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Methylenetetrahydrofolate Reductase, Alcohol Dehydrogenase, Diet, and Risk of Colorectal Adenomas¹

Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston Massachusetts 02115 [E. G., E. B. R., C. S. F., W. C. W., D. J. H.]; Department of Nutrition, Harvard School of Public Health, Boston Massachusetts 02115 [E. G., S. A. S-W., E. B. R., W. C. W.]; Department of Epidemiology, Harvard School of Public Health, Boston Massachusetts 02115 [E. G., E. B. R., W. C. W., D. J. H.]; Department of Community and Preventive Medicine, Mount Sinai School of Medicine, New York, New York 10029 [J. C., C. P.]; Department of Adult Oncology, Dana-Farber Cancer Institute, Boston Massachusetts 02115 [C. S. F.]; and Harvard Center for Cancer Prevention, Harvard School of Public Health, Boston Massachusetts 02115 [D. J. H.]

An increased occurrence of colorectal cancer and its adenoma precursor is observed among individuals with low intakes or circulating levels of folate, especially if alcohol intake is high, although results have not been statistically significant in all studies. We examined folate and alcohol intake and genetic polymorphisms in methylenetetrahydrofolate reductase [MTHFR 667T (alaval) and MTHFR 1298AC (glnala)] (associated with reduced MTHFR activity) and in alcohol dehydrogenase 3 [ADH₃ (2-2) associated with decreased alcohol catabolism] in relation to risk of colorectal adenoma in the Health Professionals Follow-Up Study. Among 379 cases and 726 controls, MTHFR genotypes were not appreciably related to risk of adenoma, but a suggestive interaction (P = 0.09) was observed between MTHFR 677CT and alcohol intake; men with TT homozygotes who consumed 30+ g/day of alcohol had an odds ratio (OR) of 3.52 [95% confidence interval (CI), 1.41–8.78] relative to drinkers of 5 g/day with the CC/CT genotypes. ADH₃ genotype alone was not appreciably related to risk, but its influence was modified by alcohol intake. Compared with fast alcohol catabolizers [ADH₃(1-1)] with low intakes of alcohol (5 g/day), high consumers of alcohol (30+ g/day) had a marked increase in risk if they had the genotype associated with slow catabolism [ADH₃(2-2); OR, 2.94; 95% CI, 1.24–6.92] or intermediate catabolism [ADH₃(1-2)] of alcohol (OR, 1.83; 95% CI, 1.03–3.26) but not if they were fast catabolizers [ADH₃(1-1); OR = 1.27; 95% CI = 0.63–2.53). In addition, an increased risk of colorectal adenoma (OR, 17.1; 95% CI, 2.1–137) was observed for those with the ADH₃(2-2) genotype and high alcohol-low folate intake compared with those with low alcohol-high folate intake and the ADH₃(1-1) genotype (P for interaction = 0.006). Our results indicate that high intake of alcohol is associated with an increased risk of colorectal adenoma, particularly among MTHFR 677TT and ADH₃(2-2) homozygotes. The findings that alcohol interacts with a folate-related gene (MTHFR) and that the interaction between alcohol and ADH₃ is stronger among those with low folate intake support the hypothesis that the carcinogenic influence of alcohol in the large bowel is mediated through folate status.

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