DNA or mRNA. In some embodiments, the inhibitor of HSD17B13 is an antisense molecule. In some embodiments, the inhibitor of HSD17B13 is an shRNA molecu le. In some embodiments, the inhibitor of HSD17B13 is an siRNA molecule.

[0334] In any of the methods described herein, administration of an in hibitor of HSD17B13 can result in the reduction or elimination of particular characteristics of liver disease. I n some embodiments, the characteristics of liver disease include, but are not limited to inflammation and fibrosis.

[0335] The present disclosu re also provides methods of treating a subject who is PNPLA3 l lel48Met positive (i.e., "PNPLA3 llel48Met+") or PNPLA3 llel44Met positive (i.e., "PNPLA3 l lel44Met+"), comprising ad ministering an inhibitor of HSD17B13 to the subject. The present disclosu re also provides methods of treating or inhibiting liver disease comprising administering an inhibitor of HSD17B13 to a human liver disease patient expressing a PNPLA3 protein comprising an I148M variation such that liver disease is treated or inhibited in the patient.

[0336] The variant PNPLA3 llel48Met positive or PNPLA3 llel44Met positive su bject can have any of the variant PNPLA3 proteins described herein. In some embodiments, the subject is also homozygous or heterozygous for functional HSD17B13. In some embodiments, the subject is homozygous for functional HSD17B13. In some embodiments, the su bject is heterozygous for fu nctional HSD17B13. In some embodiments, the su bject is homozygous for the HSD17B13 loss- of-function variant. The subject can have any of the functional HSD17B13 proteins described herein.

[0337] In some embodiments, the subject who is PNPLA3 llel48Met+ or PNPLA3 llel44Met+ has been determined to be PNPLA3 llel48Met+ or PNPLA3 llel44Met+ by detection of a PNPLA3 protein in a sample from the subject, wherein the variant PNPLA3 protein comprises a methionine at a position corresponding to position 148 according to SEQ ID NO:42, or comprises a methionine at a position corresponding to position 144 according to SEQ ID NO:43. The variant PNPLA3 llel48Met positive or PNPLA3 llel44Met positive subject can have any of the variant PNPLA3 proteins described herein.

[0338] In some embodiments, the subject who is PNPLA3 llel48Met+ has been determined to be PNPLA3 llel48Met+ by detection of a PNPLA3 protein in a sample from the subject, wherein the variant PNPLA3 protein comprises a methionine at a position corresponding to position 148 according to SEQ ID NO:42. In some embodiments, the variant PNPLA3 protein in the sample comprises the amino acid sequence according to SEQ ID NO:42.

[0339] In some embodiments, the subject who is PNPLA3 llel44Met+ has been determined to be PNPLA3 llel44Met+ by detection of a PNPLA3 protein in a sample from the subject, wherein the variant PNPLA3 protein comprises a methionine at a position corresponding to position 144 according to SEQ ID NO:43. In some embodiments, the variant PNPLA3 protein in the sample comprises the amino acid sequence according to SEQ ID NO:43.

[0340] In some embodiments, the variant PN PLA3 protein that comprises the methionine at the position corresponding to position 148 according to SEQ I D NO:42, or that comprises the methionine at the position corresponding to position 144 according to SEQ I D NO:43 is identified by amino acid sequencing or immunoassay as described herein.

[0341] In some embodiments, the subject who is PNPLA3 llel48Met+ or PNPLA3 llel44Met+ has been determined to be PNPLA3 llel48Met+ or PNPLA3 llel44Met+ by detection of a nucleic acid molecu le encoding a PNPLA3 protein in a sample from the subject, wherein the variant PNPLA3 protein comprises a methionine at a position corresponding to position 148 according to SEQ ID NO:42, or comprises a methionine at a position corresponding to position 144 according to SEQ ID NO:43. The variant PN PLA3 llel48Met positive or PN PLA3 llel44Met positive subject can have any of the variant PNPLA3 nucleic acid molecu les described herein.

[0342] In some embodiments, the subject who is PNPLA3 llel48Met+ has been determined to be PNPLA3 llel48Met+ by detection of a nucleic acid molecule encoding a PNPLA3 protein in a sample from the subject, wherein the variant PNPLA3 protein comprises a methionine at a position corresponding to position 148 according to SEQ ID NO:42. In some embodiments, the variant PN PLA3 protein in the sample comprises the amino acid sequence according to SEQ ID NO:42.

[0343] In some embodiments, the subject who is PNPLA3 llel44Met+ has been determined to be PNPLA3 llel44Met+ by detection of a nucleic acid molecule encoding PNPLA3 protein in a sample from the subject, wherein the variant PNPLA3 protein comprises a methionine at a position corresponding to position 144 according to SEQ ID NO:43. In some embodiments, the variant PN PLA3 protein in the sample comprises the amino acid sequence according to SEQ ID NO:43.

