Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation
Authors: Huang Jie , Sabater-Lleal Maria , Asselbergs Folkert W. , Tregouet David , Shin So-Youn , Ding Jingzhong , Baumert Jens , Oudot-Mellakh Tiphaine , Folkersen Lasse , Johnson Andrew D. , Smith Nicholas L. , Williams Scott M. , Ikram Mohammad A. , Kleber Marcus E. , Becker Diane M. , Truong Vinh , Mychaleckyj Josyf C. , Tang Weihong , Yang Qiong , Sennblad Bengt , Moore Jason H. , Williams Frances M. K. , Dehghan Abbas , Silbernagel Günther , Schrijvers Elisabeth M. C. , Smith Shelly , Karakas Mahir , Tofler Geoffrey H. , Silveira Angela , Navis Gerjan J. , Lohman Kurt , Chen Ming-Huei , Peters Annette , Goel Anuj , Hopewell Jemma C. , Chambers John C. , Saleheen Danish , Lundmark Per , Psaty Bruce M. , Strawbridge Rona J. , Boehm Bernhard O. , Carter Angela M. , Meisinger Christa , Peden John F. , Bis Joshua C. , McKnight Barbara , Öhrvik John , Taylor Kent , Franzosi Maria Grazia , Seedorf Udo , Collins Rory , Franco-Cereceda Anders , Syvänen Ann-Christine , Goodall Alison H. , Yanek Lisa R. , Cushman Mary , Müller-Nurasyid Martina , Folsom Aaron R. , Basu Saonli , Matijevic Nena , van Gilst Wiek H. , Kooner Jaspal S. , Hofman Albert , Danesh John , Clarke Robert , Meigs James B. ,   DIAGRAM Consortium, Kathiresan Sekar , Reilly Muredach P. ,   CARDIoGRAM Consortium, Klopp Norman , Harris Tamara B. , Winkelmann Bernhard R. , Grant Peter J. , Hillege Hans L. , Watkins Hugh ,   C4D Consortium, Spector Timothy D. , Becker Lewis C. , Tracy Russell P. , März Winfried , Uitterlinden Andre G. , Eriksson Per , Cambien Francois ,   CARDIOGENICS Consortium, Morange Pierre-Emmanuel , Koenig Wolfgang , Soranzo Nicole , van der Harst Pim , Liu Yongmei , O'Donnell Christopher J. , Hamsten Anders 
Published: September 2012

Abstract
We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 × 10−8) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 × 10−10); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 × 10−8); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10−8). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.