title: Thermolabile methylenetetrahydrofolate reductase and factor V Leiden in the risk of deep-vein thrombosis.
abstract: Mild hyperhomocysteinemia is an established risk factor for both arteriosclerosis and thrombosis, and may be caused by genetic and environmental factors. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the cofactor for the methylation of homocysteine to methionine. Individuals 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 identified as the cause of reduced enzyme activity and thermolability of the protein. We studied the frequency of the homozygous mutant (+/+) genotype in 471 patients with deep-vein thrombosis and 474 healthy controls enrolled in The Leiden Thrombophilia Study (LETS), its interaction with factor V Leiden, and assessed the association between the MTHFR genotypes and plasma homocysteine concentration. Homozygosity for the 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 suggest 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, irrespective of factor V Leiden genotype.
authors.affiliation: Department of Pediatrics, University Hospital Nijmegen, The Netherlands.
authors.forename: L A
authors.initials: LA
authors.lastname: Kluijtmans
authors.forename: M
authors.initials: M
authors.lastname: den Heijer
authors.forename: P H
authors.initials: PH
authors.lastname: Reitsma
authors.forename: S G
authors.initials: SG
authors.lastname: Heil
authors.forename: H J
authors.initials: HJ
authors.lastname: Blom
authors.forename: F R
authors.initials: FR
authors.lastname: Rosendaal
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D005165:Factor V / Q000235:genetics*; D006710:Homocysteine / Q000097:blood; D006720:Homozygote; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008875:Middle Aged; D009154:Mutation; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics*; D012307:Risk Factors; D013924:Thrombophlebitis / Q000097:blood / Q000235:genetics*
chemical_list: C095381:factor V Leiden; D006710:Homocysteine; D005165:Factor V; D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2)