The association between plasminogen activator inhibitor type 1 (PAI-1) levels, PAI-1 4G/5G polymorphism, and myocardial infarction: a Mendelian randomization meta-analysis

Abstract

Background: The circulating levels of plasminogen activator inhibitor type 1 (PAI-1) are increased in individuals carrying the 4G allele at position -675 of the PAI-1 gene. In turn, overexpression of PAI-1 has been found to affect both atheroma and thrombosis. However, the association between PAI-1 levels and the incidence of myocardial infarction (MI) is complicated by the potentially confounding effects of well-known cardiovascular risk factors. The current study tried to investigate in parallel the association of PAI-1 activity with the PAI-1 4G/5G polymorphism, with MI, and some components of metabolic syndrome (MetS). Methods: Using meta-analytical Mendelian randomization approaches, genotype-disease and genotype-phenotype associations were modeled simultaneously. Results: According to an additive model of inheritance and the Mendelian randomization approach, the MI-related odd ratio for individuals carrying the 4G allele was 1.088 with 95% confidence interval (CI) 1.007, 1.175. Moreover, the 4G carriers had, on average, higher PAI-1 activity than 5G carriers by 1.136 units (95% CI 0.738, 1.533). The metaregression analyses showed that the levels of triglycerides (p = 0.005), cholesterol (p = 0.037) and PAI-1 (p = 0.021) in controls were associated with the MI risk conferred by the 4G carriers. Conclusions: The Mendelian randomization meta-analysis confirmed previous knowledge that the PAI-1 4G allele slightly increases the risk for MI. In addition, it supports the notion that PAI-1 activity and established cardiovascular determinants, such as cholesterol and triglyceride levels, could lie in the etiological pathway from PAI-1 4G allele to the occurrence of MI. Further research is warranted to elucidate these interactions.

Genetic risk factors of atherothrombosis

“…Similarly, negative findings have been reported in an elderly cohort. 105 More recently, by using the MR meta--analysis approach, Nikolopoulos et al 106 confirmed a previous observation that the PAI-1 4G allele slightly increases the MI risk.…”

Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease

“…As a protein biomarker, the genetic locus encoding the PAI‐1 transcript has clear biological function in determining circulating PAI‐1 levels. The 4G/5G polymorphism in the promoter region of SERPINE1 has been consistently reported to be a functional variant influencing PAI‐1 expression 27, 49. Knockout of Serpine1, a mouse ortholog, creates PAI‐1 deficiency 50.…”

“…Given that genotypes are assigned randomly from parents to offspring during meiosis, the causal effect of PAI‐1 on CHD risk can be estimated by the ratio of a SNP(IV)‐PAI‐1 association to SNP(IV)‐CHD association 25, 26. Using the MR method, a previous study suggested a causal association of PAI‐1 with myocardial infarction and blood triglycerides 27. However, in that study, the association of the SNP, the “4G/5G” polymorphism (rs1799889) in SERPINE1, with PAI‐1 and CHD risk was based on a meta‐analysis using published candidate gene studies between 1993 and 2010 27.…”

Independent Predictors of Major Adverse Events following Coronary Stenting over 28 Months of Follow-Up

“…These facts may partly explain the discrepancies between our index data and previously reported evidence. A recent, elegant meta-analysis study suggested that polymorphisms in the gene encoding PAI-1 increased the risk of myocardial infarction, resulting in increased PAI-1 activity [23]. Importantly, PAI-1 levels were associated with a higher risk of restenosis and ST after DES implantation [24].…”