rs698
mixedMag 5.0This is a protein-altering variant in the ADH1C gene.
Key Literature Trait Associations
Alcohol dependence
The rs698 T allele (gamma1, fast oxidizer) is associated with increased risk of alcohol dependence and abuse. Li et al. (2012) meta-analyzed 6,796 cases and 6,938 controls across multiple ancestries and found OR=1.51 (95% CI 1.31–1.73, p=1×10⁻⁸) overall, with a markedly stronger effect in East Asians (OR=2.14, p=4×10⁻³³). The mechanistic hypothesis is that fast ethanol oxidation reduces acetaldehyde accumulation, thereby diminishing the aversive flushing response that normally deters heavy drinking—particularly relevant in populations where ADH1B*2 is also common. ClinVar designates the C allele as Protective against alcohol dependence.
Alcohol Metabolism Rate
ADH1C encodes one of the primary liver alcohol dehydrogenases. The rs698 variant (Ile350Val) creates fast (Ile/A, ADH1C*1) and slow (Val/G, ADH1C*2) enzyme forms — the fast form is 40-65% more active. G/G individuals metabolize alcohol more slowly, meaning alcohol stays in the bloodstream longer. This accounts for ~12% of individual variation in alcohol clearance rate. Because rs698 is in near-complete LD with ADH1B (rs1229984), the ADH1C contribution is secondary to the larger ADH1B effect.
Coronary heart disease
The rs698 T allele (gamma1, fast oxidizer) is associated with higher coronary heart disease risk among moderate alcohol drinkers, compared to the protective C (gamma2) genotype. The landmark Physicians' Health Study (Hines et al., 2001, NEJM) found that gamma2 homozygous moderate drinkers had an 86% reduction in MI risk (RR=0.14), an effect mediated by sustained HDL elevation. The Second Northwick Park Heart Study (n=2,773) confirmed a 78% CHD risk reduction in gamma2 moderate drinkers (HR=0.22, p=0.02). This association is specifically observed in moderate drinkers and depends on alcohol consumption; abstainers show little genotype effect.
HDL cholesterol
The rs698 C allele (gamma2, slow oxidizer) is associated with higher HDL cholesterol levels among moderate alcohol drinkers. Because slow oxidation prolongs ethanol's presence in circulation, it extends the HDL-raising effect per drink. Hines et al. (2005) found that gamma2 homozygous moderate drinkers had approximately 5.3 mg/dL higher HDL than gamma1 homozygotes (p=0.02). This effect was present in men and postmenopausal women not using hormone therapy, but absent in premenopausal women, suggesting modulation by estrogen. The effect is not independent of alcohol consumption and disappears in abstainers.
Pancreatitis
The rs698 T allele (*1, gamma1) is associated with elevated risk of pancreatitis, particularly chronic alcoholic pancreatitis. A meta-analysis of 9 studies (Fang et al., 2015) found OR=1.53 (95% CI 1.12–2.10) for the heterozygous comparison and OR=1.44 (95% CI 1.07–1.95) for the dominant model. The association was strongest for chronic alcoholic pancreatitis (OR=1.64, 95% CI 1.17–2.29). The proposed mechanism is that rapid ethanol oxidation increases local acetaldehyde production in the pancreas, promoting oxidative stress and inflammatory injury. Evidence is primarily from Caucasian populations.
Breast cancer
The rs698 T allele (*1, gamma1) shows a modest and context-dependent association with breast cancer, primarily relevant in alcohol-consuming women. A meta-analysis of 4 studies (1,969 cases, 2,244 controls; Mao et al., 2015) found no statistically significant independent association overall (allelic OR=1.05, 95% CI 0.96–1.16), but among drinkers specifically the combined *1 genotype showed elevated risk (OR=1.35, 95% CI 1.03–1.76). The ADH1C gamma1 isoform may increase local mammary acetaldehyde production during alcohol metabolism, a known carcinogen. The association is not considered clinically actionable independent of alcohol consumption.
▶ClinVar annotation
▶Research that mentions this SNP (6)
▶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.
▶Further clarification of the contribution of the ADH1C gene to vulnerability of alcoholism and selected liver diseasesMeta-analysisN=13,734Dawei Li et al.(2012)· Human Genetics
Meta-analysis of 53 studies (6,796 cases, 6,938 controls) examining ADH1C Ile350Val (rs698) association with alcohol dependence and alcohol-related liver disease across multiple populations. The variant showed strong association in combined populations (P=1×10⁻⁸, OR=1.51) with much stronger effects in Asian populations (P=4×10⁻³³, OR=2.14), supporting that the ADH1C 350Ile allele reduces risk for alcoholism and related diseases.
▶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.
▶ADH1A variation predisposes to personality traits and substance dependenceAssociationN=1,523Lingjun Zuo et al.(2010)· American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
ADH1A genetic variation predisposes to personality traits and substance dependence across multiple population groups. Agreeableness and Conscientiousness were associated with ADH1A diplotypes, haplotypes, and genotypes in European-American and African-American subjects (p range: 1.7×10⁻⁴ to 0.055), with effects modified by sex and age. Substance dependence was significantly associated with ADH1A variants (p range: 0.008 to 0.060), suggesting ADH1A's role in both personality phenotyping and addiction vulnerability.
▶A single nucleotide polymorphism in the alcohol dehydrogenase 7 gene (alanine to glycine substitution at amino acid 92) is associated with the risk of squamous cell carcinoma of the head and neckAssociationN=2,239Sheng Wei et al.(2010)· Cancer
Hospital-based case-control study of 1,110 SCCHN cases and 1,129 controls examining alcohol dehydrogenase gene polymorphisms. ADH7 A92G (rs1573496: C>G) GG and combined CG+GG genotypes were associated with decreased SCCHN risk (adjusted OR 0.32, 95% CI 0.13-0.82 for GG; adjusted OR 0.74, 95% CI 0.59-0.94 for CG+GG). ADH1B R48H (rs1229984: G>A) showed no overall association with SCCHN risk in this non-Hispanic White population.
Gene information from NCBI Gene. Variant classifications from ClinVar.
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