Methionine Synthase D919G Polymorphism, Folate Metabolism, and Colorectal Adenoma Risk

Methionine synthase [5-methyltetrahydrofolate-homocysteine S-methyltransferase (MTR)] is involved in folate-mediated one-carbon metabolism, a pathway known to play a role in colorectal carcinogenesis. We investigated whether the MTR D919G polymorphism was associated with risk of colorectal adenoma in a colonoseopy-based study of 513 cases and 609 controls from Minneapolis, MN. Adenoma risk appeared nonsignificantly increased among women with DG or GG genotype [adjusted odds ratio (OR) versus DD, 1.4; 95% confidence interval (CI), 0.9-2.1] but not men (OR, 1.0; 95% CI, 0.7-1.5). An interaction with methionine intake was observed among women, such that low versus high intake was associated with a 2.3-fold increased risk only among those with DG or GG genotype (95% CI, 1.1-4.9; P for interaction = 0.05). Similarly, risk associated with alcohol intake was not elevated among women with the DD genotype; however, consumption of >7 g of alcohol/day versus none was associated with an increased risk among women with DG or GG genotype (adjusted OR, 2.5; 95% CI, 1.4-4.4; P for interaction = 0.03). An interaction between MTR D919G and the thymidylate synthase (TS or TYMS) 3'-untranslated region polymorphism 1494del6 was also observed among women (P for interaction = 0.007). No evidence of interaction with intake of folate, vitamin B₁₂, or vitamin B₆ or with genotype at MTHFR C677T or the TS enhancer region 28-bp repeat polymorphism was seen. These findings add to what is known about the complexities of genetic variations in one-carbon-metabolizing enzymes in relation to colorectal carcinogenesis.