Epistatic effects of polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1 levels

Genomics. 2007 Mar;89(3):362-9. doi: 10.1016/j.ygeno.2006.11.004. Epub 2007 Jan 5.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bradykinin / genetics*
  • Cohort Studies
  • Epistasis, Genetic*
  • Female
  • Fibrinolysis / genetics*
  • Humans
  • Male
  • Middle Aged
  • Peptidyl-Dipeptidase A / genetics
  • Plasminogen Activator Inhibitor 1 / blood*
  • Plasminogen Activator Inhibitor 1 / genetics
  • Polymorphism, Genetic*
  • Receptor, Angiotensin, Type 1 / genetics
  • Receptor, Bradykinin B2 / genetics
  • Renin-Angiotensin System / genetics*
  • Sex Characteristics
  • Tissue Plasminogen Activator / blood*

Substances

  • Plasminogen Activator Inhibitor 1
  • Receptor, Angiotensin, Type 1
  • Receptor, Bradykinin B2
  • SERPINE1 protein, human
  • ACE protein, human
  • Peptidyl-Dipeptidase A
  • Tissue Plasminogen Activator
  • Bradykinin