rs671
mixedMag 9.0This is a protein-altering variant in the ALDH2 gene.
Key Literature Trait Associations
Alcohol Flush Reaction
rs671 is the canonical 'Asian flush' variant: a missense change in ALDH2 encoding the Glu504Lys substitution. The Lys504 (A allele) protein is catalytically nearly inactive: heterozygotes retain only ~6% of wild-type ALDH2 activity and homozygotes have <1%. After drinking, acetaldehyde accumulates producing the characteristic alcohol flush syndrome: facial flushing, tachycardia, nausea, and headache. The A allele explains 29.2% of variance in flushing response, making it one of the largest effect-size pharmacogenomic variants in the human genome. The A allele reaches ~22% frequency in East Asians but is extremely rare (<1%) in all other ancestral groups.
Alcohol Consumption (Drinking Behavior)
rs671-G (wild-type, functional ALDH2) is strongly associated with regular alcohol drinking compared to the A (Lys504) allele. In a large Japanese population GWAS (n>50,000), the G allele showed an OR of 6.25 for drinking behavior, the most significant variant association in the study. This quantifies the enormous behavioral deterrent effect of the Lys504 variant: A-allele carriers are approximately 6-fold less likely to become regular drinkers than GG homozygotes.
Alcohol use disorder
The rs671 G allele (functional ALDH2) is strongly associated with increased risk of alcohol dependence and alcohol use disorder, as carriers can metabolize acetaldehyde efficiently without aversive flushing. Conversely, the A allele (ALDH2*2) is powerfully protective: a Thai GWAS found genome-wide significant association with alcohol dependence symptoms (p=5.8×10⁻¹⁰). Among Japanese alcohol-dependent men, ALDH2*2 was markedly underrepresented, and a 2017 American cohort study confirmed the protective effect of ALDH2*2 against developing alcohol dependence, though social factors (peer drinking) could partially attenuate the genetic protection. This SNP is one of the strongest known genetic protectors against alcohol use disorder.
Esophageal Cancer (Alcohol-Related)
The ALDH2 rs671 A (Lys504) allele substantially increases esophageal cancer risk among individuals who regularly consume alcohol. Impaired ALDH2 activity means acetaldehyde cannot be efficiently cleared, resulting in prolonged exposure of the esophageal epithelium to a known Group 1 carcinogen. A meta-analysis of 31 studies found AG heterozygotes have OR 1.39 for esophageal squamous cell carcinoma; among alcohol-drinking males the OR rises to 4.39. Paradoxically, AA homozygotes have reduced cancer risk because the severe flush reaction almost completely prevents alcohol consumption.
Coronary heart disease
The rs671 A allele associates with increased coronary heart disease and myocardial infarction risk in East Asian populations. A Japanese GWAS (n=11,736) identified rs671 at genome-wide significance for coronary artery disease (OR=1.43, p=2×10⁻³⁴). Meta-analyses corroborate this: one covering 7,358 subjects found OR=1.36 for CHD and OR=1.64 for MI; another in 9,616 subjects found RR=1.20 for CAD and RR=1.32 for MI. The mechanism may involve impaired clearance of reactive aldehydes from oxidative stress in cardiac tissue, independent of alcohol intake, though residual confounding from drinking behavior cannot be excluded.
Essential hypertension
The rs671 G allele (ALDH2*1, wild-type) associates with higher blood pressure and increased essential hypertension risk in East Asian populations, while the A allele (ALDH2*2) is protective. A large 2020 systematic review and meta-analysis (11,051 hypertensive patients and 15,926 normotensive controls across 30 studies) found A allele carriers had OR ~0.71–0.80 for essential hypertension across genetic models, with lower systolic (−1.78 mmHg) and diastolic (−1.09 mmHg) blood pressure. The paradox is likely mediated through reduced alcohol consumption in A allele carriers, as sub-group analysis found stronger protection in male drinkers. An updated 2024 meta-analysis (n=90,888) confirmed GG individuals had higher blood pressure and metabolic risk.
Type 2 diabetes mellitus
The rs671 G allele (wild-type ALDH2*1) is associated with higher type 2 diabetes risk in East Asian populations, while the A allele appears protective. A meta-analysis of 8 studies (2,374 cases, 6,694 controls) found the ALDH2*1/*1 (GG) genotype had OR=0.31 for T2DM vs. *2/*2 (AA), and the 2024 updated meta-analysis (n=90,888) confirmed elevated fasting blood glucose and triglyceride levels in GG carriers. The mechanism may partly reflect confounding by alcohol intake (A allele carriers drink less), though a direct role of endogenous aldehyde metabolism in pancreatic beta-cell function has been proposed. Evidence is primarily from East Asian populations and requires replication in other ancestries.
