Abstract
BackgroundVascular fibrinolytic balance is maintained primarily by interplay of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1). Previous research has shown that polymorphisms in genes from the renin-angiotensin (RA), bradykinin, and fibrinolytic systems affect plasma concentrations of both t-PA and PAI-1 through a set of gene-gene interactions. In the present study, we extend this finding by exploring the effects of polymorphisms in genes from these systems on incident cardiovascular disease, explicitly examining two-way interactions in a large population-based study.Methodology/Principal FindingsData from the population-based PREVEND study in Groningen, The Netherlands (n = 8,138) were analyzed. The effects of the polymorphisms and their interactions on cardiovascular events were analyzed via Cox proportional hazards models. There was no association between five of the six polymorphisms singly and risk of cardiovascular disease. There was a significant main effect for the ACE I/D polymorphism for both dominant and additive coding schemes. There were significant interactions between the following polymorphism pairs even after adjustment for known risk factors: ACE I/D & PAI-1 4G/5G (p = 0.012), BDKRB2 C181T & ACE I/D (p = 0.016), BDKRB2 C58T & ACE I/D (p = 0.025), BDKRB2 exon 1 I/D & AT1R A1166C (p = 0.017), and BDKRB2 C58T & AT1R A1166C (p = 0.015).Conclusions/SignificanceThis study suggests possible interactions between genes from the RA, bradykinin, and fibrinolytic systems on the risk of cardiovascular disease, extending previous research that has demonstrated that interactions among genes from these systems influence plasma concentrations of both t-PA and PAI-1. Further explorations of these interactions are needed.
Highlights
Both tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) are involved in thrombus formation and degradation
Conclusions/Significance: This study suggests possible interactions between genes from the RA, bradykinin, and fibrinolytic systems on the risk of cardiovascular disease, extending previous research that has demonstrated that interactions among genes from these systems influence plasma concentrations of both t-PA and PAI-1
Because there is some evidence that the prediction of plasma t-PA/PAI-1 levels by these polymorphisms may differ by sex [9] and that the relationship between plasma concentrations of t-PA/PAI-1 and cardiovascular disease-related traits may differ by sex [22], we evaluated whether the significant interactions differed by sex by fitting three-way interactions in both the unadjusted and adjusted models
Summary
Both tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) are involved in thrombus formation and degradation. Vascular fibrinolytic balance is determined by the competing effects of t-PA and PAI-1 [1]. Previous research has shown that infusion of angiotensin II increases PAI-1 levels in both hypertensive and normotensive patients [4]. We found significant interactions between polymorphisms from the renin-angiotensin (RA), bradykinin, and fibrinolytic systems on the plasma concentrations of t-PA and PAI-1 in two independent studies [10,11]. Vascular fibrinolytic balance is maintained primarily by interplay of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1). Previous research has shown that polymorphisms in genes from the reninangiotensin (RA), bradykinin, and fibrinolytic systems affect plasma concentrations of both t-PA and PAI-1 through a set of gene-gene interactions. We extend this finding by exploring the effects of polymorphisms in genes from these systems on incident cardiovascular disease, explicitly examining two-way interactions in a large populationbased study
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