Background: Normative alcohol use (or drinking behavior) influences the risk of cardiovascular disease in a multi-faceted manner. To identify susceptibility gene variants for drinking behavior, a 2-staged genome-wide association study was performed in a Japanese population.
Methods and Results: In the stage-1 scan, 733 cases and 729 controls were genotyped with 456,827 SNP markers. The associated loci without redundancy of linkage disequilibrium were further examined in the stage-2 general population panel comprising 2,794 drinkers (≥once per week), 1,521 chance drinkers (<once per week), and 1,351 non-drinkers. Along with genome-wide exploration, we aimed to replicate the trait association of a candidate gene SNP previously reported (rs1229984 in
ADH1B). A cluster of 12 SNPs on 12q24 were found to significantly (P<5×10
-8) associate with drinking behavior in stage 1, among which rs671 (a Glu-to-Lys substitution at position 504) in the
ALDH2 gene showed the strongest association (odds ratio (OR)=0.16, P=3.6×10
-211 in the joint analysis). The association was also replicated for rs1229984 (OR=1.20, P<3.6×10
-4). Furthermore,
ALDH2 504Lys was associated with several metabolic traits, eg, lower levels of high-density lipoprotein cholesterol and liver enzymes-AST, ALT, and γGTP-by interacting with alcohol intake.
Conclusions: Our results confirm
ALDH2 as a major locus regulating drinking behavior in the Japanese, indicating that the
ALDH2 504Lys variant exerts pleiotropic effects on risk factors of cardiovascular disease among drinkers. (
Circ J 2011;
75: 911-918)
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