▶GWAS Catalog Trait Associations (71)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
GWAS Catalog Trait Associations (71)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
▶ClinVar annotation
Alcohol sensitivity, acute; Alcohol dependence; Susceptibility to hangover; ESOPHAGEAL CANCER, ALCOHOL-RELATED, SUSCEPTIBILITY TO; AMED syndrome, digenic; ethanol response - Toxicity; ALDH2-related disorder; NITROGLYCERIN, POOR RESPONSE TO
View on ClinVar →▶Research that mentions this SNP (11)
▶Genome‐Wide Association Study of Lean Nonalcoholic Fatty Liver Disease Suggests Human Leukocyte Antigen as a Novel Candidate LocusAssociationN=11,375Ken Yoshida et al.(2020)· Hepatology Communications
A two-stage genome-wide association study (GWAS) of lean nonalcoholic fatty liver disease (NAFLD) in Japanese patients identified HLA as a novel candidate locus, with rs2076529 (OR 1.19, P=2.10E-06) showing significant association with whole NAFLD. HLA-B*54:01 allele carriers demonstrated altered gut microbiota composition, with reduced Verrucomicrobia and Akkermansia, suggesting HLA may influence NAFLD susceptibility through microbiome regulation.
▶Association between rs2188380 and the risk of breast cancer in southwest Chinese populationAssociationN=222Lin Huang et al.(2019)· Journal of Clinical Laboratory Analysis
Case-control study investigating the association between rs2188380 and breast cancer risk in a southwest Chinese population (104 cases, 112 controls). The C/C genotype of rs2188380 was associated with increased breast cancer risk compared with T/T genotype (OR = 9.241, 95% CI = 1.122-76.101, P = 0.039), with the association remaining significant after age adjustment (OR = 8.788, 95% CI = 1.063-72.636, P = 0.044).
▶NPT1/SLC17A1 Is a Renal Urate Exporter in Humans and Its Common Gain‐of‐Function Variant Decreases the Risk of Renal Underexcretion GoutAssociationN=3,103Toshinori Chiba et al.(2015)· Arthritis & Rheumatology
This replication study analyzed 2255 variants in LD with GWAS-identified gout/serum urate susceptibility loci in 1255 Han Chinese gout patients and 1848 controls. Twenty-three variants (41%) showed nominal association (p<0.05), with the strongest signal at ABCG2 rs1481012 (p=8.96×10⁻¹¹, OR=1.890). Previous gout-associated loci including ABCG2, SLC2A9, GCKR, ALDH2, and CNIH2 were replicated, while cumulative genetic risk scores showed that individuals with ≥8 risk alleles had significantly increased gout risk (OR=16.361 for ≥12 alleles).
▶ALDH2 is associated to alcohol dependence and is the major genetic determinant of "daily maximum drinks" in a GWAS study of an isolated rural Chinese sample.AssociationN=313Quillen EE et al.(2014)· American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics
Genome-wide association study of alcohol dependence and related phenotypes in 313 males from extended Han Chinese pedigrees in Northern Hunan Province. ALDH2 rs671 (Glu504Lys) was identified as the major genetic determinant, with genome-wide significant associations for alcohol dependence (p=4.73×10⁻⁸), maximum drinks in 24 hours (p=1.54×10⁻¹⁶), and facial flushing response (p=4.75×10⁻²⁶). The rs671 variant explained 7.9% of AD phenotypic variation, 22.9% of maximum drinks variation, and 29.2% of flushing response variation. A previously reported candidate SNP rs10774610 in CCDC63 was confirmed but shown to result from linkage disequilibrium with ALDH2.
▶Extended genetic effects of ADH cluster genes on the risk of alcohol dependence: from GWAS to replicationAssociationN=1,371Byung Lae Park et al.(2013)· Human Genetics
This GWAS and replication study in a Korean cohort identified genetic associations with alcohol dependence (AD), with the ADH gene cluster on chromosome 4q22-q23 and ALDH2 on 12q24 showing the strongest signals. The most significant finding was ADH1B rs1229984 (H47R) with p=2.63×10⁻²¹ and OR=2.35 in the replication cohort of 975 subjects. Conditional analyses revealed that ADH1B rs1229984 is likely the sole functional marker driving effects across the ADH cluster.
▶Single nucleotide polymorphisms of ADH1B, ADH1C and ALDH2 genes and esophageal cancer: A population‐based case–control study in ChinaAssociationN=1,925Ming Wu et al.(2013)· International Journal of Cancer
Population-based case-control study in China examining alcohol dehydrogenase and aldehyde dehydrogenase gene polymorphisms in esophageal cancer. ADH1B rs1229984 G-allele showed significant association with esophageal cancer risk (OR=1.34, dominant model), and ALDH2 rs671 showed significant gene-environment interaction with alcohol consumption, with moderate/heavy drinkers carrying ALDH2 A allele and ADH G allele at highest risk. No association found for ADH1C rs698 polymorphism.
