A second common variant in the methylenetetrahydrofolate reductase (MTHFR)gene and its relationship to MTHFR enzyme activity, homocysteine, and cardiovascular disease risk

Molecular defects in genes encoding enzymes involved in homocysteine metabo lism may account for mild hyperhomocysteinemia, an independent and graded r isk factor for cardiovascular disease (CVD). We examined the relationship o f two polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene , the 677C -->T and 1298A -->C variants, to MTHFR activity, homocysteine co ncentrations, and risk of CVD in a population of 190 vascular disease patie nts and 601 apparently healthy controls. The mean specific and residual MTH FR activities were significantly lower in 677CT and 677TT individuals (both P <0.001). The 1298A -->C mutation alone showed no effect on MTHFR activit ies. However, when the 677C -->T genotype was taken into account, the 1298A -->C mutation also caused a significant decrease in MTHFR activities, whic h was observed in both the homozygous 1298CC (P <0.001) and the heterozygou s 1298AC states (P=0.005). Both the 677TT as the 677CT genotypes were assoc iated with significantly higher fasting and postload homocysteine, levels t han 677CC (P <0.001 and P=0.003, respectively). The 1298A -->C mutation had no effect on fasting, or postload homocysteine levels. Since homocysteine itself is considered to be positively associated with the risk of CVD, thes e findings indicate that the 1298A -->C mutation cannot be considered a maj or risk factor for CVD.