We examined the relationship of a common polymorphism (667C→T) of the methylenetetrahydrofolate reductase (MTHFR) gene with the risk of colorectal cancer in a case-control study conducted in the Health Professionals Follow-up Study. MTHFR genotypes were ascertained from blood samples among 144 men previously diagnosed with colorectal cancer and 627 controls. The adjusted odds ratio (OR) for the MTHFR variant homozygous (val/val) genotype was 0.57 [95% confidence interval (CI), 0.30–1.06]. High dietary intake of methionine (OR, 0.27; 95% CI, 0.06–1.20) and low consumption of alcohol (OR, 0.11; 95% CI, 0.01–0.85) were associated with reduced incidence of colorectal cancer. Alcohol intake was a stronger risk factor among men with the val/val genotype (P, trend = 0.01), and consumption of five or more alcoholic drinks per week abolished the reduced risk of colorectal cancer among val/val individuals (P, interaction = 0.02). The inverse association of methionine with colorectal cancer risk was slightly stronger among individuals with the MTHFR val/val genotype. These data suggest that dietary methyl supply is particularly critical among MTHFR val/val individuals. When dietary methyl supply is high, MTHFR val/val individuals may be at reduced risk of colorectal cancer probably because higher levels of 5,10-methylenetetrahydrofolate may prevent imbalances of nucleotide pools during DNA synthesis. In contrast, when 5-methyltetrahydrofolate is depleted by alcohol consumption, val/val individuals may be less able to compensate, leading to potentially oncogenic alterations in DNA methylation.
This study was supported by Research Grants CA55075, CA62984, CA70817, and HL35464 from NIH. J. C. is supported by Training Grant ES07069 and K. K. is supported by Research Grant ES 00002 from the National Institute for Environmental Health Sciences. D. H. is partially supported by American Cancer Society Faculty Research Award FRA-455.