MTHFR 677C → T genotype modulates the effect of a 5-year supplementation with B-vitamins on homocysteine concentration: The SU.FOL.OM3 randomized controlled trial

Aims To study how MTHFR 677C -> T genotype modulates the effect of supplementation with B-vitamins on total homocysteine (tHcy) and B-vitamin concentrations. Methods 2381 patients with a personal history of cardiovascular disease were randomly assigned to one of four groups: 1) B-vitamins alone (560 mu g of 5-methyl-THF, 3 mg of vitamin B-6 and 20 mu g of vitamin B-12), 2) n-3 fatty acids alone (600 mg of EPA and DHA in a 2: 1 ratio), 3) B-vitamins and n-3 fatty acids, and 4) placebo. Participants were followed up for 4.7 years. At baseline and annually thereafter, biological parameters were assessed. Multivariate and linear mixed models were fit to study the interaction between B-vitamins and MTHFR genotype. Results Among supplemented participants, concentrations of all three B-vitamins increased during the first year (all p<0.0001) across MTHFR genotype categories. tHcy decreased by 26.3% during the first year (p<0.0001), then steadily increased throughout the 5 years (p(trend) < 0.001). However, at the end of follow-up, that increase was smaller among TT than among CT or CC subjects (p(interaction)<0.02). At baseline, the difference in tHcy concentrations between TT homozygous and CC homozygous subjects was 2.33 mu mol/l (p<0.001). After 5 years, that difference was reduced to 1.06 mu mol/l and remained statistically significant (p<0.001). Conclusion Participants with the TT genotype exhibited a lower 5-year decrease in tHcy concentrations following a B-vitamin supplementation than did participants with the CC or CT genotype.