MTHFR gene

The MTHFR gene codes for a key enzyme in folate metabolism. A large number of studies have associated the presence of common variants in the C677T and A1298C populations with a decreased folate metabolic capacity that could be related to several clinical conditions.

The MTHFR gene encodes for the enzyme methylene tetrahydrofolate reductase which plays a key role in folate and homocysteine metabolism by catalyzing the conversion of dietary ingested folate (vitamin B9) into the main circulating form of folate which is used in the conversion pathway of homocysteine to methionine. Methionine is an essential amino acid, not only for the constitution of the body's proteins, but also for DNA methylation and regulation of gene expression. In this sense, changes in the MTHFR gene sequence can lead to deficiency of this enzyme, and with this, to alterations in the folate conversion cycle and in the generation of methionine from homocysteine, which can lead to low levels of folate in blood and elevated levels of homocysteine in blood and urine (homocystinuria).

Variants in the MTHFR gene C677T and A1298C are two of the most common polymorphisms in the general population. Approximately 60-70% of individuals will have at least one of these variants, 8.5% will be homozygous (two copies) for one of them, and 2.25% will be compound heterozygous carriers (one copy of each variant). Both variants have been associated with reduced MTHFR enzyme activity, and reduced efficiency in folic acid processing. The C677T change decreases the affinity of MTHFR and its cofactor, which favors thermolability and decreases enzyme activity, whereas A1298C directly decreases enzyme activity. Hence, these variants have been associated with a variety of conditions, including various cancers, coronary artery disease, altered plasma lipid levels and neural tube closure defects, as well as thrombophilias, fertility problems and complications during pregnancy.

However, despite the vital role of folate and MTHFR in its metabolism, scientific findings remain inconsistent and without statistically significant evidence that these polymorphisms have an impact on routine clinical practice. In this context, the American College of Medical Genetics and Genomics does not recommend the determination of the two common polymorphisms on a routine basis, and likewise, the American Academy of Nutrition and Dietetics does not recommend dietary interventions. This is because both variants have high frequencies in the general population, and there are no clinically meaningful interventions that can be offered to carriers, so their identification is not currently useful.

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Genes analyzed



MTHFR genetic testing: Controversy and clinical implications. Australian Journal for General Practitioners 2016; 45(4):237-240.

Wan L et al. Methylenetetrahydrofolate reductase and psychiatric diseases. Transl Psychiatry 2018; 8, 242.

Leclerc D et al. Molecular Biology of Methylenetetrahydrofolate Reductase (MTHFR) and Overview of Mutations/Polymorphisms. Madame Curie Bioscience Database [May 2022].

Liu F et al. 5,10-methylenetetrahydrofolate reductase C677T gene polymorphism and peripheral arterial disease: A meta-analysis. Vascular. 2020:1708538120982698.

Osadnik T et al. Genetic and environmental factors associated with homocysteine concentrations in a population of healthy young adults. Analysis of the MAGNETIC study. Nutr Metab Cardiovasc Dis. 2020;30(6):939-947.

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