title: Epistatic effects of polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1 levels.
abstract: Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) directly influence thrombus formation and degradation and thereby risk for arterial thrombosis. Activation of the renin-angiotensin system has been linked to the production of PAI-1 expression via the angiotensin II type 1 receptor (AT1R). In addition, bradykinin can induce the release of t-PA through a B2 receptor mechanism. In the present study, we aimed to investigate the epistatic effects of polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1 levels in a large population-based sample (n=2527). We demonstrated a strong significant interaction within genetic variations of the bradykinin B2 gene (P=0.002) and between ACE and bradykinin B2 (p=0.003) polymorphisms on t-PA levels in females. In males, polymorphisms in the bradykinin B2 and AT1R gene showed the most strong effect on t-PA levels (P=0.006). In both females and males, the bradykinin B2 gene interacted with AT1R gene on plasma PAI-1 levels (P=0.026 and P=0.039, respectively). In addition, the current study found a borderline significant interaction between PAI 4G5G and ACE I/D on plasma t-PA and PAI-1 levels. These results support the idea that the interplay between the renin-angiotensin, bradykinin, and fibrinolytic systems might play an important role in t-PA and PAI-1 biology.
authors.affiliation: Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Folkert W
authors.initials: FW
authors.lastname: Asselbergs
authors.forename: Scott M
authors.initials: SM
authors.lastname: Williams
authors.forename: Patricia R
authors.initials: PR
authors.lastname: Hebert
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Coffey
authors.forename: Hans L
authors.initials: HL
authors.lastname: Hillege
authors.forename: Gerjan
authors.initials: G
authors.lastname: Navis
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Vaughan
authors.forename: Wiek H
authors.initials: WH
authors.lastname: van Gilst
authors.forename: Jason H
authors.initials: JH
authors.lastname: Moore
mesh_terms: D001920:Bradykinin / Q000235:genetics*; D015331:Cohort Studies; D004843:Epistasis, Genetic; D005260:Female; D005342:Fibrinolysis / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood* / Q000235:genetics; D011110:Polymorphism, Genetic; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D043782:Receptor, Bradykinin B2 / Q000235:genetics; D012084:Renin-Angiotensin System / Q000235:genetics*; D012727:Sex Characteristics; D010959:Tissue Plasminogen Activator / Q000097:blood*
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D044140:Receptor, Angiotensin, Type 1; D043782:Receptor, Bradykinin B2; C051321:SERPINE1 protein, human; C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A; D010959:Tissue Plasminogen Activator; D001920:Bradykinin