[0344] In some embodiments, the nucleic acid molecule encoding the variant PNPLA3 protein is genomic DNA, mRNA, or cDNA derived from mRNA. In some embodiments, the genomic DNA comprises an ATG codon at the positions corresponding to positions 5107 to 5109 according to SEQ ID NO:31. In some embodiments, the genomic DNA comprises the nucleotide sequence according to SEQ ID NO:31. In some embodiments, the genomic DNA encoding the variant PN PLA3 protein that comprises the ATG codon is identified by nucleic acid sequencing or hybridization of a probe, as described herein.

[0345] In some embodiments, the mRNA comprises an AUG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:34. In some embodiments, the mRNA comprises the nucleotide sequence according to SEQ ID NO:34. I n some embodiments, the mRNA comprises an AUG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:35. In some embodiments, the mRNA comprises the nucleotide sequence according to SEQ ID NO:35. In some embodiments, the mRNA encoding the variant PNPLA3 protein that comprises the AUG codon is identified by nucleic acid sequencing or hybridization of a probe, as described herein.

[0346] In some embodiments, the cDNA comprises an ATG codon at the positions

[0347] corresponding to positions 442 to 444 according to SEQ ID NO:38. In some embodiments, the cDNA comprises the nucleotide sequence according to SEQ ID NO:38. In some embodiments, the cDNA comprises an ATG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:39. In some embodiments, the cDNA comprises the nucleotide sequence according to SEQ ID NO:39. In some embodiments, the cDNA encoding the variant PNPLA3 protein that comprises the ATG codon is identified by nucleic acid sequencing or hybridization of a probe, as described herein.

[0348] Administration of the inhibitor of HSD17B13 can be by any suitable route including, but not limited to, parenteral, intravenous, oral, subcutaneous, intra-arterial, intracranial, intrathecal, intraperitoneal, topical, intranasal, or intramuscular. Pharmaceutical compositions for administration are desirably sterile and substantially isotonic and manufactu red under GM P conditions. Pharmaceutical compositions can be provided in unit dosage form (i.e., the dosage for a single administration). Pharmaceutical compositions can be formulated using one or more physiologically and pharmaceutically acceptable carriers, diluents, excipients or auxiliaries. The formu lation depends on the route of ad ministration chosen. The term "pharmaceutically acceptable" means that the carrier, diluent, excipient, or auxiliary is compatible with the other ingredients of the formulation and not substantially deleterious to the recipient thereof. ln some embodiments, the subject has a liver disease or is susceptible to developing a liver disease. In some embodiments, the liver disease is a chronic liver disease. In some embodiments, the chronic liver disease is nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), non-alcoholic steatohepatitis (NASH), cirrhosis, steatosis, or hepatocellu lar carcinoma. In some embodiments, the liver disease is an alcoholic liver disease. In some embodiments, the alcoholic liver disease comprises one or more of cirrhosis, steatosis, or hepatocellular carcinoma resulting from alcohol consumption. In some embodiments, the liver disease is a non-alcoholic liver disease. I n some embodiments, the non-alcoholic liver disease comprises nonalcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). In some embodiments, the non-alcoholic liver disease comprises one or more of cirrhosis, steatosis, or hepatocel lular carcinoma not caused by alcohol consumption.

[0349] The present disclosu re also provides methods for treating a patient with a liver disease therapeutic agent, wherein the patient is suffering from a liver disease. The methods comprise determining whether or not a sample from the subject comprises: i) a first nucleic acid encoding a PNPLA3 protein comprising an I148M variation and a second nucleic acid encoding a fu nctional HSD17B13 protein, and / or ii) a PNPLA3 protein comprising an I148M variation and a fu nctional HSD17B13 protein. In some embodiments, the methods comprise determining whether or not a sample from the subject comprises a first nucleic acid encoding a PNPLA3 protein comprising an I148M variation and a second nucleic acid encoding a functional HSD17B13 protein. In some embodiments, the methods comprise determining whether or not a sample from the subject comprises a PNPLA3 protein comprising an I148M variation and a fu nctional HSD17B13 protein.

[0350] In some embodiments, this determination is carried out by obtaining or having obtained a biological sample from the patient. In some embodiments, the methods fu rther comprise performing or having performed a genotyping assay on the biological sample to determine if the patient has a first nucleic acid encoding a PNPLA3 protein comprising an I148M variation and a second nucleic acid encoding a functional HSD17B13 protein. I n some embodiments, the methods further comprise performing or having performed an assay on the biological sample to determine if the patient has a PNPLA3 protein comprising an I148M variation and a functional HSD17B13 protein.

