Thirty-five healthy adults who were homozygous for the methylenetetrahydrofolate reductase (MTHFR) TT genotype, 26 heterozygotes (CT), and 28 with the wild-type genotype (CC) were randomly assigned to receive, in double-blind fashion, 1.6 mg/day of riboflavin or placebo for 12 weeks. In the TT group, riboflavin supplementation decreased the mean homocysteine concentration by 22% (from 16.1 micromol/L at baseline to 12.5 micromol/L; p = 0.003 compared with baseline; p = 0.007 compared with the 6% increase over baseline in the placebo group). In the subgroup of TT subjects with lower riboflavin status at baseline (n = 16), the mean homocysteine concentration decreased by 40% with riboflavin supplementation (from 22.0 to 13.2 micromol/L; p = 0.010). Homocysteine levels did not change in the CC or CT groups, even though those groups had been pre-selected for suboptimal riboflavin status.

Comment: MTHFR is an enzyme that catalyzes the conversion of homocysteine to methionine. Individuals homozygous for the MTHFR 677C  T polymorphism require higher-than-normal amounts of folic acid in order to maintain low plasma homocysteine levels. They also have reduced activity of the MTHFR enzyme as a result of inappropriate loss of the flavin adenine dinucleotide (FAD) cofactor, of which riboflavin is a component. In the present study, riboflavin supplementation decreased homocysteine concentrations substantially in people with the MTHFR 677 TT genotype, particularly those with initially low riboflavin status. The authors of this report suggested that these findings might explain why this common polymorphism carries an increased risk of coronary heart disease in Europe but not in North America, where riboflavin fortification has existed for more than 50 years. Since nearly 20% of the population is homozygous for this polymorphism, homocysteine-lowering therapy should include not only folic acid, vitamin B6, and vitamin B12, but also riboflavin.

McNulty H, et al. Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C  T polymorphism. Circulation. 2006;113:74-80.