Strong protective effect of the aldehyde dehydrogenase gene (ALDH2) 504lys (*2) allele against alcoholism and alcohol-induced medical diseases in Asians
Open accessAbstract
Alcohol is oxidized to acetaldehyde, which in turn is oxidized to acetate. The aldehyde dehydrogenase 2 gene (ALDH2) is the most important gene responsible for acetaldehyde metabolism. Individuals heterozygous or homozygous for the lys (A or *2) allele at the single nucleotide polymorphism (SNP) glu504lys (rs671) of ALDH2 have greatly reduced ability to metabolize acetaldehyde, which greatly decreases their risk for alcohol dependence (AD). Case-control studies have shown association between this SNP and alcohol dependence as well as alcohol-induced liver disease. However, some studies have produced insignificant results. Using cumulative data from the past 20 years predominately from Asian populations (from both English and Chinese publications), this meta-analysis sought to examine and update whether the aggregate data provide new evidence of statistical significance for the proposed association. Our results (9,678 cases and 7,331 controls from 53 studies) support a strong association of alcohol abuse and dependence, with allelic P value of 3 × 10(-56) and OR of 0.23 (0.2, 0.28) under the random effects model. The dominant model (lys-lys + lys-glu vs. glu-glu) also showed strong association with P value of 1 × 10(-44) and OR of 0.22 (0.18, 0.27). When stricter criteria and various sub-group analyses were applied, the association remained strong (for example, OR = 0.23 (0.18, 0.3) and P = 2 × 10(-28) for the alcoholic patients with alcoholic liver disease, cirrhosis, or pancreatitis). These findings provide confirmation of the involvement of the human ALDH2 gene in the pathogenesis of AD as well as alcohol-induced medical illnesses in East-Asians.
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Substantially different rates of alcohol use disorder across populations are partially explained by differences in availability and genetic differences impacting alcohol metabolism.
“substantially different rates of alcohol use disorder across populations are partially explained by differences in availability and genetic differences impacting alcohol metabolism50.”
From Clinical use of current polygenic risk scores may exacerbate health disparities (2019) · cites this paper as [50]
The Results (page not provided) report that the protective ALDH2 allele varies in frequency across populations and is strongly associated with lower odds of alcohol abuse or dependence. The Introduction explains how the allele impairs alcohol metabolism and can deter drinking. The paper does not establish that differences in alcohol availability explain population-level differences in alcohol use disorder rates. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe rs671 polymorphism in ALDH2 has an even stronger effect on risk for alcohol dependence than rs1229984 but is rare except in some Asian populations.
“Another functional polymorphism, rs671 in ALDH2 (Glu504Lys), strongly affects alcohol metabolism by blocking conversion of acetaldehyde to acetate and has an even stronger effect on risk for AD, but is rare except in some Asian populations8,12,13”
From Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders (2018) · cites this paper as [12]
Variants in the genes responsible for alcohol metabolism, especially ADH1B and ALDH2, have been strongly implicated in alcohol dependence.
“Variants in the genes responsible for alcohol metabolism, especially ADH1B and ALDH2, have been strongly implicated8–13.”
From Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders (2018) · cites this paper as [12]
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Alcohol and Aldehyde Dehydrogenases: Molecular Aspects
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- Authors
- Li, D., Zhao, H., & Gelernter, J.
- Affiliations
- Yale University (US)
- Corresponding author
- Li, Dawei
- Venue
- Human Genetics
- Published
- 2011-11-20
- Volume
- 131
- Issue
- 5
- Pages
- 725-737
- ISSN
- 0018-7348 (ISSN-L)
- 0340-6717
- 1432-1203
- PMC
- PMC3548401
- OpenAlex
- W2002696968
- Cited by
- 158
- References
- 102
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 11 · 2023: 5 · 2022: 17 · 2021: 11 · 2020: 11 · 2019: 16 · 2018: 11 · 2017: 12 · 2016: 10 · 2015: 10 · 2014: 12 · 2013: 13 · 2012: 6
- FWCI
- 6.98
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Human Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism (AA11330, AA 12870, AA017535, R01AA017535, R01AA011330, P50AA012870)
- National Institute on Drug Abuse (DA-12849, DA 12690, R01DA012690, R01DA012849)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- ALDH2, rs671, alcoholism, alcoholic liver disease, alcoholic cirrhosis, alcoholic pancreatitis, acetaldehyde metabolism, genetic susceptibility, East Asian populations
- MeSH terms
- Aldehyde Dehydrogenase, Mitochondrial, Alcohol Drinking, Alcoholism, Aldehyde Dehydrogenase, Alleles, Humans, Liver Cirrhosis, Liver Diseases, Alcoholic, Pancreatitis, Case-Control Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Asian People, Disease Resistance
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