[0351] In some embodiments, when the patient has a nucleic acid encoding a PNPLA3 protein comprising an I148M variation and / or has a PNPLA3 protein comprising an I148M variation, and has a nucleic acid encoding a functional HSD17B13 protein and / or has a functional HSD17B13 protein, then the method further comprises administering an inhibitor of HSD17B13 to the patient. In some embodiments, when the patient has a nucleic acid encoding a PNPLA3 protein comprising an I148M variation and / or has a PNPLA3 protein comprising an I148M variation, and has a nucleic acid encoding a functional HSD17B13 protein and / or has a functional HSD17B13 protein, then the method further comprises administering an inhibitor of HSD17B13 to the patient and ad ministering a liver disease therapeutic agent to the patient. In some

[0352] embodiments, when the patient has a nucleic acid encoding a PNPLA3 protein comprising an I 148M variation and / or has a PNPLA3 protein comprising an I148M variation, but does not have a nucleic acid encoding a functional HSD17B13 protein and / or has a functional HSD17B13 protein, then the method further comprises administering a liver disease therapeutic agent to the patient.

[0353] Examples of liver disease therapeutic agents include, but are not limited to, Disulfiram, Naltrexone, Acamprosate, Prednisone, Prednisone, Azathioprine, Penicillamine, Trientine, Deferoxamine, Ciprofloxacin, Norofloxacin, Ceftriaxone, Ofloxacin, Amoxicillin-clavulanate, Phytonadione, Bumetanide, Fu rosemide, Hydrochlorothiazide, Chlorothiazide, Amiloride, Triamterene, Spironolactone, Octreotide, Atenolol, Metoprolol, Nadolol, Propranolol, Timolol, and Carvedilol.

[0354] Additional examples of liver disease therapeutic agents (e.g., for use in chronic hepatitis C treatment) include, but are not limited to, ribavirin, paritaprevir, simeprevir (Olysio), grazoprevir, ledipasvir, ombitasvir, elbasvir, daclatasvir (Daklinza), dasabuvir, ritonavir, sofosbuvir, vel patasvir, voxilaprevir, glecaprevir, pibrentasvir, peginterferon alfa-2a, peginterferon alfa-2b, and interferon alfa-2b.

[0355] Additional examples of liver disease therapeutic agents (e.g., for use in nonalcoholic fatty liver disease) include, but are not limited to, weight loss inducing agents such as orlistat or sibutramine; insulin sensitizing agents such as thiazolidinediones (TZDs), metformin, and meglitinides; lipid lowering agents such as statins, fibrates, and omega-3 fatty acids; atioxidants such as, vitamin E, betaine, N-Acetyl-cysteine, lecithin, silymarin, and beta-carotene; anti TNF agents such as pentoxifylline; probiotics, such as VSL#3; and cytoprotective agents such as u rsodeoxycholic acid (UDCA). Other suitable treatments include ACE inhibitors / ARBs, oligofructose, and Incretin analogs.

[0356] Additional examples of liver disease therapeutic agents (e.g., for use in NASH) include, but are not limited to, obeticholic acid (Ocaliva®), Selonsertib, Elafibranor, Cenicriviroc, GR_M D_02, MGL_3196, IM M124E, arachidyl amido cholanoic acid (Aramchol™), GS0976, Emricasan, Volixibat, NGM282, GS9674, Tropifexor, MN_001, LMB763, Bl_1467335,

[0357] MSDC_0602, PF_05221304, DF102, Saroglitazar, BMS986036, Lanifibranor, Semaglutide, Nitazoxanide, GRI_0621, EYP001, VK2809, Nalmefene, LI K066, MT_3995, Elobixibat,

[0358] Namodenoson, Foralumab, SAR425899, Sotagliflozin, EDP_305, Isosabutate, Gemcabene, TERN_101, KBP_042, PF_06865571, DUR928, PF_06835919, NGM313, BMS_986171,

[0359] Namacizumab, CER_209, ND_L02_s0201, RTU_1096, DRX_065, IONIS_DGAT2Rx, INT_767, NC OOl, Seladepar, PXL770, TERN_201, NV556, AZD2693, SP_1373, VK0214, Hepastem, TG FTX4, RLBN1127, GKT_137831, RYI_018, CB4209-CB4211, and JH_0920.

[0360] The present disclosu re also provides in hibitors of HSD17B13 for use in the

[0361] manufacture of a medicament for the treatment of liver disease in a human subject who is PNPLA3 llel48Met positive or PNPLA3 llel44Met positive and who is also homozygous or heterozygous for functional HSD17B13. In some embodiments, the su bject is homozygous for PNPLA3 llel48Met variant or PNPLA3 llel44Met variant. In some embodiments, the su bject is heterozygous for PNPLA3 llel48Met variant or PNPLA3 llel44Met variant. In some

[0362] embodiments, the subject is homozygous for functional HSD17B13. In some embodiments, the su bject is heterozygous for functional HSD17B13.

