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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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BackgroundGWAS of 165,084 Japanese individuals identified nine loci associated with dietary habits
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InfluentialThe genetics of alcohol dependence
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BackgroundInfluentialGenome-wide association study of pathological gambling
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“A number of NS variants have already been strongly associated with many of these traits, such as rs671 (Glu504Lys) in ALDH2 with alcohol intake [23], rs17632542 [Ile179Thr] in KLK3 and circulating PSA levels [24,25] and rs198977 [Arg250Trp] in KLK2 and the ratio of free to total PSA [26].”
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Identification of type 2 diabetes loci in 433,540 East Asian individualsPreprint
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BackgroundCardioprotection induced by a brief exposure to acetaldehyde: role of aldehyde dehydrogenase 2
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Common variants at 12q24 are associated with drinking behavior in Han Chinese
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“In addition, one GWAS performed in the Japanese population confirmed ALDH2 as a major locus regulating drinking behavior (13), and rs671 in the ALDH2 gene showed the strongest association between 4780 drinkers and 1940 nondrinkers in their joint analysis (OR: 0.”
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InfluentialMental health dished up—the use of iPSC models in neuropsychiatric research
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“GWA studies for quantity of alcohol consumption, however, have only identified a handful of genes so far (Chen et al., 2012; Schumann et al., 2011; Takeuchi et al., 2011).”
Association between ALDH2 and ADH1B Polymorphisms and the Risk for Colorectal Cancer in Koreans
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“Certain polymorphisms in ADH1B and ALDH2 are particularly common in East Asians, affecting drinking behaviors [8-12].”
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“12 pleiotropic region, the functional nonsynonymous variant rs671 on ALDH2 which encodes the aldehyde dehydrogenase 2 family, has been reported to be associated with coronary artery diseases, blood pressure and alcohol consumption and is common in East-Asian populations in contrast to monomorphic in Europeans [7, 24].”
BackgroundXing, F., Matsumiya, T., Hayakari, R., Yoshida, H., Kawaguchi, S., Takahashi, I., Nakaji, S., & Imaizumi, T. (2016) · PLoS ONE · doi:10.1371/journal.pone.0151173 · Cited by 21
“To exclude the potential impact of the quality of these samples, we performed genotyping of rs671 in the ALDH2 gene, which affects dinking behaviour in the Japanese population, in these samples [24].”
MethodMeta-Analysis on Associations of Alcohol Metabolism Genes With Alcohol Use Disorder in East Asians
Zaso, M. J., Goodhines, P. A., Wall, T. L., & Park, A. (2019) · Alcohol and Alcoholism · doi:10.1093/alcalc/agz011 · Cited by 20
“All three alleles have demonstrated consistent, protective associations with alcohol use and AUD across genome-wide association studies (Takeuchi et al., 2011; Park et al., 2013; Quillen et al., 2014) and meta-analyses (Whitfield, 1997; Luczak et al.”
BackgroundSutoh, Y., Hachiya, T., Suzuki, Y., Komaki, S., Ohmomo, H., Kakisaka, K., Wang, T., Takikawa, Y., & Shimizu, A. (2020) · Scientific Reports · doi:10.1038/s41598-020-73263-1 · Cited by 21
Katsarou, M., Karakonstantis, K., Demertzis, N. S., Vourakis, E., Σκαρπαθιώτη, Α., Nosyrev, A. E., Tsatsakis, A. M., Kalogridis, T., & Drakoulis, N. (2017) · Pharmacology Research & Perspectives · doi:10.1002/prp2.326 · Cited by 20
“Polymorphism rs671 has been associated with reduced desire for alcohol consumption and protective role against alcohol dependence (Takeuchi et al. 2011).”
BackgroundGenomics and epigenomics of addiction
Maldonado, R. J., Calvé, P., García‐Blanco, A., Domingo‐Rodriguez, L., Senabre, E., & Martín‐García, E. (2021) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32843 · Cited by 24
“…with alcohol pharmacokinetics, such as alcohol dehydrogenase (ADH1B-ADH1C) and aldehyde dehydrogenase (ALDH2) as well some other genes linked with regulatory protein functions, such as the SERPINC1, GCKR, SGOL1, KLB, AUTS2, and TF (Clarke et al., 2017; Takeuchi et al., 2011; Way et al., 2015).”
