5,10-methylenetetrahydrofolate reductase 677C → T and 1298A → C mutations are genetic determinants of elevated homocysteine

Background: Methylenetetrahydrofolate reductase (MTHFR) is one of the main regulatory enzymes of homocysteine metabolism. Elevated plasma total homocysteine (tHcy) is a major risk for cardiovascular disease. A common 677C→ T mutation in the MTHFR gene results in decreased enzymic activity, and contributes to increased plasma tHcy, in association with low plasma folate. A recently described 1298A→ C mutation in the MTHFR gene clearly reduces MTHFR activity (although to a lesser extent than the 677C→ T) but its effect on plasma tHcy levels is not yet clear. Aim: To investigate the frequency of these two MTHFR polymorphisms in a Portuguese population, and to correlate the MTHFR genotype with the biochemical phenotype at the level of homocysteine and folate concentrations. Design: Prospective population survey. Methods: We studied 117 healthy volunteers (71 females, 46 males). The 677C→ T and 1298A→ C mutations were screened by PCR-RFLP. Levels of plasma tHcy and folate, and red blood cell folate, were determined. Results: The allele frequencies of the 677C→ T and 1298A→ C mutations were 0.33 and 0.28, respectively. Homozygotes for the 677C→ T mutation had significantly elevated plasma tHcy and RBC folate levels and significantly lowered plasma folate concentrations than subjects without the mutation. The 1298A→ C mutation showed a significant effect on plasma tHcy, but not on plasma folate or RBC folate levels. Discussion: The observed 677T allele frequency is not consistent with the idea of a north-south gradient as previously suggested. The 1298A→ C mutation is common in Portugal. Both MTHFR mutations showed effects on plasma tHcy levels.