Homocysteine concentrations in MTHFR genotype are independent of folic acid supplementation

July 20, 2011

According to a new study in US-Chinese cooperation, carriers of the MTHFR677TT polymorphisms were associated with lower levels of folate in their plasma and red blood cells (RBC) and with higher plasma homocysteine levels than individuals with CT or CC genotype – irrespective of the folic acid supplementation dose.

The large, population-based, double-blind study examined whether the methylene tetrahydrofolate reductase MTHFR677C?T genotype modifies the response to folic acid supplementation over a period of six months and three months after discontinuation (1). The MTHFR enzyme is responsible for the synthesis of 5-methylTHF (tetrahydrofolate) – the coenzyme that plays a crucial role in endogenous production of THF and subsequent DNA synthesis. The MTHFR genotype is associated with modifications of disease and risk of neural tube defects (NTD). According to the authors, genetic variation in the one-carbone metabolism pathway (centred around folate and an important pathway for any study related to folate or DNA methylation) may be important in understanding a population’s response to folic acid supplementation and fortified foods. Folate is the primary methyl-group donor for processes such as DNA methylation reactions, nucleotide synthesis and DNA repair mechanisms.

932 women of reproductive-age from northern China were recruited as participants. MTHFR genotyping was performed to identify C?T mutation at position 677. 327 (35,1%) of all women in the trial were homozygous for the MTHFR677TT variant, 443 (47%) were heterozygous (CT) and 163 (17,4%) were homozygous (CC). Different subgroups within each of these genotypes received different supplement doses of folic acid: 100 ?g/d, 400 ?g/d, 4,000 ?g/d and 4,000 ?g/wk. The participants came from a population with no exposure to fortified foods. The study design allowed for a precise determination of the effect of MTHFR genotype on long-term exposure to folic acid alone. Plasma and RBC folate concentrations and plasma homocysteine concentrations were measured at baseline, then after one, three and six months of supplementation with folic acid and finally after three months without supplementation. Results showed that folate and homocysteine concentrations in plasma and RBC were consistently associated with MTHFR genotype in the supplementation trial, regardless of the folic acid dose. MTHFR TT was associated with lower folate concentrations, and the trend of TT< CC was even clear at the highest doses. Folic acid doses of 100 ?g/d or 4,000 ?g/wk did not reduce high homocysteine concentrations in the subjects with the MTHFR TT genotype. The authors concluded: “MTHFR genotype was an independent predictor of plasma and RBC folate and plasma homocysteine concentrations and did not have a significant interaction with folic acid dose during supplementation.”


  1. Crider K.S. et al. MTHFR677C? genotype is associated with folate and homocysteine concentrations in a large, population-based double-blind trial of folic acid supplementation. Am J Clin Nutr 2011; 93(6):1365–1372.