A Common Mutation in the Methylenetetrahydrofolate Reductase Gene (C677T) Increases the Risk for Deep-Vein Thrombosis in Patients With Mutant Factor V (Factor V:Q ⁵⁰⁶ )

Abstract

Hyperhomocysteinemia is a frequent risk factor for deep-vein thrombosis. A common mutation (C677T) in the gene encoding for methylenetetrahydrofolate reductase (MTHFR) is responsible, in the homozygous state, for decreased enzyme activity and mild hyperhomocysteinemia and is associated with increased risk for cardiovascular disease. We studied the prevalence of C677T MTHFR in 77 patients with deep-vein thrombosis and in 154 age- and sex-matched healthy control subjects. In the same individuals, we also evaluated the frequency of the coexistence of C677T MTHFR with mutant factor V:Q506, a common risk factor for deep-vein thrombosis. Sixteen patients (20.8%) and 35 control subjects (22.7%) were homozygous for the C677T MTHFR mutation (odds ratio [OR] = 0.8, 95% confidence interval [CI] = 0.4-2.0). Sixteen patients (20.8%) and 4 control subjects (2.6%) had factor V:Q506; of them, 10 patients and 3 control subjects had isolated factor V:Q506 (adjusted OR = 6.3, 95% CI = 1.6-25.3) and 6 patients and 1 control subject also had C677T MTHFR (adjusted OR = 17.3, 95% CI = 2.0-152.9). The OR for the coexistence of the two mutations was 65% to 75% higher than the expected joint effect calculated by either an additive (OR = 6.0) or multiplicative (OR = 4.4) model. The homozygous C677T mutation of MTHFR per se is not a risk factor for deep-vein thrombosis but increases the risk associated with factor V:Q506. Due to the high prevalence of C677T MTHFR, it is likely that previous studies, which did not look for this mutation, overestimated the relative risk of thrombosis associated with factor V:Q506 alone.

Association between polymorphisms of folate- and methionine-metabolizing enzymes and susceptibility to malignant lymphoma

“…3 A gene-dose effect was not observed in this study. Most of the reported associations with diseases or biomarkers for these polymorphisms did not show this effect, 11,12,14,16,17,19,20,23,24,26 suggesting that disease susceptibility is not determined in a gene-dose manner. The threshold of susceptibility may differ among gene polymorphisms, depending on the biologic mechanism.…”

“…This in turn reduces the chance for the misincorporation of uracil into DNA, a cause of double-strand breaks during uracil excision repair. 9,10 Neural tube defect, 8,11 coronary artery disease, 7,12,13 cerebrovascular disease, 14,15 venous thrombotic disease, 16,17 colorectal cancer, 18,19 and endometrial cancer 20 are reported to be associated with these polymorphisms. Skibola et al 21 reported a link between acute lymphoblastic leukemia and 2 polymorphisms of MTHFR and concluded there is lower susceptibility with either mutant.…”

An association of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism and common carotid atherosclerosis

“…Causes of atherosclerosis attributed to Hcy include endothelial cell injury, accelerated proliferation of smooth muscle cells (Harker et al 1976), LDL oxidation promotion, thrombosis formation by accelerated prothrombin activity, and, recently reported, a mechanism acting via active oxygen (Welch and Loscalzo 1998). Accordingly, the relation between MTHFR gene polymorphism and atherosclerosis by IMT thickening has been suggested to be affected by Hcy (Cattaneo et al 1997;Christensen et al 1997;Kluijtmans et al 1997;Morita et al 1997). Despite these findings, it is difficult to clarify the relation between the MTHFR T allele and carotid artery stenosis (Girelli et al 1998;Nakata et al 1998).…”

“…There have been numerous genetic association studies of the MTHFR C677T variant, particularly in the homozygous state, which have shown both the presence (Arruda et al 1997;Cattaneo et al 1997;Christensen et al 1997;Kluijtmans et al 1997;Morita et al 1997) and absence (Anderson et al 1997;Legnani et al 1997;Ma et al 1996;Press et al 1999;Rees et al 1997;Schwartz et al 1997) of significant associations with such end points as coronary heart disease, myocardial infarction, thrombo-occlusive disease, and cerebrovascular disease. However, the relationship between elevated plasma Hcy concentration and the end points of vascular disease appears to be consistent, even in those studies that failed to show an association with the MTHFR C677T variant.…”

Low Plasma Levels of Vitamin B 6 Are Independently Associated With a Heightened Risk of Deep-Vein Thrombosis

“…9 Second, the presence of a thermolabile variant of the enzyme methylenetetrahydrofolate reductase resulting from a C-to-T substitution at nucleotide 677 of the encoding gene, 10 which is often associated with mild hyperhomocysteinemia, does not seem to increase the risk of venous thromboembolsim, 1 although it might increase this risk in patients with factor V Leiden. 11,12 Finally, the administration of high doses of vitamin B 6 to patients with homocystinuria caused by deficient activity of cystathionine-␤-synthase is associated with considerable reduction in their thrombotic risk, despite the fact that their plasma Hcy levels remain moderately increased. 13 Although several explanations may be proposed to reconcile the above findings with the hypothesis that moderate hyperhomocysteinemia is a risk factor for venous thromboembolism, 1,14 we should consider the hypothesis that high Hcy levels are either a consequence of venous thrombosis or just a marker of other diseases and/or deficiencies of B vitamins, which can by themselves be responsible for biochemical abnormalities that increase the risk of venous thrombosis independently of circulating Hcy levels.…”