BackgroundLiu, Y.-R., Tantoh, D. M., Lin, C.-C., Hsiao, C.-H., & Liaw, Y. (2021) · Arthritis Research & Therapy · doi:10.1186/s13075-021-02497-9 · Cited by 20
“ALDH2 polymorphisms contribute not only to the metabolism of ethanol and acetaldehyde [25] but also impact predisposition to alcohol-related morbid conditions like hyperuricemia and gout among Asians [18, 19, 26–28].”
BackgroundInfluentialShin, C., Kwack, K., Cho, N. H., Kim, S. H., & Baik, I. (2015) · Nutrition Research and Practice · doi:10.4162/nrp.2015.9.1.79 · Cited by 20
“The ALDH2 polymorphism is reportedly associated with alcohol consumption [2,3], cancer [4,5], hypertension [6,7], diabetes mellitus [8], and coronary artery disease (CAD) [9-11] primarily among Asian populations.”
BackgroundOff-target phenotypes in forensic DNA phenotyping and biogeographic ancestry inference: A resource
Bradbury, C., Köttgen, A., & Staubach, F. (2018) · Forensic Science International Genetics · doi:10.1016/j.fsigen.2018.10.010 · Cited by 22
Matsumoto, A., Vasiliou, V., Kawamoto, T., Tanaka, K., & Ichiba, M. (2014) · Alcoholism Clinical and Experimental Research · doi:10.1111/acer.12462 · Cited by 19
“Practically, lifespan reduction by high-dose EtOH consumption is unlikely to occur in people with ALDH2*2/*2 because the ALDH2*2 allele has a major effect on the level of alcohol drinking (Takeuchi et al., 2011).”
BackgroundYang, C., Li, C., Kranzler, H. R., Farrer, L. A., Zhao, H., & Gelernter, J. E. (2013) · Human Genetics · doi:10.1007/s00439-013-1399-8 · Cited by 19
“From a GWas in Japanese, a cluster of 12 snPs in the alDH2 gene were significantly associated with aD (takeuchi et al. 2010). the strong effect of alDH2 on aD risk in asian populations has been confirmed by meta-analysis (li et al. 2012) and by a recent GWas conducted by us in a Chinese population…”
BackgroundMethodInfluentialIndependent effects of ADH1B and ALDH2 common dysfunctional variants on gout risk
Sakiyama, M., Matsuo, H., Akashi, A., Shimizu, S., Higashino, T., Kawaguchi, M., Nakayama, A., Naito, M., Kawai, S., Nakashima, H., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-02528-z · Cited by 20
Sasakabe, T., Wakai, K., Kawai, S., Hishida, A., Naito, M., Suzuki, S., Nindita, Y., Arisawa, K., Kita, Y., Hara, M., et al. (2017) · Journal of Epidemiology · doi:10.2188/jea.je20160189 · Cited by 19
“20,21 In alcoholic men, a low odds ratio for a high LDL cholesterol level was reported in those with the ADH1B His allele.”
Association of Alcohol Drinking and Helicobacter pylori Infection
Du, P., Zhang, C., Wang, A., Ma, Z., Shen, S., & Li, X. (2021) · Journal of Clinical Gastroenterology · doi:10.1097/mcg.0000000000001638 · Cited by 18
Heme oxygenase 1 protects ethanol-administered liver tissue in Aldh2 knockout mice
Matsumoto, A., Thompson, D., Chen, Y., Vasiliou, V., Kawamoto, T., & Ichiba, M. (2016) · Alcohol · doi:10.1016/j.alcohol.2016.02.004 · Cited by 16
Genotyping of single nucleotide polymorphisms using the SNP-RFLP method
Saifullah, S., & Tsukahara, T. (2018) · BioScience Trends · doi:10.5582/bst.2018.01102 · Cited by 16
“, 2011, genotyped the SNP, rs671, in the Japanese population and found a strong association with alcoholism and subsequently also with cardiovascular diseases, particularly for individuals with the AA genotype at this locus (7).”
