Abstract
The proteins, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1), act in concert to balance thrombus formation and degradation, thereby modulating the development of arterial thrombosis and excessive bleeding. PAI-1 is upregulated by the renin-angiotensin system (RAS), specifically by angiotensin II, the product of angiotensin converting enzyme (ACE) cleavage of angiotensin I, which is produced by the cleavage of angiotensinogen (AGT) by renin (REN). ACE indirectly stimulates the release of t-PA which, in turn, activates the corresponding fibrinolytic system. Single polymorphisms in these pathways have been shown to significantly impact plasma levels of t-PA and PAI-1 differently in Ghanaian males and females. Here we explore the involvement of epistatic interactions between the same polymorphisms in central genes of the RAS and fibrinolytic systems on plasma t-PA and PAI-1 levels within the same population (n = 992). Statistical modeling of pairwise interactions was done using two-way ANOVA between polymorphisms in the ETNK2, RENIN, ACE, PAI-1, t-PA, and AGT genes. The most significant interactions that associated with t-PA levels were between the ETNK2 A6135G and the REN T9435C polymorphisms in females (p = 0.006) and the REN T9435C and the TPA I/D polymorphisms (p = 0.005) in males. The most significant interactions for PAI-1 levels were with REN T9435C and the TPA I/D polymorphisms (p = 0.001) in females, and the association of REN G6567T with the TPA I/D polymorphisms (p = 0.032) in males. Our results provide evidence for multiple genetic effects that may not be detected using single SNP analysis. Because t-PA and PAI-1 have been implicated in cardiovascular disease these results support the idea that the genetic architecture of cardiovascular disease is complex. Therefore, it is necessary to consider the relationship between interacting polymorphisms of pathway specific genes that predict t-PA and PAI-1 levels.
Highlights
Preventing excessive blood loss following vessel injury is controlled through a process known as hemostasis
The fibrinolytic pathway is partially regulated by the renin-angiotensin system; this has been demonstrated by studies that show pharmacological inhibition of the angiotensin converting enzyme (ACE) indirectly stimulates release of tissue plasminogen activator (t-PA) [2] while reducing levels of its inhibitor, plasminogen activator inhibitor-1 (PAI-1) [3]
The most significant of these gene-gene interactions occurred between the ETNK2 A6135G variant and the REN T9435C variant (p = 0.006, r2 = 1.82%), but the largest r2 was for an interaction between markers REN T9435C and ETNK2 A6135G (p = 0.011, r2 = 2.27%) (Table S2)
Summary
Preventing excessive blood loss following vessel injury is controlled through a process known as hemostasis. The tight regulatory mechanisms of hemostasis manage this response to prevent thrombus formation. One mechanism involved in this balance is fibrinolysis, the physiological breakdown of fibrin, an essential component of blood clots. Upon release of the serine protease tissue plasminogen activator (t-PA) from vascular endothelial cells, circulating plasminogen is cleaved to produce plasmin, a proteolytic enzyme responsible for the degradation of fibrin [1]. The fibrinolytic pathway is partially regulated by the renin-angiotensin system; this has been demonstrated by studies that show pharmacological inhibition of the angiotensin converting enzyme (ACE) indirectly stimulates release of t-PA [2] while reducing levels of its inhibitor, plasminogen activator inhibitor-1 (PAI-1) [3]. Clinical evidence indicates that plasma concentrations of t-PA and PAI-1 can serve as biomarkers of first myocardial infarction [7,8], atherosclerosis [9], ischemic stroke [10] and ischemic heart disease [11]
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