[0363] In some embodiments, the inhibitor of HSD17B13 is for use in the treatment of a liver disease in a human subject having a PNPLA3 protein comprising a methionine at a position corresponding to position 148 according to SEQ ID NO:42, or a nucleic acid molecule encoding a PNPLA3 protein comprising a methionine at a position corresponding to position 148 according to SEQ ID NO:42, or comprising a methionine at a position corresponding to position 144 according to SEQ ID NO:43, or a nucleic acid molecule encoding a PNPLA3 protein comprising a methionine at a position corresponding to position 148 according to SEQ ID NO:43. In some embodiments, the variant PNPLA3 protein comprises a methionine at a position corresponding to position 148 according to SEQ ID NO:42. In some embodiments, the variant PNPLA3 protein comprises the amino acid sequence according to SEQ ID NO:42. In some embodiments, the variant PN PLA3 protein comprises a methionine at a position corresponding to position 144 according to SEQ ID NO:43. In some embodiments, the variant PNPLA3 protein comprises the amino acid sequence according to SEQ ID NO:43. ln some embodiments, the nucleic acid molecule encoding the variant PNPLA3 protein is genomic DNA. In some embodiments, the genomic DNA comprises an ATG codon at the positions corresponding to positions 5107 to 5109 according to SEQ ID NO:31. In some embodiments, the genomic DNA comprises the nucleotide sequence according to SEQ ID NO:31.

[0364] In some embodiments, the nucleic acid molecule encoding the variant PNPLA3 protein is mRNA. In some embodiments, the mRNA comprises an AUG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:34. In some embodiments, the mRNA comprises the nucleotide sequence according to SEQ ID NO:34. I n some embodiments, the mRNA comprises an AUG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:35. In some embodiments, the mRNA comprises the nucleotide sequence according to SEQ ID NO:35.

[0365] In some embodiments, nucleic acid molecule encoding the variant PNPLA3 protein is cDNA. In some embodiments, the cDNA comprises an ATG codon at the positions

[0366] corresponding to positions 442 to 444 according to SEQ ID NO:38. In some embodiments, the cDNA comprises the nucleotide sequence according to SEQ ID NO:38. In some embodiments, the cDNA comprises an ATG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:39. In some embodiments, the cDNA comprises the nucleotide sequence according to SEQ ID NO:39.

[0367] In some embodiments, the liver disease is a chronic liver disease. In some

[0368] embodiments, the chronic liver disease is nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), non-alcoholic steatohepatitis (NASH), cirrhosis, steatosis, or hepatocellu lar carcinoma. In some embodiments, the liver disease is an alcoholic liver disease. In some embodiments, the alcoholic liver disease comprises one or more of cirrhosis, steatosis, or hepatocellular carcinoma resulting from alcohol consumption. In some embodiments, the liver disease is a non-alcoholic liver disease. I n some embodiments, the non-alcoholic liver disease comprises nonalcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). In some embodiments, the non-alcoholic liver disease comprises one or more of cirrhosis, steatosis, or hepatocel lular carcinoma not caused by alcohol consumption.

[0369] In some embodiments, the human subject is homozygous or heterozygous for fu nctional HSD17B13. In some embodiments, the su bject is homozygous for functional HSD17B13. In some embodiments, the subject is heterozygous for functional HSD17B13. ln any of the methods described herein, a probe or primer or an alteration-specific probe or an alteration-specific primer can be specifically complementary to or specifically hybridize with a single nucleic acid species. For example, a probe or primer or an alteration- specific probe or an alteration-specific primer specifically complementary to or specifically hybridizing with a nucleic acid molecule for HSD17B13 transcript A, transcript B, transcript E, or transcript I (e.g., any of the mRNA, cDNA, RNA transcript, or cDNA transcript for functional HSD17B13 described herein) is not complementary to or does not hybridize with any of the nucleic acid molecules for a variant HSD17B13 (e.g., any of the mRNA, cDNA, RNA transcripts, or cDNA transcripts for variants C, D, F, G, H of HSD17B13).

[0370] The present disclosu re also provides an inhibitor of HSD17B13 for use in the treatment of a liver disease in a human subject having a PNPLA3 protein comprising an I148M variation and having a functional HSD17B13 protein. In some embodiments, the hu man subject has been tested positive for a PNPLA3 protein comprising an I148M variation and for a functional HSD17B13 protein. In some embodiments, the treatment comprises determining whether or not the hu man subject has a PN PLA3 protein comprising an I 148M variation and a functional HSD17B13 protein. In some embodiments, the human subject has been identified as being a candidate for treating or inhibiting a liver disease by inhibiting HSD17B13 by using any of the methods as defined herein.

