Genome‐Wide Association Study Identifies Loci for Liver Enzyme Concentrations in Mexican Americans: The GUARDIAN Consortium

Abstract

Objective: Mexican-American ancestry populations are at increased risk of non-alcoholic fatty liver disease (NALFD). Our objective was to determine whether loci in known and novel genes were associated with variation of aspartate aminotransferase (AST, n=3644), alanine aminotransferase (ALT, n=3595) and gamma-glutamyl transferase (GGT, n=1577) by conducting the first genome-wide association study (GWAS) of liver enzymes, which commonly measure liver function, in Mexican-American ancestry. Methods: Levels of AST, ALT, and GGT were determined by enzymatic colorimetric assays. A multi-cohort Mexican-American ancestry GWAS was performed. SNPs were tested for association with liver outcomes by multivariable linear regression using an additive genetic model. Association analyses were carried out separately in each cohort followed by a non-parametric meta-analysis. Results: In the PNPLA3 gene, rs4823173 (P=3.44×10−10), rs2896019 (P=7.29×10−09), and rs2281135 (P=8.73×10−09), were significantly associated with AST levels. Although not genome-wide significant, these same SNPs were the top hits for ALT (P=7.12×10−08, P=1.98×10−07, and P=1.81×10−07, respectively). The strong correlation (r2=1.0) for these SNPs indicates a single hit in the PNPLA3 gene. No genome-wide significant associations were found for GGT. Conclusion: PNPLA3, a locus previously identified with ALT, AST, and NAFLD in European and Japanese GWAS, is also associated with liver enzymes in Mexican-American ancestry populations.

Patatin‐Like Phospholipase Domain‐Containing Protein 3 I148M and Liver Fat and Fibrosis Scores Predict Liver Disease Mortality in the U.S. Population

“…Similarly, rs2281135, along with I148M in the same linkage disequilibrium block, was associated with NAFLD presence and severity and with elevated ALT in a genome‐wide association study in a Korean population . Among Mexican Americans, rs2281135 was associated with increased ALT, and among men with higher AST in one population and with both aminotransferases in a multicohort genome‐wide association study conducted by the GUARDIAN Consortium …”

“…(10)(11)(12)(13)(14) Subsequently, a relationship of PNPLA3 variations with serum liver enzyme elevation was shown, including a strong association with rs2281135 in Mexican-American populations. (15,16) rs2281135 was also associated with NAFLD diagnoses in Estonian Biobank electronic health records and with NAFLD and elevated alanine aminotransferase (ALT) in a Korean population. (17,18) rs2281135 is an intronic variant in linkage disequilibrium with I148M in blacks, whites, and Mexican Americans.…”

“…(19) rs2281135 is less well studied, but associations with liver disease were reported. (16) In an exploratory phenome-wide association study linking genetic variants, including liverdisease-associated SNPs, to electronic health records from the Estonian Biobank, rs2281135 was associated with ICD-10, Clinical Modification code K76 (nonalcoholic liver diseases, including NAFLD). (17) In that study, rs2281135 was used as a proxy for I148M, which was not available on the screening array used by the Biobank and met the minimum linkage disequilibrium criterion of r 2 ≥ 0.6 set by the investigators.…”

“…(18) Among Mexican Americans, rs2281135 was associated with increased ALT, and among men with higher AST in one population and with both aminotransferases in a multicohort genome-wide association study conducted by the GUARDIAN Consortium. (15,16) In a recent study of primary health care records of over 17 million adults from four European databases, rates of recorded NAFLD increased from 0.6% in 2007 to 1.85% in 2014. (41) These findings highlight the need for broader physician education and simple, robust evaluation tools that can be implemented in primary care settings.…”

GWAS of serum ALT and AST reveals an association ofSLC30A10Thr95Ile with hypermanganesemia symptoms

“…Circulating liver enzymes are sensitive biomarkers of liver injury; in particular, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are released into the circulation during damage to hepatocyte membranes 1,2 . One powerful approach for understanding the molecular basis of liver disease has been to perform genome-wide association studies (GWAS) of levels of circulating liver enzymes across large population samples 1,[3][4][5][6][7][8][9][10][11][12][13] . Combined GWAS of ALT and AST have previously revealed genetic associations providing potential therapeutic targets for liver disease such as PNPLA3 14 and HSD17B13 15 .…”