C677T and AI298C Polymorphisms of the Methylenetetrahydrofolate Reductase Gene: Incidence and Effect of Combined Genotypes on Plasma Fasting and Post-Methionine Load Homocysteine in Vascular Disease (Molecular Diagnostics and Genetics‪)‬

The enzyme methylenetetrahydrofolate reductase (MTHFR;[1] EC 1.5.1.20) plays a critical role in homocysteine metabolism by catalyzing the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the methyl-group donor in the [B.sub.12] dependent remethylation of homocysteine to methionine. Severe deficiency of the MTHFR enzyme leads to homocystinuria, a rare inborn error of metabolism characterized by highly increased blood and urine homocysteine concentrations. Moderately reduced concentrations of MTHFR, often associated with the common thermolabile form of this enzyme, may lead to hyperhomocysteinemia, as characterized by mild to moderately increased concentrations of plasma total homocysteine (tHcy). Hyperhomocysteinemia has been reported in individuals with occlusive vascular diseases (1, 2), and recent studies have demonstrated that moderately increased tHcy, whether measured after fasting or 2-6 h after a methionine load, is associated with an increased risk for coronary artery disease (CAD) (3-7). In addition, high plasma tHcy concentrations have been reported to be a risk factor for deep-vein thrombosis (DVT) in the general population (8,9). Two common polymorphisms that may contribute to hyperhomocysteinemia have been reported in the MTHFR gene. The C677T (Ala-to-Val) transition, which produces thermolability and somewhat reduced enzyme activity in vitro, was first described by Kang et al. (10). Individuals homozygous for the C677T mutation have moderately increased concentrations of fasting plasma tHcy, especially in the presence of low (15.4 nmol/L) plasma folate (11), and this mutation is more prevalent in patients with CAD (17%) than in controls (5%) (10,12) . Although some studies have confirmed this observation (13), most recent studies do not support an association between the C677T polymorphism and CAD (14-17). Likewise, homozygosity for the C677T polymorphism has been implicated as a risk factor for venous thrombosis (18,19); however, not all studies support this finding (20, 21).