Effect of Riboflavin Status on the Homocysteine-Lowering Effect of Folate in Relation to the MTHFR (C677T) Genotype (Nutrition‪)‬

Current evidence suggests that increased plasma homocysteine (hyperhomocysteinemia) is a risk factor for cardiovascular disease in the general population (1, 2), although it is unclear whether homocysteine itself is the causal factor. Homocysteine is a metabolite of methionine, and once formed, it can be metabolized by transsulfuration through a vitamin [B.sub.6] dependent pathway or remethylated to methionine in a folate- and vitamin [B.sub.12]-dependent reaction. Genetic defects or inadequate provision of these vitamin cofactors can increase plasma total homocysteine (tHcy) (4) concentrations. Methylenetetrahydrofolate reductase (MTHFR) is a FAD-dependent enzyme that catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate (5MeTHF), which acts as a methyl donor for homocysteine remethylation. A common mutation in the MTHFR gene (677C [right arrow] T) has been identified with a frequency of 0.32 in Caucasian populations. Individuals homozygous (TT) for this mutation have ~50% of the normal MTHFR activity (3). This reduced activity is associated with a reduced ability to catalyze the reduction of 5,10-methylenetetrahydrofolate to 5MeTHF and predisposes homozygous individuals to hyperhomocysteinemia. It has been proposed that individuals with the TT genotype are more likely to have vascular disease because, in combination with a low folate status, these TT individuals had higher plasma concentrations of homocysteine than do those with the CT and CC genotypes. However, a recent metaanalysis has failed to confirm this (4).