A Polymorphism of the Methionine Synthase Gene: Association with Plasma Folate, Vitamin B₁₂, Homocyst(e)ine, and Colorectal Cancer Risk

Abstract

We previously reported (J. Chen et al., Cancer Res., 56:4862–4864, 1996; J. Ma et al., Cancer Res., 57: 1098–1102, 1997) that a 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism (677C→T, ala→val) was associated with lower risk of colorectal cancer. In this study, we examined the relationship of a polymorphism (2756A→G, asp→gly) in the gene (MTR) for methionine synthase, another important enzyme in the same folate/methionine/homocyst(e)ine metabolic pathway, with risk of colorectal cancer among 356 cases and 476 cancer-free controls. The frequency of the homozygous variant genotype (gly/gly) was slightly lower among cases (3%) than controls (5%). The odds ratio for the gly/gly genotype was 0.59 [95% confidence interval (CI), 0.27–1.27] compared with those with the homozygous wild type (asp/asp). There were no significant differences in plasma levels of folate, vitamin B12, and homocyst(e)ine (tHcy) among the MTR genotypes, in contrast to the MTHFR polymorphism. However, similar to the interaction observed for the MTHFR polymorphism among men who consumed less than 1 alcoholic drink/day, those with the gly/gly genotype had a lower risk of colorectal cancer with an odds ratio of 0.27 (95% CI, 0.09–0.81) compared with those with the asp/asp genotype. The possible association of the MTR polymorphism with lower risk of colorectal cancer especially among those with low alcohol consumption, in the same direction as for the MTHFR polymorphism, is intriguing. However, our study had limited statistical power because of the low frequency of the MTR variant genotype, which is reflected in the wide CIs. Hence, these findings need to be confirmed in larger populations.