Comprehensive survey of common genetic variation at the plasminogen activator inhibitor-1 locus and relations to circulating plasminogen activator inhibitor-1 levels

Background - Using a linkage disequilibrium (LD) - based approach, we sought to comprehensively define common genetic variation at the plasminogen activator inhibitor-1 ( PAI-1) locus and relate common single nucleotide polymorphisms ( SNPs) and haplotypes to plasma PAI-1 levels. Methods and Results - In reference pedigrees, we defined LD structure across a 50-kb genomic segment spanning the PAI-1 locus via a dense SNP map ( 1 SNP every 2 kb). Eighteen sequence variants that capture underlying common genetic variation were genotyped in 1328 unrelated Framingham Heart Study participants who had plasma PAI-1 antigen levels measured. Regression analyses were used to examine associations of individual SNPs and of inferred haplotypes with multivariable-adjusted PAI-1 levels. Two genetic variants, SNP rs2227631 and the 4G/5G polymorphism, were strongly associated ( P < 0.0001) with PAI-1 levels. SNP rs2227631 is in tight LD ( D' = 0.97, r(2) = 0.78) with the 4G/5G polymorphism, which makes it difficult to distinguish which of these 2 polymorphisms is responsible for the association with PAI-1 levels. In stepwise analysis considering all polymorphisms tested, 3 SNPs, rs2227631 ( or the correlated 4G/5G polymorphism), rs6465787,and rs2227674, each explained 2.5%, 1%, and 1%, respectively, of the residual variance in multivariable-adjusted PAI-1 levels ( stepwise P < 0.0001, P = 0.04, and P = 0.03, respectively). A single common haplotype, at 50% frequency among Framingham Heart Study participants, was strongly associated with higher PAI-1 levels ( haplotype-specific P = 0.00001). The susceptibility haplotype harbors the minor alleles of SNP rs2227631 and the 4G/5G polymorphism. Conclusions - Three sequence variants at the PAI-1 locus, in sum, explain approximate to 5% of the residual variance in multivariable-adjusted PAI-1 levels. For quantitative cardiovascular traits such as circulating biomarkers, defining LD structure in a candidate gene followed by association analyses with both SNPs and haplotypes is an effective approach to localize common susceptibility alleles.