Abstract
Liver tests (LT), especially to measure AST, ALT and GGT levels, are widely used to evaluate the risk of alcohol-related liver disease (ALD). In this study, we investigated the potential genetic factors that modulate the association between LTs and alcohol consumption. We conducted a genome-wide interaction meta-analysis in 7856 Japanese subjects from Tohoku Medical Megabank Community-Based Cohort (TMM CommCohort) study recruited in 2013, and identified 2 loci (12q24 and 2p16) with genome-wide significance (P > 5 × 10–8). The significant variants in the 12q24 included rs671, a variant associated with alcohol intolerance and located at a coding exon of ALDH2. We found that the amount of alcohol consumption was associated with increased level AST/ALT ratio among the subjects with the rs671 GA genotype. The elevated AST/ALT ratio among subjects with moderate-to-high levels of drinking behavior and the rs671 GA genotype was due to decreased levels of ALT, which was not accompanied with significant differences in AST levels. Although the interaction effect was significant in both men and women, the effect was much larger in men. Our results suggest that the impact of alcohol consumption on LT varies according to the ALDH2 genotype, providing an insight for the accurate screening of ALD in drinkers with the rs671 GA genotype.
Highlights
Liver tests (LT), especially to measure AST, ALT and gamma-glutamyl transpeptidase (GGT) levels, are widely used to evaluate the risk of alcohol-related liver disease (ALD)
Using meta-analysis of the summaries of the genome-wide interaction analysis, we found that a variant in aldehyde dehydrogenase 2 (ALDH2) was significantly associated with ALT levels and the AST/ALT ratio through moderate-to-high alcohol consumption
We identified 2 loci associating LT with alcohol consumption. 12q24 is known as a locus harboring rs[671], a missense variant of the ALDH2 gene, which is responsible for acute alcohol flashing[40]
Summary
Liver tests (LT), especially to measure AST, ALT and GGT levels, are widely used to evaluate the risk of alcohol-related liver disease (ALD). We found that the amount of alcohol consumption was associated with increased level AST/ALT ratio among the subjects with the rs[671] GA genotype. Multiple studies suggested that the risk of alcohol misuse have heritability, the scale is still controversial[17] These genetic risks of alcohol misuse may result in increases in LT levels. The recently developed genome-wide variant × environment interaction analysis is a promising approach for the identification of genetic factors associated with markers indicative of risk for lifestyle diseases, via an interaction effect with environmental factor[20]. A previous study used genome-wide interaction analysis, resulting in the successful identification of the interaction between novel variants and the amount of daily sodium intakes in blood pressure[21]
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