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

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.

SUBMITTER: Huang J

PROVIDER: S-EPMC3520624 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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

Huang Jie J Sabater-Lleal Maria M Asselbergs Folkert W FW Tregouet David D Shin So-Youn SY Ding Jingzhong J Baumert Jens J Oudot-Mellakh Tiphaine T Folkersen Lasse L Johnson Andrew D AD Smith Nicholas L NL Williams Scott M SM Ikram Mohammad A MA Kleber Marcus E ME Becker Diane M DM Truong Vinh V Mychaleckyj Josyf C JC Tang Weihong W Yang Qiong Q Sennblad Bengt B Moore Jason H JH Williams Frances M K FM Dehghan Abbas A Silbernagel Günther G Schrijvers Elisabeth M C EM Smith Shelly S Karakas Mahir M Tofler Geoffrey H GH Silveira Angela A Navis Gerjan J GJ Lohman Kurt K Chen Ming-Huei MH Peters Annette A Goel Anuj A Hopewell Jemma C JC Chambers John C JC Saleheen Danish D Lundmark Per P Psaty Bruce M BM Strawbridge Rona J RJ Boehm Bernhard O BO Carter Angela M AM Meisinger Christa C Peden John F JF Bis Joshua C JC McKnight Barbara B Öhrvik John J Taylor Kent K Franzosi Maria Grazia MG Seedorf Udo U Collins Rory R Franco-Cereceda Anders A Syvänen Ann-Christine AC Goodall Alison H AH Yanek Lisa R LR Cushman Mary M Müller-Nurasyid Martina M Folsom Aaron R AR Basu Saonli S Matijevic Nena N van Gilst Wiek H WH Kooner Jaspal S JS Hofman Albert A Danesh John J Clarke Robert R Meigs James B JB Kathiresan Sekar S Reilly Muredach P MP Klopp Norman N Harris Tamara B TB Winkelmann Bernhard R BR Grant Peter J PJ Hillege Hans L HL Watkins Hugh H Spector Timothy D TD Becker Lewis C LC Tracy Russell P RP März Winfried W Uitterlinden Andre G AG Eriksson Per P Cambien Francois F Morange Pierre-Emmanuel PE Koenig Wolfgang W Soranzo Nicole N van der Harst Pim P Liu Yongmei Y O'Donnell Christopher J CJ Hamsten Anders A

Blood 20120918 24

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 ...[more]

PMID: 22990020

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Project description:Vascular endothelial growth factor (VEGF) is an angiogenic and neurotrophic factor, secreted by endothelial cells, known to impact various physiological and disease processes from cancer to cardiovascular disease and to be pharmacologically modifiable. We sought to identify novel loci associated with circulating VEGF levels through a genome-wide association meta-analysis combining data from European-ancestry individuals and using a dense variant map from 1000 genomes imputation panel. Six discovery cohorts including 13,312 samples were analyzed, followed by in-silico and de-novo replication studies including an additional 2,800 individuals. A total of 10 genome-wide significant variants were identified at 7 loci. Four were novel loci (5q14.3, 10q21.3, 16q24.2 and 18q22.3) and the leading variants at these loci were rs114694170 (MEF2C, P = 6.79 x 10(-13)), rs74506613 (JMJD1C, P = 1.17 x 10(-19)), rs4782371 (ZFPM1, P = 1.59 x 10(-9)) and rs2639990 (ZADH2, P = 1.72 x 10(-8)), respectively. We also identified two new independent variants (rs34528081, VEGFA, P = 1.52 x 10(-18); rs7043199, VLDLR-AS1, P = 5.12 x 10(-14)) at the 3 previously identified loci and strengthened the evidence for the four previously identified SNPs (rs6921438, LOC100132354, P = 7.39 x 10(-1467); rs1740073, C6orf223, P = 2.34 x 10(-17); rs6993770, ZFPM2, P = 2.44 x 10(-60); rs2375981, KCNV2, P = 1.48 x 10(-100)). These variants collectively explained up to 52% of the VEGF phenotypic variance. We explored biological links between genes in the associated loci using Ingenuity Pathway Analysis that emphasized their roles in embryonic development and function. Gene set enrichment analysis identified the ERK5 pathway as enriched in genes containing VEGF associated variants. eQTL analysis showed, in three of the identified regions, variants acting as both cis and trans eQTLs for multiple genes. Most of these genes, as well as some of those in the associated loci, were involved in platelet biogenesis and functionality, suggesting the importance of this process in regulation of VEGF levels. This work also provided new insights into the involvement of genes implicated in various angiogenesis related pathologies in determining circulating VEGF levels. The understanding of the molecular mechanisms by which the identified genes affect circulating VEGF levels could be important in the development of novel VEGF-related therapies for such diseases.

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

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

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