The Ala(222)Val single nucleotide polymorphism (SNP) in the gene for
5,10-methylenetetrahydrofolate reductase (MTHFR), a critical
enzyme in one-
carbon metabolism, has been associated with
colorectal cancer risk. Many
enzymes are involved in one-
carbon metabolism, and SNPs in the corresponding genes may play a role in colorectal
carcinogenesis. We examined 24 nonsynonymous SNPs in 13 genes involved in the one-
carbon metabolism pathway in relation to the risk of
colorectal cancer in a case-control study nested in the Nurses' Health Study and the Health Professionals Follow-up Study cohorts. Among 376 men and women with
colorectal cancer and 849 controls, a reduced risk of
colorectal cancer was observed for
Val/Val versus Ala carriers of MTHFR Ala(222)Val [odds ratio (OR), 0.66; 95% confidence interval (CI), 0.43-1.00]. An increased risk was suggested for the variant carrier genotypes versus homozygous wild-type for
betaine hydroxymethyltransferase Arg(239)Gln (OR, 1.40; 95% CI, 1.07-1.83) and two linked SNPs in
methionine synthase reductase, Ser(284)Thr (OR, 1.85; 95% CI, 1.05-3.27) and Arg(415)Cys (OR, 2.03; 95% CI, 1.15-3.56). The other SNPs were not associated with
colorectal cancer risk. Also, none of the SNPs were associated with risk in subgroups of dietary methyl status or were jointly associated with
colorectal cancer risk in combination with another SNP, except possibly SNPs in
methionine synthase and
transcobalamin II. However, these analyses of gene-diet interactions were limited in statistical power. Our results corroborate previous findings for MTHFR Ala(222)Val and suggest that other genes involved in one-
carbon metabolism, particularly those that affect DNA methylation, may be associated with
colorectal cancer risk.