[0371] In some embodiments, the variant PN PLA3 protein comprises a methionine at the position corresponding to position 148 according to SEQ ID NO:42. In some embodiments, the variant PN PLA3 protein comprises the amino acid sequence according to SEQ ID NO:42, or an amino acid sequence having at least 90% sequence identity to SEQ ID NO:42 and comprising the I 148M variation. In some embodiments, the nucleic acid molecule encoding the variant PNPLA3 protein is genomic DNA. In some embodiments, the genomic DNA comprises an ATG codon at the positions corresponding to positions 5107 to 5109 according to SEQ ID NO:31. In some embodiments, the genomic DNA comprises the nucleotide sequence according to SEQ ID NO:31, or a nucleotide sequence having at least 90% sequence identity to SEQ I D NO:31 and encoding a PNPLA3 protein which comprises the I148M variation. In some embodiments, the nucleic acid molecule encoding the variant PNPLA3 protein is mRNA. In some embodiments, the mRNA comprises an AUG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:34. In some embodiments, the mRNA comprises the nucleotide sequence according to SEQ ID NO:34, or a nucleotide sequence having at least 90% sequence identity to SEQ I D NO:34 and encoding a PNPLA3 protein which comprises the I148M variation. I n some embodiments, the mRNA comprises an AUG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:35. In some embodiments, the mRNA comprises the nucleotide sequence according to SEQ ID NO:35, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:35 and encoding a PNPLA3 protein which comprises the I 148M variation. In some embodiments, the nucleic acid molecule encoding the variant PNPLA3 protein is cDNA. In some embodiments, the cDNA comprises an ATG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:38. In some embodiments, the cDNA comprises the nucleotide sequence according to SEQ ID NO:38, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:38 and encoding a PNPLA3 protein which comprises the I148M variation. In some embodiments, the cDNA comprises an ATG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:39. In some embodiments, the cDNA comprises the nucleotide sequence according to SEQ ID NO:39, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:39 and encoding a PNPLA3 protein which comprises the I148M variation.

[0372] In some embodiments, the liver disease is a chronic liver disease. In some

[0373] embodiments, the chronic liver disease is nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), non-alcoholic steatohepatitis (NASH), cirrhosis, steatosis, or hepatocellu lar carcinoma. In some embodiments, the liver disease is an alcoholic liver disease. In some embodiments, the alcoholic liver disease comprises one or more of cirrhosis, steatosis, or hepatocellular carcinoma resulting from alcohol consumption. In some embodiments, the liver disease is a non-alcoholic liver disease. I n some embodiments, the non-alcoholic liver disease comprises nonalcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). In some embodiments, the non-alcoholic liver disease comprises one or more of cirrhosis, steatosis, or hepatocel lular carcinoma not caused by alcohol consumption.

[0374] In some embodiments, the human subject is homozygous or heterozygous for fu nctional HSD17B13.

[0375] All patent documents, websites, other publications, accession nu mbers and the like cited above or below are incorporated by reference in their entirety for all purposes to the same extent as if each individual item were specifical ly and individually indicated to be so incorporated by reference. If different versions of a sequence are associated with an accession number at different times, the version associated with the accession number at the effective filing date of this application is meant. The effective filing date means the earlier of the actual filing date or filing date of a priority application referring to the accession number if applicable. Likewise, if different versions of a publication, website or the like are published at different times, the version most recently published at the effective filing date of the application is meant unless otherwise indicated. Any feature, step, element, embodiment, or aspect of the present disclosure can be used in combination with any other feature, step, element, embodiment, or aspect unless specifically indicated otherwise. Although the present disclosure has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be apparent that certain changes and modifications may be practiced within the scope of the appended claims.[037...

Claims

What is Claimed:

1. A method for identifying a hu man subject as a candidate for treating or inhibiting a liver disease, the method comprising:determining whether or not a sample from the subject comprises:i) a first nucleic acid encoding a patatin like phospholipase domain containing 3 (PNPLA3) protein comprising an I148M variation and a second nucleic acid encoding a functional HSD17B13 protein; and / orii) a PNPLA3 protein comprising an I148M variation and a functional HSD17B13 protein; andidentifying the subject as a candidate for treating or inhibiting a liver disease by inhibiting HSD17B13 when both the first and second nucleic acids as defined in i) and / or both of the proteins as defined in ii) are detected.

2. The method according to claim 1 wherein the first nucleic acid molecule comprises genomic DNA, mRNA, or a cDNA obtained from mRNA.

3. The method according to claim 2, wherein:the genomic DNA comprises an ATG codon at the positions corresponding to positions 5107 to 5109 according to SEQ ID NO:31;the mRNA comprises an AUG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:34;the mRNA comprises an AUG codon at the positions corresponding to positions 430 to432 according to SEQ ID NO:35;the cDNA comprises an ATG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:38; orthe cDNA comprises an ATG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:39.

4. The method according to claim 2 or claim 3, wherein :the genomic DNA comprises the nucleotide sequence according to SEQ ID NO:31, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:31 and encoding a PNPLA3 protein which comprises the I148M variation;the mRNA comprises the nucleotide sequence according to SEQ I D NO:34, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:34 and encoding a PNPLA3 protein which comprises the I148M variation;the mRNA comprises the nucleotide sequence according to SEQ I D NO:35, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:35 and encoding a PNPLA3 protein which comprises the I148M variation;the cDNA comprises the nucleotide sequence according to SEQ I D NO:38, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:38 and encoding a PNPLA3 protein which comprises the I148M variation; orthe cDNA comprises the nucleotide sequence according to SEQ I D NO:39, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:39 and encoding a PNPLA3 protein which comprises the I148M variation.

