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Confirmation of ALDH2 as a Major Locus of Drinking Behavior and of Its Variants Regulating Multiple Metabolic Phenotypes in a Japanese Population
Open accessAbstract
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.
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Metadata
- Authors
- Takeuchi, F., Isono, M., Nabika, T., Katsuya, T., Sugiyama, T., Yamaguchi, S., Kobayashi, S., Ogihara, T., Yamori, Y., Fujioka, A., & Kato, N.
- Affiliations
- National Center for Global Health and Medicine (JP)
- Shimane University (JP)
- The University of Osaka (JP)
- The Institute of Medical Science, Asahi Life Foundation (JP)
- Shimane University Hospital (JP)
- Osaka Prefectural Medical Center (JP)
- Mukogawa Women's University (JP)
- Amagasaki Health Medical Foundation
- ORCID
- Venue
- Circulation Journal
- Publisher
- Japanese Circulation Society
- Published
- 2011
- Volume
- 75
- Issue
- 4
- Pages
- 911-918
- ISSN
- 1346-9843 (ISSN-L)
- 1347-4820
- OpenAlex
- W2038050993
- Cited by
- 146
- References
- 39
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 10 · 2023: 7 · 2022: 9 · 2021: 16 · 2020: 10 · 2019: 12 · 2018: 11 · 2017: 16 · 2016: 11 · 2015: 9 · 2014: 13 · 2013: 10 · 2012: 5
- FWCI
- 6.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Journal (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Funders
- National Center for Global Health and Medicine
- National Institute of Biomedical Innovation
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- ALDH2, drinking behavior, alcohol consumption, rs671, ADH1B, rs1229984, alcohol metabolism, HDL cholesterol, liver enzymes, cardiovascular risk, pleiotropy, Japanese population
- MeSH terms
- Aldehyde Dehydrogenase, Mitochondrial, Adult, Aged, Aged, 80 and over, Aldehyde Dehydrogenase, Cardiovascular Diseases, Drinking Behavior, Humans, Japan, Male, Middle Aged, Risk Factors, Amino Acid Substitution, Genetic Predisposition to Disease, Mutation, Missense, Polymorphism, Single Nucleotide, Asian People, Genome-Wide Association Study, Genetic Loci
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