Optimization of dietary folate or low-dose folic acid supplements lower homocysteine but do not enhance endothelial function in healthy adults, irrespective of the methylenetetrahydrofolate reductase (C677T) genotype

Objectives We sought to study the effect of low-dose folic acid supplementa tion or optimization of dietary folate intake on plasma homocysteine and en dothelial function in healthy adults. Background Elevated homocysteine is associated with cardiovascular disease, but it is not known whether this relationship is causal. Individuals homoz ygous (TT) for the C677T mutation in the methylenetetrahydrofolate reductas e (MTHFR) gene (similar to 12% of the population) have increased homocystei ne levels, particularly in association with suboptimal folate intake. Methods Healthy subjects (n=126; 42 of each MTHFR genotype) were included i n this cross-over study of three interventions of four months each: 1) plac ebo plus natural diet; 2) daily 400-mug folic acid supplement plus natural diet; and 3) increased dietary folate intake to 400 mug/day. Results At baseline, homocysteine was inversely related to plasma folate an d was higher in TT homozygotes. For the whole group, plasma folate increase d by 46% after dietary folate and by 79% after supplementation, with reduct ions of homocysteine of 14% and 16%, respectively. Within the genotype, TT homozygotes exhibited the most marked changes in these variables. Brachial artery endothelial function, as determined by a change in end-diastolic dia meter in response to increased flow, was not changed by increased folate in take (98 +/- 73 mum at baseline, 110 +/- 69 mum after a high-folate diet, 1 14 +/- 59 mum after supplementation and 118 +/- 68 mum after placebo). Plas ma von Willebrand factor antigen was unaltered. Conclusions Optimization of dietary folate or low-dose folic acid supplemen tation reduces plasma homocysteine but does not enhance endothelial functio n, irrespective of the MTHFR (C667T) genotype. (J Am Coll Cardiol 2001;38:1 799-805) (C) 2001 by the American College of Cardiology.