Genomic
DNA hypomethylation has been associated with colorectal
carcinogenesis.
Methionine synthase A2756G (MTR A2756G) is a common nonsynonymous polymorphism in the gene that encodes
methionine synthase, a key
enzyme in the pathway leading to DNA methylation. Several studies, but not all, have reported relatively lower plasma
homocysteine among individuals with the AG or GG genotype. Meanwhile, higher plasma
homocysteine was associated with genomic
DNA hypomethylation in healthy volunteers. We therefore hypothesized that minor allele carriers possess a decreased risk of colorectal
adenoma, and examined this hypothesis in a case-control study of colorectal
adenoma in Japan involving 723 cases and 670 controls. An unconditional logistic regression model was used to estimate odds ratios (OR) and their 95% confidence intervals (95% CI) for colorectal
adenoma after adjustment for potential confounders. Despite the lack of an overall association, we observed a significant interaction between MTR A2756G and alcohol intake (P for interaction = 0.007). Compared with never drinkers with the AA genotype, never drinkers with the AG or GG genotype exhibited a significantly decreased risk (OR, 0.56; 95% CI, 0.34-0.90) whereas heavy drinkers with the same genotypes showed a substantially increased risk (OR, 1.90; 95% CI, 1.04-3.46). In addition, a marginally significant interaction was observed with
folate intake (P for interaction = 0.07). The G allele may confer protection against colorectal
adenoma in the presence of a considerably good
folate status. Our findings add to increasing evidence that DNA methylation plays an important role even at an early stage of colorectal
carcinogenesis.