5. The method according to any one of claims 1 to 4, wherein detecting the first nucleic acid comprises:sequencing at least a portion of the first nucleic acid, wherein the portion comprises the codon which encodes the I148M variation; orhybridizing the first nucleic acid with a probe or primer that specifically hybridizes to a portion of the first nucleic acid, wherein the portion comprises the codon encoding the I148M variation.

6. The method according to claim 5, wherein the probe or primer is an allele-specific probe or primer, and wherein the probe or primer optionally comprises a label.

7. The method according to any one of claims 1 to 6, fu rther comprising determining whether the su bject is homozygous or heterozygous for the I148M variation.

8. The method according to any one of claims 1 to 7, wherein the second nucleic acid comprises genomic DNA, mRNA, or a cDNA obtained from mRNA.

9. The method according to claim 8, wherein:the genomic DNA comprises an adenine at the position corresponding to position 12,667 according to SEQ ID NO:1;the genomic DNA comprises the nucleotide sequence according to SEQ ID NO:1, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:1 and encoding a fu nctional HSD17B13 proteinthe mRNA comprises the nucleotide sequence according to SEQ I D NO:3, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:3 and encoding a fu nctional HSD17B13 protein;the imRNA comprises the nucleotide sequence according to SEQ I D NO:4 or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:4 and encoding a fu nctional HSD17B13 protein;the mRNA comprises the nucleotide sequence according to SEQ I D NO:7 or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:7 and encoding a fu nctional HSD17B13 protein;the mRNA comprises the nucleotide sequence according to SEQ I D NO:ll or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:1l and encoding a fu nctional HSD17B13 protein;the cDNA comprises the nucleotide sequence according to SEQ I D NO:12 or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:12 and encoding a fu nctional HSD17B13 protein;the cDNA comprises the nucleotide sequence according to SEQ I D NO:13 or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:13 and encoding a fu nctional HSD17B13 protein;the cDNA comprises the nucleotide sequence according to SEQ I D NO:16 or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:16 and encoding a fu nctional HSD17B13 protein; orthe cDNA comprises the nucleotide sequence according to SEQ I D NO:20 or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:20 and encoding a fu nctional HSD17B13 protein.

10. The method according to any one of claims 1 to 9, wherein detecting the second nucleic acid comprises:sequencing the second nucleic acid; orhybridizing the second nucleic acid with a probe or primer that specifically hybridizes to a portion of the second nucleic acid, wherein the portion comprises the adenine at the position corresponding to position 12,667 according to SEQ I D NO:l.

11. The method according to claim 107wherein the probe or primer is an allele-specific probe or primer, and wherein the probe or primer optionally comprises a label.

12. The method according to any one of claims 1 to 11, further comprising determining whether the su bject is homozygous or heterozygous for the second nucleic acid encoding a fu nctional HSD17B13 protein in the sample.

13. The method according to any one of claims 1 to 12, further comprising administering an inhibitor of HSD17B13 to the subject.

14. The method according to any one of claims 1 to 13, wherein the liver disease is an alcoholic liver disease.

15. The method according to claim 14, wherein the alcoholic liver disease comprises one or more of cirrhosis, steatosis, or hepatocellular carcinoma resu lting from alcohol consumption.

16. The method according to any one of claims 1 to 13, wherein the liver disease is a nonalcoholic liver disease.

17. The method according to claim 16, wherein the non-alcoholic liver disease comprises nonalcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

18. The method according to claim 16, wherein the non-alcoholic liver disease comprises one or more of cirrhosis, steatosis, or hepatocellular carcinoma not caused by alcohol consumption.

19. A method of treating or inhibiting a liver disease, comprising administering an inhibitor of hyd roxysteroid 17-beta dehydrogenase 13 (HSD17B13) to a hu man liver disease patient expressing a patatin like phospholipase domain containing 3 (PNPLA3) protein comprising an I 148M variation such that the liver disease is treated or inhibited in the patient.

20. The method according to claim 19, wherein the liver disease is an alcoholic liver disease.

21. The method according to claim 20, wherein the alcoholic liver disease comprises one or more of cirrhosis, steatosis, or hepatocellular carcinoma resu lting from alcohol consumption.

22. The method according to claim 19, wherein the liver disease is a non-alcoholic liver disease.

23. The method according to claim 22, wherein the non-alcoholic liver disease comprises nonalcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

24. The method according to claim 22, wherein the non-alcoholic liver disease comprises one or more of cirrhosis, steatosis, or hepatocellular carcinoma not caused by alcohol consumption.

