Abstract 17360: Genome-Wide Meta-Analysis of Plasminogen Activator Inhibitor Type 1 (PAI-1) Identifies a New Locus Independent of the Serpine1 4G/5G Polymorphism
Introduction: Thrombosis underlies myocardial infarction and other cardiovascular diseases (CVD). Plasminogen activator inhibitor type 1 (PAI-1) is produced by the vascular endothelium and is considered an important regulatory element in fibrinolysis. In some populations, high plasma levels of PAI-1 (antigen or activity) have been associated with CVD. Twin studies have indicated that a major genetic component contributes to the variance of most haemostatic factors, with an estimated heritability of up to 0.60 for PAI-1. A number of common polymorphisms have been identified in SERPINE1, the gene encoding PAI-1, but only the 4G/5G variant located 675 base pairs from the transcriptional start site has been consistently associated with plasma PAI-1 levels.
Methods & Results: Here, we report a meta-analysis of genome-wide association studies (GWAS) of PAI-1 comprising 5 cohorts with European ancestry, with a sample size of over 15,000. In the discovery phase, we identified genome-wide significant signals (association p-value less than 5*10−8) for a SNP that is a proxy for the 4G/5G polymorphism and another region that is about 250kb upstream of SERPINE1. We found that these two signals are independent based on linkage disequilibrium (LD) calculation and conditional analysis. We are now conducting replication experiments in independent cohorts of both European and African-American ancestry with a total sample size of over 10,000 and will then perform in-silico association studies of CVD risk for those SNPs that remain significant in the replication phase.
Discussion: This is the first adequately powered unbiased study to examine the genetics of plasma PAI-1, a biomarker that has been extensively studied in relation to the metabolic syndrome and implicated in CVD. Our findings will contribute to the understanding of the regulation, biological role and clinical relevance of PAI-1.
- © 2010 by American Heart Association, Inc.