Confirmation of ALDH2 as a Major locus of drinking behavior and of its variants regulating multiple metabolic phenotypes in a Japanese population.
paper
Cited
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- Authors
- Takeuchi, Fumihiko; Isono, Masato; Nabika, Toru; Katsuya, Tomohiro; Sugiyama, Takao; Yamaguchi, Shuhei; Kobayashi, Shotai; Ogihara, Toshio; Yamori, Yukio; Fujioka, Akihiro; Kato, Norihiro
- Year
- 2011
- Journal
- Circulation journal : official journal of the Japanese Circulation Society
- PMID
- 21372407
- DOI
- 10.1253/circj.cj-10-0774
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 (β₯ 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<5Γ10(-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=3.6Γ10(-211) in the joint analysis). The association was also replicated for rs1229984 (OR=1.20, P<3.6Γ10(-4)). Furthermore, ALDH2 504Lys was associated with several metabolic traits, eg, lower levels of high-density lipoprotein cholesterol and liver enzymes-AST, ALT, and Ξ³GTP-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.
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