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(Circulation. 2005;112:1728-1735.)
© 2005 American Heart Association, Inc.

Epidemiology

Comprehensive Survey of Common Genetic Variation at the Plasminogen Activator Inhibitor-1 Locus and Relations to Circulating Plasminogen Activator Inhibitor-1 Levels

Sekar Kathiresan, MD^*; Stacey B. Gabriel, PhD^*; Qiong Yang, PhD; Amy L. Lochner, AB; Martin G. Larson, ScD; Daniel Levy, MD; Geoffrey H. Tofler, MD; Joel N. Hirschhorn, MD, PhD; Christopher J. O’Donnell, MD, MPH

From the National Heart, Lung, and Blood Institute’s Framingham Heart Study (S.K., Q.Y., M.G.L, D.L., C.J.O.), Framingham, Mass; Broad Institute of Harvard University and Massachusetts Institute of Technology (S.K., S.B.G., A.L.L., J.N.H., C.J.O.), Cambridge, Mass; Department of Biostatistics (Q.Y.), Boston University School of Public Health; Department of Neurology (Q.Y.), Boston University School of Medicine; Department of Mathematics and Statistics (M.G.L.), Boston University, Boston, Mass; Royal North Shore Hospital (G.H.T.), Sydney, Australia; Divisions of Genetics and Endocrinology (J.N.H.), Children’s Hospital and Department of Genetics, Harvard Medical School, Boston, Mass; and Cardiology Division (S.K., C.J.O.), Massachusetts General Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Christopher J. O’Donnell, MD, MPH, Framingham Heart Study, 73 Mt Wayte Ave, Suite No. 2, Framingham, MA 01702-5827. E-mail odonnellc{at}nhlbi.nih.gov

Received July 15, 2004; de novo received March 8, 2005; revision received May 31, 2005; accepted June 17, 2005.

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, r²=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 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.

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