Review Article
The effect of the plasminogen activator inhibitor-1 4G/5G polymorphism on the thrombotic risk

https://doi.org/10.1016/j.thromres.2007.09.005Get rights and content

Abstract

Plasminogen activator inhibitor (PAI-1), is the central component of the fibrinolytic system. A deletion/insertion (4G/5G) polymorphism in the promoter region of the PAI-1 gene has been correlated with levels of plasma PAI-1. The 4G allele is associated with higher levels of PAI-1, and might increase the risk for intravascular thrombosis. However, the contribution of this genetic variant to the risk for thrombosis, both arterial and venous, has not been clearly established. A broad spectrum of findings regarding the effect of the 4G allele on thrombotic risk in different target organs has been reported. Our aim is to summarize the variable influence of this polymorphism on thrombotic events in different tissues or organs and explain the underlying mechanisms accounting for these differences.

Introduction

An altered balance between the fibrinolytic and procoagulant systems might significantly contribute to the pathophysiology of thrombus formation. This hemostatic imbalance may be the result of an impaired fibrinolytic action that in combination with either enhanced procoagulant or defective anticoagulant mechanisms, increases the chances for thrombotic events to occur. During fibrinolysis, plasminogen is converted to plasmin, which in turn dissolves fibrin clots. This conversion occurs in the presence of urokinase plasminogen activator (u-PA), or tissue plasminogen activator (t-PA) and is regulated to a significant extent by the serine protease inhibitor, plasminogen activator inhibitor-1 (PAI-1) [1] (Fig. 1). Because of its major role in the regulation of the fibrinolytic process, PAI-1 overexpression may compromise normal fibrin clearance mechanisms and promote pathological fibrin deposition and thrombotic events [2].

PAI-1 is synthesized in various tissues and cell types including liver, spleen [3], adipocytes [4], and endothelial cells. Its synthesis is regulated by various agents including insulin [5], lipids [6], glucose [7]), endotoxin and inflammatory cytokines [8]. The human PAI-1 gene is located at chromosome 7q22 [9]. A genetic polymorphism of this gene has been identified in the promoter region, where one allele has a sequence of four guanosines (4G) and the other has five guanosines (5G) at − 675 bp upstream from the mRNA initiation point [10]. Both the 4G and 5G alleles have a binding site for an activator of transcription. However, the 5G allele has an additional binding site for a repressor, leading therefore to lower transcription rates and less PAI-1 activity [11]. Thus, the 4G allele has been linked with moderately higher plasma PAI-1 levels [12], [13]. However, the nature of this polymorphism can be more accurately described as response polymorphism, since PAI-1 is considered a strong acute-phase reactant. This means that different PAI-1 levels between 4G and 5G are more apparent in the presence of environmental and/or disease factors, which stimulate PAI-1 expression [14].

Data regarding the effect of this genetic variant to the risk for thrombosis, both arterial and venous, are numerous and contradictory. Three meta-analyses have recently been published about the contribution of the 4G/5G polymorphism to cardiovascular, ischemic stroke and venous thromboembolism risk [15], [16], [17]. The results of these studies are presented in Table 1. Based on these latest findings, our aim is to summarize the variable influence of this polymorphism on thrombotic risk in different target organs and attempt to explain the underlying mechanisms accounting for these differences.

Section snippets

The relation of the PAI-1 4G/5G polymorphism with cardiovascular disease

A meta-analysis of 9 studies showed a 20% increased risk of myocardial infarction attributed to the 4G/4G genotype [18]. A weaker positive association has also been reported by a recent meta-analysis including 37 studies which yielded a per-allele relative risk of about 1.06 for coronary disease in subjects with the − 675 4G variant [15]. However, this finding might merely be an artifact of selective publication. Thus, the question that still remains is how strong is the predictive value of this

The relation of the PAI-1 4G/5G polymorphism with ischemic stroke

The spectrum of findings regarding the relationship between 4G/5G polymorphism of the PAI-1 gene and stroke is quite confusing. Some authors consider that the 4G/4G genotype confers an increased risk for stroke [25], [26], while others have supported a neutral or even protective effect of the same genotype against cerebrovascular events [27], [28], [29], [30], [31]. A recent meta-analysis failed to demonstrate a significant association, neither positive nor negative, between the 4G/5G

The relation of the PAI-1 4G/5G polymorphism with venous thromboembolism

Data regarding the association between the presence of allele 4G and the risk for venous thrombotic episodes (VTE) have also been controversial. Most studies have found no relationship between the − 675 4G/5G polymorphism and the development of VTE in unselected patients [37], [38], [39]. However, this polymorphism has been shown to increase the risk for VTE in patients with other congenital or acquired prothrombotic disorders [40], [41], [42], [43], although this was not a consistent finding

The effect of the 4G/5G polymorphism on prognosis in patients with acute severe diseases

Several reports suggest that 4G/4G patients might have a genetic susceptibility to high PAI-1 responses after exposure to noxious factors. PAI-1 is considered an acute-phase reactant and its release is regulated by various inflammatory factors, including interleukin-1, TNF-α, and TGF-β [47]. These agonists directly affect PAI-1 gene expression [48]. Thus, it is assumed that elevation of PAI-1 levels after stressful events, like severe inflammatory diseases or life-threatening disorders, in

Conclusions

PAI-1 is a characteristic biological example of how complicated and unpredictable could be the influence of the same enzyme on different tissues or organs. Improper study designs, case definitions, and selection of controls, can easily increase bias and lead to misleading findings. On the contrary, large sample sizes, detailed description of the eligibility criteria, random selection of the control group from the population that gave rise to the cases, a test for the HWE and the proper

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