Plasminogen Activator Inhibitor-2 Polymorphism Associates with Recurrent Coronary Event Risk in Patients with High HDL and C-Reactive Protein Levels

James P Corsetti,Dan Ryan,Charles E Sparks,Peter Salzman,Wojciech Zareba,Arthur J Moss,Lynette Kay Rogers

doi:10.1371/journal.pone.0068920

James P Corsetti, Dan Ryan + Show 5 more

Open Access

https://doi.org/10.1371/journal.pone.0068920

Copy DOI

Journal: PloS one	Publication Date: Jul 9, 2013
Citations: 41	License type: CC BY 4.0

Affiliation: University of Rochester

Abstract

The objective of this work was to investigate whether fibrinolysis plays a role in establishing recurrent coronary event risk in a previously identified group of postinfarction patients. This group of patients was defined as having concurrently high levels of high-density lipoprotein cholesterol (HDL-C) and C-reactive protein (CRP) and was previously demonstrated to be at high-risk for recurrent coronary events. Potential risk associations of a genetic polymorphism of plasminogen activator inhibitor-2 (PAI-2) were probed as well as potential modulatory effects on such risk of a polymorphism of low-density lipoprotein receptor related protein (LRP-1), a scavenger receptor known to be involved in fibrinolysis in the context of cellular internalization of plasminogen activator/plansminogen activator inhibitor complexes. To this end, Cox multivariable modeling was performed as a function of genetic polymorphisms of PAI-2 (SERPINB, rs6095) and LRP-1 (LRP1, rs1800156) as well as a set of clinical parameters, blood biomarkers, and genetic polymorphisms previously demonstrated to be significantly and independently associated with risk in the study population including cholesteryl ester transfer protein (CETP, rs708272), p22phox (CYBA, rs4673), and thrombospondin-4 (THBS4, rs1866389). Risk association was demonstrated for the reference allele of the PAI-2 polymorphism (hazard ratio 0.41 per allele, 95% CI 0.20-0.84, p=0.014) along with continued significant risk associations for the p22phox and thrombospondin-4 polymorphisms. Additionally, further analysis revealed interaction of the LRP-1 and PAI-2 polymorphisms in generating differential risk that was illustrated using Kaplan-Meier survival analysis. We conclude from the study that fibrinolysis likely plays a role in establishing recurrent coronary risk in postinfarction patients with concurrently high levels of HDL-C and CRP as manifested by differential effects on risk by polymorphisms of several genes linked to key actions involved in the fibrinolytic process.

Highlights

Inflammation is widely believed to play a major role in the development of atherosclerosis [1,2]
We have investigated this notion in terms of both incident [9,10] as well as recurrent [11] cardiovascular disease (CVD) risk in population studies that have demonstrated high-risk for patients with concurrently high levels of high-density lipoprotein (HDL) cholesterol (HDLC) and C-reactive protein (CRP)
In view of this result, the parent study population was divided into quadrants based on CRP (2.2 mg/L) and high-density lipoprotein cholesterol (HDL-C) (0.96 mmol/L) median levels

Summary

Introduction

Inflammation is widely believed to play a major role in the development of atherosclerosis [1,2]. Evidence is accumulating that one of the processes promoted by inflammation and contributing to atherogenesis is the dysfunctional transformation of high-density lipoprotein (HDL) particles This transformation is thought to result in a change in HDL from anti-atherogenic to pro-atherogenic [1,3,4,5,6,7,8]. To investigate potential pathways leading to increased risk in such individuals, we have assessed associations of risk with functional genetic polymorphisms related to multiple processes involved in development of atherosclerosis These have included polymorphisms of genes involved in lipoprotein metabolism (CETP, LPL) [10,11], oxidative stress (CYBA) [12], and thrombogenesis (THBS4) [12].

Objectives

Methods

Results

Conclusion