Homocysteine, 5, 10-Methylenetetrahydrofolate Reductase 677CT Polymorphism, Nutrient Intake, And Incident Cardiovascular Disease in 24 968 Initially Healthy Women (Molecular Diagnostics and Genetics) (Clinical Report‪)‬

Moderate increases of plasma homocysteine have been associated with a higher risk of cardiovascular disease (CVD) [9] in observational studies, in particular case-control studies (1, 2). However, recent clinical trials in populations at high risk for CVD have failed to show treatment benefits with dietary interventions that lower homocysteine, such as folate and B-vitamins (3-5). High concentrations of homocysteine may result from genetic or environmental and dietary factors that disrupt homocysteine metabolism (6, 7). Methylenetetrahydrofolate reductase (MTHFR) is the enzyme that catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine (7,8). The MTHFR 677CT polymorphism, an alanine-to-valine substitution, results in the production of a thermolabile enzyme with decreased activity, with TT homozygotes having ~50% reduction in enzyme activity (6, 7). The T allele has been associated with higher CVD risk in some studies but not others (9-12). It has been proposed that predisposed individuals who have 1 or more copies of the T allele may become at increased CVD risk in the setting of a low dietary intake of folate or B-vitamins (8), the latter being important cofactors in homocysteine metabolism, and the resulting gene-diet interaction has been postulated to be a risk factor for CVD (13).