Thermolabile Methylenetetrahydrofolate Reductase and Factor V Leiden in the Risk of Deep-Vein Thrombosis
Leo A. J. Kluijtmans (1), Martin den Heijer (2), Pieter H. Reitsma (3), Sandra G. Heil (1), Henk J. Blom (1), Frits R. Rosendaal (3), (4)
From the (1) Department of Pediatrics, University Hospital Nijmegen, The Netherlands, (2) Department of International Medicine, Twee Steden Hospital, Tilburg, The Netherlands, (3) Department of Hemostasis and Thrombosis, University Hospital Leiden, The
Summary Mild hyperhomocysteinemia is an established risk factor for both arteriosclerosisand thrombosis, and may be caused by genetic and environmentalfactors. Methylenetetrahydrofolate reductase (MTHFR) catalyzesthe reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate,the cofactor for the methylation of homocysteine tomethionine. Individuals with the thermolabile variant of MTHFR havedecreased MTHFR activities, resulting in elevated plasma homocysteineconcentrations. A homozygous 677C T transition in theMTHFR gene has recently been identified as the cause of reducedenzyme activity and thermolability of the protein. We studied the frequencyof the homozygous mutant (+/+) genotype in 471 patients withdeep-vein thrombosis and 474 healthy controls enrolled in The LeidenThrombophilia Study (LETS), its interaction with factor V Leiden, andassessed the association between the MTHFR genotypes and plasmahomocysteine concentration. Homozygosity for the 677C T polymorphismwas 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 (+/+) genotypewas observed in carriers of factor V Leiden. Our data suggest that,although the homozygous mutant genotype is associated with elevatedplasma homocysteine concentrations, this homozygous mutation itselfis not a genetic risk factor for deep-vein thrombosis, irrespective of factorV Leiden genotype.