ADH3 genotype, alcohol intake and breast cancer risk.
Moderate alcohol consumption of approximately 1-2 drinks per day has been associated with a 30-50% increase in breast cancer risk. Individuals differ in their ability to metabolize alcohol through genetic differences in alcohol dehydrogenase (ADH), the enzyme that catalyzes the oxidation of approximately 80% of ethanol to acetaldehyde, a known carcinogen. Individuals differ in their ADH genotype, and one locus in particular (ADH3) is polymorphic in Caucasian populations. Using data from the Long Island Breast Cancer Study Project, we examined whether fast metabolizers of alcohol, as measured by the ADH3(1-1) genotype, have a higher risk of breast cancer from alcohol intake compared with those individuals who are slow metabolizers, but consume similar amounts of alcohol. We combined genotyping information with questionnaire data on 1047 breast cancer cases and 1101 controls and used unconditional logistic regression methods to estimate multivariate-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) between alcohol intake and breast cancer risk. Among individuals homozygous for the fast metabolizing allele (ADH(3)1-1), a lifetime alcohol consumption of 15-30 g/day (approximately 1-2 drinks per day) increased breast cancer risk by 2-fold (OR=2.0, 95% CI=1.1-3.5). In contrast, the increase in risk from a lifetime alcohol consumption of 15-30 g/day was less pronounced in the intermediate and slow metabolizing groups, respectively: ADH3(1-2) (OR=1.5, 95% CI 0.9-2.4) and ADH(3)2-2 (OR=1.3, 95% CI 0.5-3.5). Fast metabolizers who drank 15-30 g/day of alcohol had 2.3 times (95% CI 1.3-4.0) greater risk of breast cancer than non-drinkers who were intermediate or slow metabolizers. This association for fast metabolizers who drank 15-30 g/day was particularly pronounced among premenopausal women (premenopausal women OR=2.9, 95 % CI=1.2-7.1; postmenopausal women OR=1.8, 95% CI=0.9-3.8). These population-based data support the hypothesis that fast metabolizers of alcohol have a higher risk of breast cancer risk, from alcohol intake than slow metabolizers.