Association of tissue plasminogen activator and plasminogen activator inhibitor polymorphism with myocardial infarction: A meta-analysis

Abstract

Introduction

To investigate whether t-PA Alu repeat insertion/deletion (I/D) and PAI-1 4 G/5 G genetic variations are associated with the risk of MI.

Methods

We conducted a meta-analysis to assess the association between the t-PA I/D and PAI-1 4 G/5 G polymorphisms and risk of MI. We also performed subgroup analyses based on ethnicity (Caucasian, Asian, and African), gender and age. Forty one eligible studies including 12,461 cases and 14,993 controls were identified to evaluate the impact of PAI-1 4 G/5 G polymorphism on MI. Seven studies investigated the relationship between t-PA I/D and MI.

Results

This meta-analysis revealed that the PAI-1 4 G allele (4 G/4 G and 4 G/5 G genotype) was associated with an increased risk of MI compared with the 5 G allele in the overall population (OR = 1.094, 95% CI = 1.021 - 1.172, p = 0.011). The relative risks of MI for 4 G/4 G genotype was increased when compared to 5 G/5 G genotype and 5 G allele, with odds ratio at 1.157 (95% CI 1.015 - 1.320, p = 0.029) and 1.126 (95% CI = 1.015 - 1.249, p = 0.025). However, the results show that the 4 G/5 G polymorphism risk for MI was not associated with ethnicity stratification as Caucasian, Asian or African population. No substantial differences in the genotype distributions were observed in the MI group and control group along the lines of gender and age. After multivariable analysis t-PA I/D polymorphism showed no consistent association with MI.

Conclusions

This study suggests that the 4 G/5 G polymorphism of PAI-1 may be a risk factor for MI in overall populations.

Introduction

Cardiovascular diseases are major health problems of highly developed as well as developing countries around the world. Myocardial infarction (MI) is one of the main causes of death from cardiovascular disease [1]. Thrombus formation has been identified as the most common mechanistic events in MI. Activation of the fibrinolytic system depends on two key proteins: tissue plasminogen activator (t-PA), a pivotal activator of plasminogen, and plasminogen activator inhibitor-1 (PAI-1), a major inhibitor of t-PA.

The t-PA is the main endogenous fibrinolytic enzyme. Increased t-PA activity causes hyperfibrinolysis, which might lead to excessive bleeding, whereas a decrease in activity results in thrombosis. The t-PA is encoded by the plasminogen activator tissue type (PLAT) gene on chromosome 8p11.21 spanning 8 coding exons. In the intron 8 of this gene insertion/deletion (I/D) polymorphism (rs4646972) in an Alu element has been reported to be associated with variable plasma levels of t-PA and increase in the risk of MI [2], [3]. However, other studies yielded contradictory results [4], [5], [6], [7], [8].

The PAI-1 is located on chromosome 7q21.3-q22 and spans approximately 12.2 kb with nine exons and eight introns. Higher levels of PAI-1 protein have been found in patients with MI compared to healthy/normal individuals [9]. In PAI-1 a single nucleotide 4 G/5 G insertion/deletion polymorphism (rs1799768) is located at position − 675 bp in the promoter sequence. The 4 G allele is associated with elevated PAI-1 levels [10], [11], [12], [13], [14], [15]. A positive association of 4 G allele and increased risk of MI [13], [14], [15], [16], [17], [18], [19], [20], [21] has been reported while other studies are negative [6], [7], [8], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49]. Although previous studies and meta-analyses have reported the relationship between PAI-1 4 G/5 G polymorphism and MI, the controversy still exist [12], [16], [17], [18].

In the context of this meta-analysis, we systematically reviewed all studies including more recent studies [3], [8], [13], [19], [20], [21] not included in previous meta-analyses [12], [16], [17], [18]. We also performed subgroup analyses based on ethnicity, gender and age to examine possible interactions between the t-PA Alu repeat I/D and PAI-1 4 G/5 G polymorphisms on risk of MI.