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Large-scale gene-centric analysis identifies novel variants for coronary artery disease

  • Adam S. Butterworth
  • , Peter Braund
  • , Martin Farrall
  • , Robert J. Hardwick
  • , Danish Saleheen
  • , John Peden
  • , Nicole Soranzo
  • , John C. Chambers
  • , Suthesh Sivapalaratnam
  • , Marcus E. Kleber
  • , Brendan Keating
  • , Atif Qasim
  • , Norman Klopp
  • , Jeanette Erdmann
  • , Themistocles L. Assimes
  • , Stephen G. Ball
  • , Anthony J. Balmforth
  • , Timothy Barnes
  • , Hanneke Basart
  • , Jens Baumert
  • Connie R. Bezzina, Eric Boerwinkle, Bernhard O. Boehm, Jessy Brocheton, Peter Bugert, Francois Cambien, Robert Clarke, Veryan Codd, Rory Collins, David Couper, L. Adrienne Cupples, Jonas S. de Jong, Patrick Diemert, Kenechi Ejebe, Clara C. Elbers, Paul Elliott, Myriam Fornage, Maria-Grazia Franzosi, Philippe Frossard, Stephen Garner, Anuj Goel, Alison H. Goodall, Christian Hengstenberg, Sarah E. Hunt, John J.P. Kastelein, Olaf H. Klungel, Harald Klüterr, Karel T. Koch, Inke R. König, Angad S. Kooner, Reijo Laaksonen, Mark Lathrop, Mingyao Li, Kiang Liu, Ruth McPherson, Muntaser D. Musameh, Solomon Musani, Christopher P. Nelson, Christopher J. O'Donnell, Halit Ongen, George Papanicolaou, Annette Peters, Bas J.M. Peters, Simon Potter, Bruce M. Psaty, Liming Qu, Daniel J. Rader, Asif Rasheed, Catherine Rice, James Scott, Udo Seedorf, Joban S. Sehmi, Nona Sotoodehnia, Klaus Stark, Jonathan Stephens, C. Ellen van der Schoot, Yvonne T. van der Schouw, Unnur Thorsteinsdottir, Maciej Tomaszewski, Pim van der Harst, Ramachandran S. Vasan, Arthur A.M. Wilde, Christina Willenborg, Bernhard R. Winkelmann, Moazzam Zaidi, Weihua Zhang, Andreas Ziegler, Paul I.W. de Bakker, Wolfgang Koenig, Winfried März, Mieke D. Trip, Muredach Reilly, Sekar Kathiresan, Heribert Schunkert, Anders Hamsten, Alistair S. Hall, Jaspal S. Kooner, Simon G. Thompson, John R. Thompson, Panos Deloukas, Willem H. Ouwehand, Hugh Watkins, John Danesh, Nilesh J. Samani, Suzanne Rafelt, Nienke Bruinsma, Lukas R. Dekker, José P. Henriques, Robbert J. de Winter, Marco Alings, Cor F. Allaart, Anton P. Gorgels, Freek W. Verheugt, Martina Mueller, Christa Meisinger, Stephanie DerOhannessian, Nehal N. Mehta, Jane Ferguson, Hakon Hakonarson, William Matthai, Robert Wilensky, J.C. Hopewell, S. Parish, P. Linksted, J. Notman, H. Gonzalez, A. Young, T. Ostley, A. Munday, N. Goodwin, V. Verdon, S. Shah, L. Cobb, C. Edwards, C. Mathews, R. Gunter, J. Benham, C. Davies, M. Cobb, J. Crowther, A. Richards, M. Silver, S. Tochlin, S. Mozley, S. Clark, M. Radley, K. Kourellias, Per Olsson, Simona Barlera, Gianni Tognoni, Stephan Rust, Gerd Assmann, Simon Heath, Diana Zelenika, Ivo Gut, Fiona Green, Anette Aly, Karolina Anner, Karin Björklund, Gun Blomgren, Barbro Cederschiöld, Karin Danell-Toverud, Per Eriksson, Ulla Grundstedt, Merja Heinonen, Mai-Lis Hellénius, Ferdinand van't Hooft, Karin Husman, Jacob Lagercrantz, Anita Larsson, Malin Larsson, Magnus Mossfeldt, Anders Mälarstig, Gunnar Olsson, Maria Sabater-Lleal, Bengt Sennblad, Angela Silveira, Rona Strawbridge, Birgitta Söderholm, John Öhrvik, Khan Shah Zaman, Nadeem Hayat Mallick, Muhammad Azhar, Abdus Samad, Mohammad Ishaq, Nabi Shah, Maria Samuel, Hilma Holm, Michael Preuss, Alexandre