A polymorphism of the methionine synthase gene: Association with plasma folate, vitamin B-12, homocyst(e)ine, and colorectal cancer risk

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-methylenetetrahy drofolate reductase (MTHFR) polymorphism (677C-->T, ala-->val) was associat ed with lower risk of colorectal cancer. In this study, we examined the rel ationship of a polymorphism (2756A-->G, asp-->gly) in the gene ((MTR) for m ethionine 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 w ere no significant differences in plasma levels of folate, vitamin B12, and homocyst(e)ine (tHcy) among the MTR genotypes, in contrast to the MTHFR po lymorphism. However, similar to the interaction observed for the MTHFR poly morphism 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 ra tio of 0.27 (95% CI, 0.09-0.81) compared with those with the asp/asp genoty pe. The possible association of the MTR polymorphism with lower risk of col orectal cancer especially among those with low alcohol consumption, in the same direction as for the MTHFR polymorphism, is intriguing. However, our s tudy 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.