BackgroundMasaoka, H., Ito, H. M., Gallus, S., Watanabe, M., Yokomizo, A., Eto, M., & Matsuo, K. (2017) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2016.12.015 · Cited by 15
“In animal experiments, acetaldehydenduced acquisition of nicotine self-administration was observed nly in adolescent rats, and not in adult rats (Belluzzi et al., 2005; alhout et al., 2007).”
BackgroundZaso, M. J., Desalu, J. M., Kim, J., Suryadevara, K., Belote, J. M., & Park, A. (2017) · The American Journal of Drug and Alcohol Abuse · doi:10.1080/00952990.2017.1339054 · Cited by 14
Importance of an Aldehyde Dehydrogenase 2 Polymorphism in Preventive Medicine
Matsumoto, A. (2018) · Nippon Eiseigaku Zasshi (Japanese Journal of Hygiene) · doi:10.1265/jjh.73.9 · Cited by 14
Choi, C. K., Yang, J.-H., Kweon, S., Cho, S., Kim, H., Myung, E., & Shin, M. (2021) · BMC Cancer · doi:10.1186/s12885-021-07993-4 · Cited by 14
Juraeva, D., Treutlein, J., Scholz, H., Frank, J., Degenhardt, F., Cichon, S., Ridinger, M., Mattheisen, M., Witt, S. H., Lang, M., et al. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.178 · Cited by 14
Alcohol increases treatment failure for Helicobacter pylori eradication in Asian populations
Yu, J., Lv, Y., Yang, P., Jiang, Y., Qin, X., & Wang, X. (2023) · BMC Gastroenterology · doi:10.1186/s12876-023-03002-z · Cited by 12
“The primary pathway by which ethanol is metabolized involves its degradation by alcohol dehydrogenase into acetaldehyde (an intermediate metabolite), which is then acted upon by ALDH and converted into acetic acid [49].”
BackgroundImatoh, T., Yengo, L., Rocheleau, G., Kamimura, S., Maeda, S., Miyazaki, M., & Froguel, P. (2018) · Lipids · doi:10.1002/lipd.12087 · Cited by 12
Tao, Y., Huang, X., Xie, Y., Zhou, X., He, X., Tang, S., Liao, M., Chen, Y., Tan, A., Chen, Y., et al. (2018) · Gene · doi:10.1016/j.gene.2018.11.001 · Cited by 11
Li, D., Li, J., & Guo, Y.-F. (2014) · Chinese Medical Journal · doi:10.3760/cma.j.issn.0366-6999.20132647 · Cited by 11
Scammell, B. H., Tchio, C. I. M., Song, Y., Nishiyama, T., Louie, T., Dashti, H. S., Nakatochi, M., Zee, P. C., Daghlas, I., Momozawa, Y., et al. (2023) · Human Molecular Genetics · doi:10.1093/hmg/ddad101 · Cited by 12
Gao, Y., Xie, X., Ma, Y.-T., Yang, Y., Li, X., Fu, Z.-Y., Zheng, Y., Ma, X., Chen, B., Liu, F., et al. (2013) · Lipids in Health and Disease · doi:10.1186/1476-511x-12-97 · Cited by 11
“From these subjects participating in CRS (n=14 618), we selected 1821 participants who were free from diabetes, hypertension, any history of CAD, or any history of taking lipid-lowering drugs.”
BackgroundInfluentialThe ALDH2 gene rs671 polymorphism is not associated with essential hypertension
Li, Z., Kong, C., Sun, K., & Wang, L. (2017) · Clinical and Experimental Hypertension · doi:10.1080/10641963.2017.1299749 · Cited by 11
“Acetaldehyde dehydrogenase 2 (ALDH2) has a critical role in the process of ethanol metabolism to detoxify acetaldehyde into acetic acid (11).”
