MTHFR 677C → T genotype modulates the effect of a 5-year supplementation with B-vitamins on homocysteine concentration: The SU.FOL.OM3 randomized controlled trial.

Leopold K Fezeu,Veronique Ducros,Valentina A Andreeva,Jean-Claude Guilland,Jean-Louis Guéant,Serge Hercberg,Pilar Galan,Natalie Colson

doi:10.1371/journal.pone.0193352

Abstract

AimsTo study how MTHFR 677C→T genotype modulates the effect of supplementation with B-vitamins on total homocysteine (tHcy) and B-vitamin concentrations.Methods2381 patients with a personal history of cardiovascular disease were randomly assigned to one of four groups: 1) B-vitamins alone (560 μg of 5-methyl-THF, 3 mg of vitamin B6 and 20 μg of vitamin B12), 2) n-3 fatty acids alone (600 mg of EPA and DHA in a 2:1 ratio), 3) B-vitamins and n-3 fatty acids, and 4) placebo. Participants were followed up for 4.7 years. At baseline and annually thereafter, biological parameters were assessed. Multivariate and linear mixed models were fit to study the interaction between B-vitamins and MTHFR genotype.ResultsAmong supplemented participants, concentrations of all three B-vitamins increased during the first year (all p<0.0001) across MTHFR genotype categories. tHcy decreased by 26.3% during the first year (p<0.0001), then steadily increased throughout the 5 years (ptrend<0.001). However, at the end of follow-up, that increase was smaller among TT than among CT or CC subjects (pinteraction<0.02). At baseline, the difference in tHcy concentrations between TT homozygous and CC homozygous subjects was 2.33 μmol/l (p<0.001). After 5 years, that difference was reduced to 1.06 μmol/l and remained statistically significant (p<0.001).ConclusionParticipants with the TT genotype exhibited a lower 5-year decrease in tHcy concentrations following a B-vitamin supplementation than did participants with the CC or CT genotype.Clinical trial registrationCurrent Controlled Trials # ISRCTN41926726.

Highlights

Homocysteine (Hcy) is a sulfur-containing amino acid that plays a major role in methionine metabolism
Concentrations of all three B-vitamins increased during the first year across Methylenetetrahydrofolate reductase (MTHFR) genotype categories. total homocysteine (tHcy) decreased by 26.3% during the first year (p
Methylenetetrahydrofolate reductase (MTHFR) converts 5,10-methylene tetrahydrofolate to 5-methyltetrahydrofolate required for the conversion of Hcy to methionine; MTHFR plays a pivotal role in Hcy metabolism [2] by contributing to lowering its plasma values

Summary

Introduction

Homocysteine (Hcy) is a sulfur-containing amino acid that plays a major role in methionine metabolism. Elevated plasma total homocysteine (tHcy) concentrations can be related to genetic defects, abnormal vitamin status, or both [1]. A common mutation exists in the gene encoding the MTHFR enzyme. Individuals who have a C-to-T substitution at base 677 of the gene (amino acid change A222V) have lower enzyme activity, higher Hcy [3] and lower folate levels than do those without this mutation [4,5,6,7]. In addition to genetic defects, inadequate plasma concentrations of vitamin cofactors (e.g., vitamin B6, vitamin B12, and folate) play an important role in the regulation of plasma tHcy concentration [4, 8]

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