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.