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

Folkert W. Asselbergs, Scott M. Williams, Patricia R. Hebert, Christopher S. Coffey, Hans L. Hillege, Gerjan Navis, Douglas E. Vaughan, Wiek H. van Gilst, Jason H. Moore*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

25 Citations (Scopus)

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 bradlikinin 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. (c) 2006 Elsevier Inc. All rights reserved.

Original languageEnglish
Pages (from-to)362-369
Number of pages8
JournalGENOMICS
Volume89
Issue number3
DOIs
Publication statusPublished - Mar-2007

Keywords

  • plasminogen
  • thrombosis
  • gene-gene interaction
  • epistasis
  • epidemiology
  • fibrinolysis
  • PLASMINOGEN-ACTIVATOR INHIBITOR-1
  • CONVERTING ENZYME-INHIBITION
  • ISCHEMIC-HEART-DISEASE
  • MYOCARDIAL-INFARCTION
  • PAI-1-4G/5G POLYMORPHISMS
  • ACE-I/D
  • IN-VIVO
  • EXPRESSION
  • RELEASE
  • HYPERTENSION

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