Relation Between Folate Status, a Common Mutation in Methylenetetrahydrofolate Reductase, and Plasma Homocysteine Concentrations

TLDR

Methylenetetrahydrofolate reductase (MTHFR) produces 5‑methyltetrahydrofolate for remethylation of homocysteine to methionine, and a common Ala→Val mutation renders the enzyme thermolabile, potentially elevating plasma homocysteine. The study screened 365 participants from the NHLBI Family Heart Study to evaluate how the MTHFR mutation interacts with vitamin coenzymes in homocysteine metabolism. Individuals with low plasma folate (<15.4 nmol/L) and the homozygous mutant genotype had 24 % higher fasting homocysteine than those with the normal genotype, while no genotype difference appeared at folate ≥15.4 nmol/L, indicating that thermolabile MTHFR carriers may require higher folate to prevent hyperhomocysteinemia.

Abstract

Background Methylenetetrahydrofolate reductase (MTHFR) synthesizes 5-methyltetrahydrofolate, the major carbon donor in remethylation of homocysteine to methionine. A common MTHFR mutation, an alanine-to-valine substitution, renders the enzyme thermolabile and may cause elevated plasma levels of the amino acid homocysteine. Methods and Results To assess the potential interaction between this mutation and vitamin coenzymes in homocysteine metabolism, we screened 365 individuals from the NHLBI Family Heart Study. Among individuals with lower plasma folate concentrations (&lt;15.4 nmol/L), those with the homozygous mutant genotype had total fasting homocysteine levels that were 24% greater ( P &lt;.05) than individuals with the normal genotype. A difference between genotypes was not seen among individuals with folate levels ≥15.4 nmol/L. Conclusions Individuals with thermolabile MTHFR may have a higher folate requirement for regulation of plasma homocysteine concentrations; folate supplementation may be necessary to prevent fasting hyperhomocysteinemia in such persons.