25. The method according to any one of claims 19 to 24, wherein the patient is obese.

26. The method according to any one of claims 19 to 25, wherein the patient has a fatty liver.

27. The method according to any one of claims 19 to 26, wherein the patient has been determined to express the variant PNPLA3 protein by detection of the variant PNPLA3 protein in a sample from the subject.

28. The method according to any one of claims 19 to 27, wherein the variant PNPLA3 protein comprises a methionine at a position corresponding to position 148 according to SEQ I D NO:42.

29. The method according to claim 26 or claim 28, wherein the variant PNPLA3 protein in the sample comprises the amino acid sequence according to SEQ ID NO:42, or an amino acid sequence having at least 90% sequence identity to SEQ ID NO:42 and comprising the I148M variation.

30. The method according to any one of claims 27 to 29, wherein the variant PNPLA3 protein is detected by amino acid sequencing or by an immunoassay.

31. The method according to any one of claims 19 to 26, wherein the subject has been determined to express the variant PNPLA3 protein by detection of a nucleic acid molecule encoding the variant PNPLA3 protein in a sample from the subject.

32. The method according to claim 31, wherein the variant PNPLA3 protein comprises a methionine at the position corresponding to position 148 according to SEQ I D NO:42.

33. The method according to claim 32, wherein the variant PNPLA3 protein comprises the amino acid sequence according to SEQ ID NO:42, or an amino acid sequence having at least 90% sequence identity to SEQ ID NO:42 and comprising the I148M variation.

34. The method according to any one of claims 31 to 33, wherein the nucleic acid molecule encoding the variant PNPLA3 protein comprises genomic DNA, mRNA, or cDNA obtained from mRNA.

35. The method according to any one of claims 31 to 34, wherein the nucleic acid molecule comprises genomic DNA comprising an ATG codon at the positions corresponding to positions5107 to 5109 according to SEQ ID NO:31.

36. The method according to claim 34 or claim 35, wherein the genomic DNA comprises the nucleotide sequence according to SEQ ID NO:31, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:31 and encoding a PNPLA3 protein which comprises the I 148M variation.

37. The method according to any one of claims 31 to 34, wherein the nucleic acid molecule comprises mRNA comprising an AUG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:34.

38. The method according to claim 34 or 37, wherein the mRNA comprises the nucleotide sequence according to SEQ ID NO:34, or a nucleotide sequence having at least 90% sequence identity to SEQ I D NO:34 and encoding a PNPLA3 protein which comprises the I148M variation.

39. The method according to any one of claims 31 to 34, wherein the nucleic acid molecule comprises mRNA comprising an AUG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:35.

40. The method according to claim 34 or claim 39, wherein the mRNA comprises the nucleotide sequence according to SEQ ID NO:35, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:35 and encoding a PNPLA3 protein which comprises the I148M variation.

41. The method according to any one of claims 31 to 34, wherein the nucleic acid molecule comprises cDNA obtained from mRNA, the cDNA comprising an ATG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:38.

42. The method according to claim 34 or claim 41, wherein the cDNA comprises the nucleotide sequence according to SEQ ID NO:38, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:38 and encoding a PNPLA3 protein which comprises the I 148M variation.

43. The method according to any one of claims 31 to 34, wherein the nucleic acid molecule comprises cDNA obtained from mRNA, the cDNA comprising an ATG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:39.

44. The method according to claim 34 or claim 43, wherein the cDNA comprises the nucleotide sequence according to SEQ ID NO:39, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:39 and encoding a PNPLA3 protein which comprises the I148M variation.

45. The method according to any one of claims 31 to 34, wherein the nucleic acid is detected by sequencing at least a portion of the nucleic acid, wherein the portion comprises a codon encoding the I148M variation.

46. The method according to any one of claims 31 to 44, wherein the nucleic acid is detected by hybridization of the nucleic acid with a probe or primer that specifically hybridizesto a portion of the nucleic acid, wherein the portion comprises a codon encoding the I148M variation.

47. The method according to claim 46, wherein the probe or primer is an allele-specific probe or primer.

48. The method according to claim 46 or claim 47, wherein the probe or primer comprises a label.

49. The method according to any one of claims 19 to 48, wherein the patient is homozygous for a gene encoding the variant PNPLA3 protein.

50. The method according to any one of claims 19 to 48, wherein the patient is heterozygous for a gene encoding the variant PNPLA3 protein.

51. The method according to claim 49 or claim 50, wherein the patient further is homozygous for a gene encoding a functional HSD17B13 protein.

52. The method according to claim 49 or claim 50, wherein the patient further is heterozygous for a gene encoding a functional HSD17B13 protein.

53. The method according to claim 51 or claim 52, wherein the functional HSD17B13 protein is a HSD17B13 protein which has at least 10% of the activity of wild type HSD17B13 protein.

54. The method according to claim 52, wherein the patient is heterozygous for the gene encoding the functional HSD17B13 protein and a gene encoding a loss of fu nction variant of HSD17B13.

