Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation
Year: 2012
Type: article
Study design: Observational Study
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.
Source: Blood
Authors: Jie Huang, 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, Sekar Kathiresan, Muredach P. Reilly, Norman Klopp, Tamara B. Harris, Bernhard R. Winkelmann, Peter J. Grant, Hans L. Hillege, Hugh Watkins, Timothy D. Spector, Lewis C. Becker, Russell P. Tracy, Winfried März, Andre G. Uitterlinden, Per Eriksson, Francois Cambien, Pierre-Emmanuel Morange, Wolfgang Koenig, Nicole Soranzo, Pim van der Harst, Yongmei Liu, Christopher J. O'Donnell, Anders Hamsten
Institutions: National Heart, Lung, and Blood Institute, Framingham Heart Study, Karolinska University Hospital, Karolinska Institutet, University Medical Center Utrecht, Inserm, Fondation pour l’innovation en Cadiométabolisme et Nutrition, Université Pierre-et-Marie-Curie, Wellcome Sanger Institute, Wake Forest University Health Sciences, Wake Forest University, Helmholtz Munich, National Heart, Lung, and Blood Institute Division of Intramural Research, Group Health Cooperative, Kaiser Permanente Washington Health Research Institute, University of Washington, VA Office of Research and Development, Seattle Epidemiologic Information and Research Center, Vanderbilt University, Rotterdam Study, Erasmus MC, Heidelberg University, Johns Hopkins University, Johns Hopkins Medicine, University of Virginia, University of Minnesota, Boston University, Dartmouth College, King's College London, Netherlands Consortium for Healthy Ageing, University of Tübingen, Universität Ulm, University Hospital Ulm, The University of Sydney, Royal North Shore Hospital, University Medical Center Groningen, University of Groningen, Centre for Human Genetics, John Radcliffe Hospital, University of Oxford, National Health Service, Ealing Hospital, Imperial College London, University of Cambridge, Center for Non-Communicable Diseases, Uppsala University, Science for Life Laboratory, University of Leeds, Cedars-Sinai Medical Center, Mario Negri Institute for Pharmacological Research, University of Münster, University of Leicester, University of Vermont, Ludwig-Maximilians-Universität München, The University of Texas Health Science Center at Houston, Harvard University, Massachusetts General Hospital, Broad Institute, Massachusetts Institute of Technology, University of Pennsylvania, National Institutes of Health, National Institute on Aging, Kardiologie Frankfurt-Sachsenhausen, Medical University of Graz
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: Wellcome Trust, National Institute for Health and Care Research, British Heart Foundation, National Institutes of Health, U.S. Public Health Service, Biotechnology and Biological Sciences Research Council, National Institute on Aging, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, U.S. National Library of Medicine, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: G100949702, G1023702118, G10717269, Multi-Ethnic Study of Atherosclerosis (MESA) Study, G118440752, G125972088, G1261793039, MESA, Genetic Determinants of Visceral Adiposity, CORONARY HEART DISEASE AND STROKE, G1276754516, CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84, G1318433929, G136105103, DYNAMICS OF HEALTH,AGING, AND BODY COMPOSITION, CHS-ULTRASOUND READING, CORONARY HEART DISEASE AND STROKE, G1640378483, MRI READING CENTER FOR THE CARDIOVASCULAR HEALTH STUDY, MESA Family Study - Columbia University Field Center, G1727292203, CORONARY HEART DISEASE AND STROKE IN PEOPLE AGED 65-84, G1909643007, Atherosclerosis Risk in Communities Study (ARIC), G2144938473, G215333750, DYNAMICS OF HEALTH, AGING, AND BODY COMPOSITION, CORONARY HEART DISEASE AND STROKE IN PEOPLE AGED 65-84, CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84, G22458031, G236442059, MESA, Clinical and Translational Science Award, Institute for Clinical and Translational Research (UL1), G250621538, CCSP FIELD CENTER, MESA Family Study, G25881238, CORONARY HEART DISEASE &STROKE IN THE ELDERLY, COMMUNITY AND COHORT SURVEILLANCE PROGRAM, G270907595, G277826483, G2800149121, CENTRAL HEMOSTATIS LABORATORY FOR CCSP, MESA, G2837638605, G290884426, G291913881, SUBCLINICAL CARDIOVASCULAR DISEASE STUDY--EBCT READING, Genetic Epidemiological Study of Venous Thromboembolism and Hemostatic Factors, WGA Study to Identify Genetic Variants Associated with CV Events in CHS, HEALTH ABC--COORDINATING UNIT, UCLA Clinical and Translational Science Institute, MESA Family Study, G34347772, G36937976, GWA for Gene-Environment Interaction Effects Influencing CHD, MESA, General Clinical Research Center, G395403786, CENTRAL BLOOD ANALYSIS LABORATORY FOR CHS, G423252844, TITLE: MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA), Atherosclerosis Risk in Communities Study (ARIC), DETERMINANTS OF CORONARY DISEASE IN HIGH RISK FAMILIES, OPTION 3. 4/1/2014 - 3/31/2015. MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA) - READING CENTER, NHLBI, MESA Family Study, MESA, Genotypic Determinants of Aspirin Response in High Risk Families, G4987078009, MESA Family Study, SUBCLINICAL CARDIOVASCULAR DISEASE STUDY-ULTRASOUND, G528395701, Bioinformatics Strategies for Genome Wide Association Studies, Genome-Wide Association for Loci Influencing CHD and Other Heart, Lung and Blood, G5479317095, Epidemiology of Venous Thrombosis and Pulmonary Embolism, Epidemiology of Precursors to Type 2 Diabetes, Atherosclerosis Risk in Communities Study (ARIC), G573134505, CHARGE consortium: omics discovery for CVD and aging phenotypes, The Framingham Heart Study, MESA, Quantitative Biology Research Institute, G66341962, G670738241, CHS-Transition Phase, Understanding the genetic basis of common human diseases: core funding for the Wellcome Trust Centre for Human Genetics., Training Program on Genetic Variation and Human Phenotypes, MESA Family Study, MESA, CHS RETINAL READING CENTER, GENETIC VARIANTS AND THROMBOSIS, CARDIOVASCULAR HEALTH STUDY--ECHOCARDIOGRAPHY, GENETIC ARCHITECTURE OF PLASMA T-PA AND PAI-1, G777822606, G786153652, G78770644, G793702358, G820615960, G8267674335, RENEWAL: Systematic approaches to the evaluation of emerging coronary risk markers. Large-scale epidemiological analyses of existing data and stored biological samples, COGNITIVE TESTS, APOE, BRAIN MRI AND RISKS OF DEMENTIA, G861947890, Hormonal trajectories in aging, Diabetes Research Center (DRC), From GWAS loci to blood pressure genes, variants & mechanisms - Renewal, G905887895, Cellular and Molecular Mechanisms of Lung Disease, G936067872, G960597250, Atherosclerosis Risk in Communities Study (ARIC), G991334795
OpenAlex ID: W2124001412