The effects of polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1 levels are dependent on environmental context

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Thrombosis is a key factor in the pathophysiology of cardiovascular disease. Important biochemical constituents of the fibrinolytic system, affecting thrombosis, include tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1). Both t-PA and PAI-1 are determined by multiple genetic and environmental factors. We aimed to investigate whether the effects of polymorphism in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on t-PA or PAI-1 levels are dependent on environmental factors in a large population-based sample from the PREVEND study in Groningen, The Netherlands (n = 2,527). We found strong evidence (P ≤ 0.02) for interaction effects of polymorphisms from the bradykinin receptor (BDKRB2) gene and alcohol consumption on t-PA in females and males and on PAI-1 in males. Only suggestive evidence (P < 0.10) was present for an interaction effect of the BDKRB2 gene and alcohol consumption on PAI-1 levels in females. Another consistent finding was evidence for an interaction between bradykinin receptor (BDKRB2) gene polymorphisms and body size as measured by body mass index and/or waist-hip-ratio. For each gender and for both t-PA and PAI-1 there was at least one BDKRB2-body size combination that exhibited suggestive (P < 0.10), significant (P lt; 0.04) and/or strong evidence (P < 0.02) for interaction. In conclusion, the genetic architecture of t-PA and PAI-1 is dependent on the environmental context such as body size and alcohol use. The present study emphasizes the importance of including environmental factors in genetic analyses to fully comprehend the genetic architecture of a specific trait.

Original languageEnglish (US)
Pages (from-to)275-281
Number of pages7
JournalHuman Genetics
Volume122
Issue number3-4
DOIs
StatePublished - Nov 2007

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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