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. 2012 Dec 6;120(24):4873-81.
doi: 10.1182/blood-2012-06-436188. Epub 2012 Sep 18.

Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation

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

Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation

Jie Huang et al. Blood. .

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.

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Figures

Figure 1
Figure 1
Manhattan plot showing the results for the 2 445 683 meta-analyzed SNPs in the discovery cohorts (a total of 19 683 subjects). SNPs are represented on the x-axis organized by chromosome. On the y-axis, statistical significance is expressed as −log10 of the P values. The horizontal line marks the P = 5.0 × 10−8 threshold of genome-wide significance.
Figure 2
Figure 2
Box plots showing the differences in expression levels of MUC3 and PAI-1. Box plots (median, interquartile range and 95% CIs) show the differences in expression levels of MUC3 (A) and PAI-1 (B) comparing MUC3-silenced cells with control cells. (C) Differences in PAI-1 released into the media comparing MUC3-silenced cells with control cells. Gene-expression and protein levels are normalized to control (nonsilenced) cells (100%).
See this image and copyright information in PMC

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