The Effects of Folic Acid Supplementation on Plasma Total Homocysteine Are Modulated by Multivitamin Use and Methylenetetrahydrofolate Reductase Genotypes

Abstract

Elevated concentration of plasma total homocysteine (tHcy) is a common risk factor for arterial occlusive diseases. Folic acid (FA) supplementation usually lowers tHcy levels, but initial tHcy and vitamin levels, multivitamin use, and polymorphisms in the gene for 5, 10-methylenetetrahydrofolate reductase (MTHFR) may contribute to variability in reduction. We tested the effects of a 3-week daily intake of 1 or 2 mg of FA supplements on tHcy levels in patients with and without coronary heart disease (CHD) who were analyzed for the C677T MTHFR mutation. Prior multivitamin intake and baseline vitamin and tHcy levels were also compared with responsiveness to folate supplementation. Both dosages of FA lowered tHcy levels similarly, regardless of sex, age, CHD status, body mass index, smoking, or plasma creatinine concentration. In non-multivitamin users, FA supplements reduced tHcy by 7% in C/C homozygotes and by 13% or 21% in subjects with one or two copies of the T677 allele, respectively; the corresponding reductions were smaller in users of multivitamins. Moreover, T/T homozygotes had elevated tHcy and increased susceptibility to high levels of tHcy at marginally low plasma folate levels, as well as enhanced response to the tHcy-lowering effects of FA. Although other factors are probably involved in the responsiveness of tHcy levels to FA supplementation, about one third of heterogeneity in responsiveness was attributable to baseline tHcy and folate levels and to multivitamin use.

Low Folate Levels and Thermolabile Methylenetetrahydrofolate Reductase as Primary Determinant of Mild Hyperhomocystinemia in Normal and Thromboembolic Subjects

“…This seems to agree with the idea that high tHcy levels are present in the plasma of homozygous subjects with the MTHFR mutation only under a certain folate concentration, whereas low folate levels per se affect the homocysteine pathway. 4,28,41 We found a significantly higher number of subjects with vitamin deficiencies in cases than in controls, implying a significant association between VTE and low vitamin levels. When the two groups were completely adjusted for age, sex, and menopausal condition, 34,42 the new ORs remained significant only for low folate levels, suggesting that some form of decreased vitamindependent enzyme activity may be connected to thrombosis.…”

“…[3][4][5] Thermolabile MTHFR is the most frequent inherited defect of the homocysteine pathway. Individuals homozygous for the MTHFR mutation have significantly higher tHcy levels than heterozygotes or normal homozygotes, 27,28,40 and they can have an increased risk for arterial thrombosis. [17][18][19] Because not all studies have reported a direct association between C677T homozygosity and VTE, 15,16,20 -22 it is possible that hyperhomocystinemia plays a greater role in developing VTE than C677T homozygosity.…”

“…27 Folate supplements reduce plasma tHcy levels, and the response to folate supplements is affected by the number of the 677T alleles in the MTHFR gene, with the strongest response in 677T homozygotes. 28 We studied 220 patients with VTE and 220 healthy control subjects to correlate the prevalence of hyperhomocystinemia with the incidence of the C677T mutation, and we investigated the role of folate and vitamin B 12 in the establishment of hyperhomocystinemia in association with VTE in subjects with thermolabile MTHFR.…”

Increased frequency of combined methylenetetrahydrofolate reductase C677T and A1298C mutated alleles in spontaneously aborted embryos

“…16 Furthermore, the level of plasma homocysteine can be lowered in homozygous individuals by folic acid supplementation. 17 About half the general population carries at least one mutated allele and the frequency of the homozygous mutated genotype (677TT) ranges from 1 to 20% depending on the population. 18 A second common polymorphism in the MTHFR gene is a 1298A?C transition (A1298C) which results in a glutamate to alanine substitution within a presumed regulatory domain of MTHFR.…”

Connective tissue: Vascular and hematological (blood) support

“…(33) Hcy is an intermediate product of the amino acid methionine and is metabolized by 2 pathways: re-methylation, which recreates methionine, and trans-sulfuration, which converts homocysteine into taurine. (34)(35)(36)(37) The re-methylation pathway transfers a methyl group to Hcy through methylcobalamin, an activated form of B-12 (which receives its methyl group from Sadenosylmethionine (SAMe) or though 5-methyltetrahydrafolate (5-MTHF), an active form of folic acid) or betaine (Trimethylglycine). (37) The structure most commonly identified as vitamin B12 is cyanocobalamin; however, this molecule does not occur naturally, to any extent, in plants, microorganisms or in animals.…”