Folate-Related Nutrients, Genetic Polymorphisms, and Colorectal Cancer Risk: the Fukuoka Colorectal Cancer Study

One-carbon metabolism plays an important role in colorectal carcinogenesis. Meta-analyses have suggestedprotective associations of folate and vitamin B6 intakes with colorectal cancer primarily based on studies inCaucasians, and genetic polymorphisms pertaining to the folate metabolism have been a matter of interest.Less investigated are the roles of methionine synthase (MTR) and thymidylate synthetase (TS) polymorphismsin colorectal carcinogenesis. In a study of 816 cases and 815 community controls in Japan, we investigatedassociations of dietary intakes of folate, methionine, vitamin B2, vitamin B6, and vitamin B12 with colorectal cancerrisk. The associations with MTR 2756A>G, MTRR 66A>G, and TSER repeat polymorphism were examined in685 cases and 778 controls. Methionine and vitamin B12 intakes were inversely associated with colorectal cancerrisk, but the associations were totally confounded by dietary calcium and n-3 fatty acids. The other nutrientsshowed no association with the risk even without adjustment for calcium and n-3 fatty acids. The TSER 2R allelewas dose-dependently associated with an increased risk. The MTR and MTRR polymorphisms were unrelatedto colorectal cancer risk. There was no measurable gene-gene or gene-nutrient interaction, but increased riskassociated with the TSER 2R allele seemed to be confined to individuals with high folate status. This study doesnot support protective associations for folate and vitamin B6. The TSER 2R allele may confer an increased riskof colorectal cancer. The role of the TSER polymorphism in colorectal carcinogenesis may differ by ethnicity.