BackgroundChen, I., Kuo, P., Yang, A. C., Tsai, S., Liu, T., Liu, H., Lan, T., Chen, H., Huang, H., Chung, R., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-75199-y · Cited by 11
Almli, L. M., Lori, A., Meyers, J. L., Shin, J., Fani, N., Maihofer, A. X., Nievergelt, C. M., Smith, A. K., Mercer, K. B., Kerley, K. A., et al. (2017) · Addiction Biology · doi:10.1111/adb.12569 · Cited by 11
“…conducting GWAS on quantitative measures of alcohol use has gained popularity (Agrawal et al. 2009; Baik et al. 2011; Heath et al. 2011; Schumann et al. 2011; Takeuchi et al. 2011; Agrawal et al. 2013; Kapoor et al. 2013; Wang et al. 2013; Xu et al. 2015; Clarke et al. 2017; Webb et al. 2017).”
BackgroundHayashida, H., Matsumoto, A., Nanri, H., Nishida, Y., Takagi, Y., & Hara, M. (2023) · Environmental Health and Preventive Medicine · doi:10.1265/ehpm.22-00276 · Cited by 10
Matsumura, Y., Li, N., Alwaseem, H., Pagovich, O. E., Crystal, R. G., Greenblatt, M. B., & Stiles, K. M. (2019) · Human Gene Therapy · doi:10.1089/hum.2019.268 · Cited by 12
“Even without alcohol consumption, the body mass index is lower in individuals with the ALDH2*2 allele.(47,48) Long-term exposure to acetaldehyde impeded growth of Wistar rats in a dose-dependent manner,(49) suggesting the increased systemic acetaldehyde after ethanol consumption in ALDH2-deficient individuals may cont…”
BackgroundZhang, L.-Q., Zhang, L.-Q., Song, X., Xue-Ke, Z., Jia, H., Zhang, P., Wang, L.-W., Meng, H., Ku, J.-W., Kong, G.-Q., et al. (2017) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2016.0089 · Cited by 9
Shang, D., Wang, P., Tang, W., Mo, R., Lai, R., Lu, J. L., Li, Z., Wang, X., Cai, W., Wang, H., et al. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.811639 · Cited by 9
“Alcohol is oxidized to acetaldehyde by ADH, and acetaldehyde is further metabolized to acetate by ALDH, which largely depends on ALDH2 (22).”
BackgroundIsomura, M., Wang, T., Yamasaki, M., Hasan, M. Z., Shiwaku, K., & Nabika, T. (2015) · Disease Markers · doi:10.1155/2015/825435 · Cited by 9
Self-citationTranslational Molecular Approaches in Substance Abuse Research
Fulton, S. L., & Maze, I. S. (2019) · Handbook of experimental pharmacology · doi:10.1007/164_2019_259 · Cited by 9
Computational and Experimental Analysis of Genetic Variants
Prokop, J. W., Jdanov, V., Savage, L., Morris, M., Lamb, N. E., VanSickle, E., Stenger, C. L., Rajasekaran, S., & Bupp, C. P. (2022) · Comprehensive physiology · doi:10.1002/cphy.c210012 · Cited by 12
Association betweenALDH2Polymorphism and Gastric Cancer Risk in a Korean Population
Choi, C. K., Kweon, S., Cho, S., Kim, H., & Shin, M. (2020) · Journal of Korean Medical Science · doi:10.3346/jkms.2020.35.e148 · Cited by 8
Sasaki, T., Nishimoto, Y., Hirata, T., Abe, Y., Takebayashi, T., & Arai, Y. (2021) · Genes · doi:10.3390/genes12060799 · Cited by 8
“E504K variation was associated with current drinking even in the Japanese Oldest Old; however, no association was found between current drinking and ADH1B variation, which is consistent with previous studies [12].”
BackgroundResultInfluentialKim, H.-Y., Choi, C. K., Kweon, S., Lee, Y. H., Nam, H., Park, K.-S., Ryu, S. Y., Choi, S.-W., & Shin, M. (2020) · Journal of Korean Medical Science · doi:10.3346/jkms.2020.35.e14 · Cited by 9
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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