55. The method according to claim 54, wherein the functional HSD17B13 protein is a HSD17B13 protein which has at least 10% of the activity of wild type HSD17B13 protein.

56. The method according to any one of claims 19 to 55, wherein the HSD17B13 in hibitor fu rther is capable of inhibiting one or more of HSD17B1, HSD17B2, HSD17B3, HSD17B4, HSD17B6, HSD17B7, HSD17B8, HSD17B10, HSD17B11, HSD17B12, HSD17B13, HSD17B14, DH RS3, or RDH10.

57. An inhibitor of HSD17B13 for use in the treatment of a liver disease in a hu man subject having a PNPLA3 protein comprising an I148M variation and having a functional HSD17B13 protein.

58. The inhibitor for the use according to claim 57, wherein the human subject has been tested positive for a PNPLA3 protein comprising an I148M variation and for a functional HSD17B13 protein.

59. The inhibitor for the use according to claim 57 or 58, wherein the treatment comprises determining whether or not the hu man subject has a PNPLA3 protein comprising an I 148M variation and a functional HSD17B13 protein.

60. The inhibitor for the use according to any one of claims 56 to 58, wherein the hu man su bject has been identified as being a candidate for treating or inhibiting a liver disease by inhibiting HSD17B13 by using the method as defined in any one of claims 1 to 18.

61. The inhibitor according to any one of claims 57 to 60, wherein the variant PNPLA3 protein comprises a methionine at the position corresponding to position 148 according to SEQ I D NO:42.

62. The inhibitor according to claim 61, wherein the variant PNPLA3 protein comprises the amino acid sequence according to SEQ ID NO:42, or an amino acid sequence having at least 90% sequence identity to SEQ ID NO:42 and comprising the I148M variation.

63. The inhibitor according to any one of claims 57 to 60, wherein the nucleic acid molecule encoding the variant PNPLA3 protein is genomic DNA.

64. The inhibitor according to claim 63, wherein the genomic DNA comprises an ATG codon at the positions corresponding to positions 5107 to 5109 according to SEQ ID NO:31.

65. The inhibitor according to claim 64, wherein the genomic DNA comprises the nucleotide sequence according to SEQ ID NO:31, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:31 and encoding a PNPLA3 protein which comprises the I148M variation.

66. The inhibitor according to any one of claims 56 to 60, wherein the nucleic acid molecule encoding the variant PNPLA3 protein is mRNA.

67. The inhibitor according to claim 66, wherein the mRNA comprises an AUG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:34.

68. The inhibitor according to claim 67, wherein the mRNA comprises the nucleotide sequence according to SEQ ID NO:34, or a nucleotide sequence having at least 90% sequence identity to SEQ I D NO:34 and encoding a PNPLA3 protein which comprises the I148M variation.

69. The inhibitor according to claim 66, wherein the mRNA comprises an AUG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:35.

70. The inhibitor according to claim 69, wherein the mRNA comprises the nucleotide sequence according to SEQ ID NO:35, or a nucleotide sequence having at least 90% sequence identity to SEQ I D NO:35 and encoding a PNPLA3 protein which comprises the I148M variation.

71. The inhibitor according to any one of claims 57 to 60, wherein the nucleic acid molecule encoding the variant PNPLA3 protein is cDNA.

72. The inhibitor according to claim 71, wherein the cDNA comprises an ATG codon at the positions corresponding to positions 442 to 444 according to SEQ ID NO:38.

73. The inhibitor according to claim 72, wherein the cDNA comprises the nucleotide sequence according to SEQ ID NO:38, or a nucleotide sequence having at least 90% sequence identity to SEQ I D NO:38 and encoding a PNPLA3 protein which comprises the I148M variation.

74. The inhibitor according to claim 71, wherein the cDNA comprises an ATG codon at the positions corresponding to positions 430 to 432 according to SEQ ID NO:39.

75. The inhibitor according to claim 74, wherein the cDNA comprises the nucleotide sequence according to SEQ ID NO:39, or a nucleotide sequence having at least 90% sequence identity to SEQ I D NO:39 and encoding a PNPLA3 protein which comprises the I148M variation.

76. The inhibitor according to any one of claims 57 to 75, wherein the liver disease is an alcoholic liver disease.

77. The inhibitor according to claim 76, wherein the alcoholic liver disease comprises one or more of cirrhosis, steatosis, or hepatocellular carcinoma resu lting from alcohol consumption.

78. The inhibitor according to any one of claims 57 to 75, wherein the liver disease is a non-alcoholic liver disease.

79. The inhibitor according to claim 78, wherein the non-alcoholic liver disease comprises nonalcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

80. The inhibitor according to claim 78, wherein the non-alcoholic liver disease comprises one or more of cirrhosis, steatosis, or hepatocellular carcinoma not caused by alcohol consumption.

81. The inhibitor according to any one of claims 57 to 80, wherein the hu man subject is homozygous or heterozygous for functional HSD17B13.