Objective: This population-based case-control study was designed to investigate the interrelationships between polymorphisms in the methylenetetrahydrofolate (MTHFR C677T and A1298C) gene and other genes (MTR A2756G; MTRR A66G and CBS 844ins68), intake of B-vitamins and colorectal cancer risk (CRC).
Methods: We interviewed 727 CRC cases of Japanese, Caucasian, or Native Hawaiian origin and 727 controls matched on sex, age, and ethnicity.
Results: Compared to the homozygous wild-type genotype, the odds ratios for subjects with one or two MTHFR 677T variant alleles were 0.8 (0.6-1.1) and 0.7 (0.5-1.1), respectively (p for gene-dosage effect: 0.04). The TT genotype was associated with a 50-60% decrease in CRC risk among subjects with high intake of folate or vitamin B6, compared to those with the CC genotype and low levels of intake. The MTHFR 1298C and CBS8 44ins68 variant alleles were also found to be weakly protective against CRC and to act jointly with the 677T allele.
Conclusions: This study provides additional evidence for a decreased CRC risk for subjects with the MTHFR 677T allele, particularly at high levels of folate and vitamin B6 intake. Our data also suggest that the relationships between CRC and the MTHFR A1298C and CBS 844ins68 polymorphisms warrant further study.