title: Tissue factor +5466A>G polymorphism determines thrombin formation following vascular injury and thrombin-lowering effects of simvastatin in patients with ischemic heart disease.
abstract: OBJECTIVE
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Cardiology, Jagiellonian University School of Medicine, 80 Pradnicka Str., 31-202 Cracow, Poland. mmundas@cyf-kr.edu.pl
authors.forename: Anetta
authors.initials: A
authors.lastname: Undas
authors.forename: Ewa
authors.initials: E
authors.lastname: Stepien
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Potaczek
authors.forename: Wiesława
authors.initials: W
authors.lastname: Tracz
mesh_terms: D000990:Antithrombin III; D001760:Bleeding Time; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D005787:Gene Frequency; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007700:Kinetics; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D010446:Peptide Fragments / Q000097:blood; D010447:Peptide Hydrolases / Q000097:blood; D011110:Polymorphism, Genetic; D011516:Prothrombin; D018570:Risk Assessment; D012307:Risk Factors; D019821:Simvastatin / Q000627:therapeutic use*; D013917:Thrombin / Q000378:metabolism*; D013925:Thromboplastin / Q000235:genetics*; D013927:Thrombosis / Q000097:blood / Q000235:genetics / Q000517:prevention & control*; D016896:Treatment Outcome
chemical_list: D005343:Fibrinolytic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010446:Peptide Fragments; C046193:antithrombin III-protease complex; C045879:prothrombin fragment 1.2; D000990:Antithrombin III; D011516:Prothrombin; D013925:Thromboplastin; D019821:Simvastatin; D010447:Peptide Hydrolases; D013917:Thrombin