Oral squamous cell cancer risk in relation to alcohol consumption and alcohol dehydrogenase-3 genotypes

Heavy alcohol consumption, particularly in combination with cigarette smoking, increases the risk of oral squamous cell carcinoma (OSCC). Alcohol dehydrogenase 3 (ADH3) converts ethanol to acetaldehyde, which is a suspected oral carcinogen. The ADH3*1 allele is associated with increased conversion of ethanol to acetaldehyde, but whether the risk of OSCC is increased among ADH3*1 carriers, or whether the risk of OSCC attributable to alcohol consumption is modified by ADH3 genotype is unclear from previous studies. We examined the association between ADH3 genotypes, alcohol consumption, and OSCC risk in a population-based study of 333 cases and 541 controls from the state of Washington. The distribution of ADH3 genotypes was similar among cases and controls: ADH3*1/*1: 32.7% cases, 36.5% controls; ADH3*1/*2: 49.0% cases, 43.1% controls: ADH3*2/*2: 18.3% cases, 20.3% controls. The age-, sex-, and race-adjusted odds ratios (OR), relative to ADH3*2/*2 carriers, were as follows: ADH*1/*1: OR, 1.0 [95% confidence interval (CI) = 0.7, 1.5]; and ADH3*1/*2: OR, 1.3 (95% CI = 1.0, 1.8). We modeled the risk of OSCC associated with alcohol consumption as modified by ADH3 genotype adjusting for age, sex, race, and cigarette smoking. Among ADH3*2 homozygotes, the risk of OSCC increased 5.3% (2.1-8.5%) with each additional alcoholic drink/week, compared with 2.5% (1.5-2.6%) and 1.2% (0.0-2.4%) among persons carrying the ADH3*1/*2 and ADH3*1/*1 genotypes, respectively. These data suggest that the ADH3*2 allele confers increased susceptibility to the effect of alcohol on OSCC risk in our population.