Methylenetetrahydrofolate reductase polymorphism interacts with riboflavin intake to influence bone mineral density

Bone mineral density is a complex trait regulated by an interaction between genetic and environmental factors. Recent studies have identified a functional polymorphism affecting codon 677 of the methylenetetrahydrofolate reductase (MTHFR) gene that is associated with reduced bone mineral density (BMD) in Japanese and Danish postmenopausal women and increased risk of fracture in elderly Danish women. Since dietary B vitamins can influence circulating homocysteine (tHcy) levels, we examined the relationship among MTHFR genotype, B complex vitamins (folate, vitamin B12, vitamin B6 and riboflavin), BMD, and rate of change in BMD in a longitudinal study of 1241 Scottish women aged 45-54 years, at the time of initial study, who were followed up for a mean (SD) of 6.6 (0.7) years. There was no significant association between BMD and either MTHFR genotype or B complex vitamins when examined separately. However, we detected a significant interaction among quartile of energy-adjusted riboflavin intake, MTHFR 'TT' genotype, and BMD (P = 0.01 for baseline FN BMD, P = 0.02 for follow-up FN BMD). Increasing dietary riboflavin intake correlated with LS BMD and FN BMD in homozygotes for the MTHFR 'T' allele, which remained significant for FN after adjustment for confounders (r = 0.192, P = 0.036 for baseline; r = 0.186, P = 0.043 at follow-up) but not in the other genotypes. This raises the possibility that riboflavin intake and MTHFR genotype might interact to regulate BMD. Further work is required to determine if this association holds true for other populations and ethnic groups.