Thrombomodulin Gene Polymorphisms and Haplotypes and the Risk of Cardiovascular Events

Abstract

Background-Thrombomodulin is an anticoagulant expressed during endothelial activation and damage. To address the potential role of allelic variants of thrombomodulin gene in the pathogenesis of cardiovascular diseases, we analyzed in a prospective follow-up study 8 single-nucleotide polymorphisms (SNPs) across the thrombomodulin locus, covering all common (Ͼ5%) haplotypes. Methods and Results-Two separate, stratified random samples of men and women 25 to 74 years of age were examined in Finland in 1992 and 1997. The total sample size was 14 140 individuals, with 7 (1997 cohort) to 10 (1992 cohort) years of follow-up. Altogether, 662 individuals had a history of cardiovascular events already at baseline. During the follow-up, 401 incident coronary events and 148 incident ischemic strokes were observed. The alleles and common haplotypes of 8 SNPs were tested in Cox proportional hazards models using incident coronary events, incident ischemic strokes, and total mortality as end points. None of the SNPs or major SNP haplotypes showed consistent association with the end points analyzed in the combined data. Conclusions-Results from this prospective, population-based study suggest that common allelic variants of the thrombomodulin gene may not significantly contribute to the risk of cardiovascular events at the population level.

Thrombomodulin gene polymorphisms in brain infarction and mortality after stroke

“…This finding is in keeping with three previous studies, which reported linkage disequilibrium between +1418C/T and -1208/-1209delTT [9,10,17].…”

“…In the 148 incident brain infarctions, none of the SNPs and the corresponding haplotypes were associated with brain infarction, myocardial infarction or death [10]. In keeping with these results, we found no significant relationship between TM gene polymorphism and brain infarction risk even when analyses were restricted to subjects without a previous vascular history.…”

“…In the Stroke Prevention in Women Study [8], there was a significant relationship between homozygous Ala455Val polymorphism and risk of brain infarction. Recently, however, the FINRISK study analyzed eight common single nucleotide polymorphisms (SNPs) of the TM gene (including +1418C/T and -1208/-1209delTT) [10] and found no consistent association between TM gene SNPs and incident coronary events, incident brain infarction and total mortality.…”

Association of the Thrombomodulin Gene c.1418C>T Polymorphism With Thrombomodulin Levels and With Venous Thrombosis Risk

“…35 As to the levels of sTM, our results indicate that increased levels are associated with higher VTE risk, and this association is, at least in part, independent of the THBD c.1418C>T polymorphism. Increased sTM levels have also been reported in patients with recurrent VTE.…”

Identification of Genetic Aberrations in Thrombomodulin Gene in Patients With Recurrent Venous Thromboembolism

“…25,35 . Furthermore, it has also been shown that THBD rs1042580, rs1962 and rs3176123 polymorphisms did not contribute significantly to the risk of cardiovascular events 23 . Another study shows that THBD rs1042580 polymorphism alone may not be a risk factor for cardiovascular events, however, in combination with polymorphisms in another gene involving coagulation pathway (Factor V gene), may contribute to risk for cardiovascular events 36 .…”