▶Genetic variants at 4q21, 4q23 and 12q24 are associated with esophageal squamous cell carcinoma risk in a Chinese populationAssociationN=4,412Yong Gao et al.(2013)· Human Genetics
A case-control study of 2,139 esophageal squamous cell carcinoma (ESCC) cases and 2,273 controls in a Chinese population examined six SNPs previously associated with upper aerodigestive tract cancers in Europeans. Four SNPs showed significant association with ESCC risk: rs1494961 at 4q21 (OR=1.15, 95% CI=1.05-1.26), rs1229984 in ADH1B at 4q23 (OR=1.24, 95% CI=1.13-1.36), rs1789924 near ADH1C at 4q23 (OR=1.20, 95% CI=1.03-1.39), and rs671 in ALDH2 at 12q24 (OR=0.83, 95% CI=0.75-0.91). Combined analysis showed significant allele-dosage effects with individuals carrying 5+ risk alleles having 1.76-fold increased ESCC risk.
▶Strong protective effect of the aldehyde dehydrogenase gene (ALDH2) 504lys (*2) allele against alcoholism and alcohol-induced medical diseases in AsiansMeta-analysisN=17,009Dawei Li et al.(2012)· Human Genetics
Meta-analysis of 53 case-control studies (9,678 cases, 7,331 controls) examining ALDH2 rs671 (glu504lys) association with alcohol dependence and alcohol-induced diseases in predominantly East Asian populations. The protective 504lys allele showed strong protective effect with P = 3×10^-56 and OR = 0.23 (95% CI 0.2-0.28) for alcohol abuse/dependence, and P = 2×10^-28, OR = 0.23 (95% CI 0.18-0.3) for alcoholic liver disease, cirrhosis, or pancreatitis.
▶Association between gout and polymorphisms in GCKR in male Han ChineseAssociationN=3,103Jing Wang et al.(2012)· Human Genetics
This replication study examined 2,255 variants in linkage disequilibrium with GWAS-identified gout/urate susceptibility loci in 1,255 Han Chinese gout patients and 1,848 controls. Twenty-three variants (41% of 56 LD-pruned variants) showed nominal association with gout (p < 0.05), with the strongest signals at ABCG2 (rs1481012, OR=1.890, p=8.96×10⁻¹¹) and SLC2A9 (rs11722228, OR=1.619, p=2.40×10⁻⁶). Cumulative genetic risk score analysis demonstrated increasing gout risk with growing numbers of risk alleles (OR=16.361 for ≥12 alleles vs ≤5 reference).
▶Clinical significance of SOD2 and GSTP1 gene polymorphisms in Chinese patients with gastric cancerAssociationN=324Zhi Xu et al.(2012)· Cancer
Case-control study of 324 Japanese male workers examining genetic polymorphisms in xenobiotic-metabolizing enzymes (CYP2E1, NAT2, GSTM1, GSTT1, GSTP1, ALDH2, SOD2) and their association with multiple chemical sensitivity (MCS). SOD2 Val16Ala polymorphism (rs4880) showed significant association with high chemical sensitivity, with adjusted OR of 4.30 (95% CI 1.23-15.03) for Ala/Ala and Val/Ala genotypes versus Val/Val, and adjusted OR of 4.53 (95% CI 1.52-13.51) in additive genetic model analysis.
▶Shortened telomeres in individuals with abuse in alcohol consumptionAssociationN=457Sofia Pavanello et al.(2011)· International Journal of Cancer
This case-control study of 457 Caucasian males (200 alcohol abusers, 257 controls) found that alcohol abusers had significantly shorter peripheral blood leukocyte telomere length (TL was 0.42 vs. 0.87 relative T/S ratio, P<0.0001), suggesting accelerated cellular aging. The ADH1B rs1229984 (Arg47His) genotype modulated this association: carriers of the ADH1B*2 allele were protected from alcohol abuse (OR=0.28, 95% CI 0.14-0.55) and showed longer telomeres, while ADH1B*1 carriers exhibited shorter telomeres and higher alcohol consumption. The rs698 ADH1C and rs671 ALDH2 polymorphisms were not associated with telomere length.
Gene information from NCBI Gene. Variant classifications from ClinVar.
Community Wiki
No community notes yet for this variant. Sign in to start one.
Comments
Sign in to join the discussion.
Loading comments…