Tissue factor +5466A>G polymorphism determines thrombin formation following vascular injury and thrombin-lowering effects of simvastatin in patients with ischemic heart disease

Abstract

We examined the hypothesis that the +5466A>G variant (rs3917643) of the tissue factor (TF) gene is associated with thrombin formation following simvastatin in patients with ischemic heart disease (IHD). Prothrombin 1.2 fragments (F1.2) and thrombin-antithrombin complexes (TAT) were assessed in 95 men with stable IHD, aged 54.4+/-6.8 years, in blood collected every 60s from the bleeding-time wounds before and after a 3-month simvastatin administration (40 mg/day). We identified 16 patients with the TF +5466AG genotype and 79 subjects with the +5466AA genotype. Baseline maximum rates of F1.2 and TAT formation and their maximum levels at the site of vascular injury, but not in venous blood, were higher in +5466G allele carriers than in those with +5466AA genotype (P<0.0001). The magnitude of reduction in maximum rates of F1.2 and TAT formation following simvastatin was larger (P<0.001) in +5466G allele carriers than in +5466AA subjects. The degree of decrease in maximum local levels of F1.2 and TAT after simvastatin was similar in both genotype groups. The presence of the +5466G allele was independently associated with the maximum velocity of F1.2 and TAT generation and maximum levels of both markers before and after simvastatin in multiple regression models (P<0.01 for all analyses). Local thrombin generation, in +5466AG and +5466AA subjects, showed no significant correlations with lipid variables. Thrombin formation following vascular injury and thrombin-lowering effect of statins in patients with IHD are at least in part genetically determined by the TF +5466A>G polymorphism.