Objective: Polymorphisms in genes involved in folate uptake and metabolism may affect folate status and, thereby, the risk of cancer. In this nested case-referent study, we related two such polymorphisms, reduced folate carrier (RFC1) 80G > A and folate hydrolase 1 (FOLH1) 1561C > T, to the risk of colorectal cancer, taking into account pre-diagnostic plasma folate and total homocysteine concentrations and the MTHFR 677C > T polymorphism, which were analysed in a previous study.
Material and methods: Subjects were 220 cases and 414 matched referents from the population-based Northern Sweden Health and Disease Study.
Results: The RFC1 80A-allele was associated with reduced plasma folate and elevated plasma total homocysteine concentrations, but the result was statistically significant only for folate. In contrast, the FOLH1 1561T-allele was associated with higher plasma folate and reduced plasma total homocysteine concentrations, and the result was statistically significant only for homocysteine. Neither polymorphism was related to the risk of colorectal cancer, either in univariate analysis or after adjusting for body mass index, current smoking, recreational and occupational physical activity and alcohol intake. Further adjustment for folate or homocysteine status or the MTHFR 677C > T polymorphism did not affect risk estimates. Subjects with the RFC1 80AA genotype in combination with low plasma folate concentrations or the MTHFR 677TT genotype had a reduced risk of colorectal cancer of borderline statistical significance.
Conclusions: These findings suggest that although the RFC1 80G > A and FOLH1 1561C > T polymorphisms may influence folate status, they are not likely to have a major independent role in the development of colorectal cancer.