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

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 (r(2)=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.