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.

Fig. 1

Polymorphisms of the renin-angiotensin, bradykinin, and fibrinolytic system show significant interactions on plasma t-PA and PAI-levels among females. Only the significant (p<0.05) and borderline significant (p<0.10) interactions are presented. The lines illustrate the interactions between genes and line thickness is inversely related to the significance level. The model of inheritance is given in parentheses. A: additive; D: dominant; R: recessive. For example, the BDKRB2 exon 1 I/D by BDKRB2 C181T interaction on t-PA levels involved a dominant by recessive effect with a p-value of 0.002.

Fig. 2

Polymorphisms of the renin-angiotensin, bradykinin, and fibrinolytic system show significant interactions on plasma t-PA and PAI-levels among males. Only the significant (p<0.05) and borderline significant (p<0.10) interactions are presented. The lines illustrate the interactions between genes and line thickness is inversely related to the significance level. The model of inheritance is given in parentheses. A: additive; D: dominant; R: recessive. For example, the AT1R A1166C by BDKRB2 C181T interaction on t-PA levels involved a dominant by additive effect with a p-value of 0.006.

Fig. 3

A consistent significant interaction is present between polymorphisms of the renin-angiotensin and bradykinin genes on plasma t-PA and PAI-1 levels among females and males. The four figures illustrate the interactions on the absolute values of the natural log transformed t-PA and PAI-1.