Confirmation of ALDH2 as a Major locus of drinking behavior and of its variants regulating multiple metabolic phenotypes in a Japanese population

Circ J. 2011;75(4):911-8. doi: 10.1253/circj.cj-10-0774. Epub 2011 Mar 1.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Aldehyde Dehydrogenase / genetics*
  • Aldehyde Dehydrogenase / metabolism
  • Aldehyde Dehydrogenase, Mitochondrial
  • Amino Acid Substitution
  • Asian Continental Ancestry Group
  • Cardiovascular Diseases / enzymology
  • Cardiovascular Diseases / genetics*
  • Drinking Behavior*
  • Genetic Loci*
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Humans
  • Japan
  • Male
  • Middle Aged
  • Mutation, Missense
  • Polymorphism, Single Nucleotide*
  • Risk Factors

Substances

  • ALDH2 protein, human
  • Aldehyde Dehydrogenase
  • Aldehyde Dehydrogenase, Mitochondrial