THERMOLABILE METHYLENETETRAHYDROFOLATE REDUCTASE AND FACTOR-V-LEIDEN IN THE RISK OF DEEP-VEIN THROMBOSIS

Mild hyperhomocysteinemia is an established risk factor for both arter iosclerosis and thrombosis,and may be caused by genetic and environmen tal factors. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofola te, the cofactor for the methylation of homocysteine to methionine. In dividuals with the thermolabile variant of MTHFR have decreased MTHFR activities, resulting in elevated plasma homocysteine concentrations. A homozygous 677C-->T transition in the MTHFR gene has recently been i dentified as the cause of reduced enzyme activity and thermolability o f the protein. We studied the frequency of the homozygous mutant (+/+) genotype in 471 patients with deep-vein thrombosis and 474 healthy co ntrols enrolled in The Leiden Thrombophilia Study (LETS), its interact ion with factor V Leiden, and assessed the association between the MTH FR genotypes and plasma homocysteine concentration. Homozygosity for t he 677C-->T polymorphism was observed in 47 (10%) patients, and in 47 (9-9%) controls (OR 1.01 [95% CI: 0.7-1.5]). No modified risk of the ( +/+) genotype was observed in carriers of factor V Leiden. Our data su ggest that, although the homozygous mutant genotype is associated with elevated plasma homocysteine concentrations, this homozygous mutation itself is not a genetic risk factor for deep-vein thrombosis, irrespe ctive of factor V Leiden genotype.