Genome-wide association study for circulating levels of plasminogen activator inhibitor-1 (PAI-1) provides novel insights into the regulation of PAI-1.

Publication Type:

Journal Article


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; Ohrvik, 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; Consortium, C-Four-D; 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


Blood (2012)


October 2012, Public Health Sciences Division


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<5x10(-8)) single nucleotide polymorphisms (SNPs) in 10,796 independent samples. We further examined associations with type 2 diabetes (T2D) and coronary artery disease (CAD), 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=3.4x10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P=3.0x10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, discovery P=2.9x10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with T2D and CAD at ARNTL (P<0.05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL, and a SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.