F.R. Stewart, Maja Barbalic, Christian Gieger, Devin Absher, Zouhair Aherrahrou, Hooman Allayee, David Altshuler, Sonia Anand, Karl Andersen, Jeffrey L. Anderson, Diego Ardissino, Lewis C. Becker, Diane M. Becker, Klaus Berger, Joshua C. Bis, S. Matthijs Boekholdt, Morris J. Brown, Mary Susan Burnett, Ian Buysschaert, John F. Carlquist, Li Chen, Robert W. Davies, George Dedoussis, Abbas Dehghan, Serkalem Demissie, Joseph Devaney, Ron Do, Angela Doering, Nour Eddine El Mokhtari, Stephen G. Ellis, Roberto Elosua, James C. Engert, Stephen Epstein, Ulf de Faire, Marcus Fischer, Aaron R. Folsom, Jennifer Freyer, Bruna Gigante, Domenico Girelli, Solveig Gretarsdottir, Vilmundur Gudnason, Jeffrey R. Gulcher, Stephanie Tennstedt, Eran Halperin, Naomi Hammond, Stanley L. Hazen, Albert Hofman, Benjamin D. Horne, Thomas Illig, Carlos Iribarren, Gregory T. Jones, J. Wouter Jukema, Michael A. Kaiser, Lee M. Kaplan, Kay-Tee Khaw, Joshua W. Knowles, Genovefa Kolovou, Augustine Kong, Diether Lambrechts, Karin Leander, Wolfgang Lieb, Guillaume Lettre, Christina Loley, Andrew J. Lotery, Pier M. Mannucci, Seraya Maouche, Nicola Martinelli, Pascal P. McKeown, Thomas Meitinger, Olle Melander, Pier Angelica Merlini, Vincent Mooser, Thomas Morgan, Thomas W. Mühleisen, Joseph B. Muhlestein, Kiran Musunuru, Janja Nahrstaedt, Markus M. Nöthen, Oliviero Olivieri, Flora Peyvandi, Riyaz S. Patel, Chris C. Patterson, Arshed A. Quyyumi, Loukianos S. Rallidis, Frits R. Roosendaal, Diana Rubin, Veikko Salomaa, M. Lourdes Sampietro, Manj S. Sandhu, Eric Schadt, Arne Schäfer, Arne Schillert, Stefan Schreiber, Jürgen Schrezenmeir, Stephen M. Schwartz, David S. Siscovick, Mohan Sivananthan, Albert V. Smith, Tamara B. Smith, Jaapjan D. Snoep, John A. Spertus, Kari Stefansson, Kathy Stirrups, Monika Stoll, W.H. Wilson Tang, Gudmundur Thorgeirsson, Gudmar Thorleifsson, Andre G. Uitterlinden, Andre M. van Rij, Benjamin F. Voight, Nick J. Wareham, George A. Wells, H.-Erich Wichmann, Jaqueline C.M. Witteman, Benjamin J. Wright, Shu Ye, Thomas Quertermous, Stefan Blankenberg, Robert Roberts, N. Charlotte Onland-Moret, Jessica van Setten, W.M. Monique Verschuren, Jolanda M.A. Boer, Cisca Wijmenga, Marten H. Hofker, Anke-Hilse Maitland-van der Zee, Anthonius de Boer, Diederick E. Grobbee, Tony Attwood, Stephanie Belz, Jason Cooper, Abi Crisp-Hihn, Nicola Foad, Jay Gracey, Emma Gray, Rhian Gwilliams, Susanne Heimerl, Jennifer Jolley, Unni Krishnan, Heather Lloyd-Jones, Ingrid Lugauer, Per Lundmark, Jasbir S. Moore, David Muir, Elizabeth Murray, Jessica Neudert, David Niblett, Karen O'Leary, Helen Pollard, Angela Rankin, Catherine M. Rice, Hendrik Sager, Jennifer Sambrook, Gerd Schmitz, Michael Scholz, Laura Schroeder, Ann-Christine Syvannen, Chris Wallace
  • Department of Public Health and Primary Care, University of Cambridge
  • Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital
  • Department of Cardiovascular Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford
  • Department of Genetics, University of Leicester
  • Center for Non-Communicable Diseases
  • Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
  • Imperial College London
  • Department of Vascular Medicine, Academic Medical Center
  • LURIC non profit LLC
  • Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia
  • Cardiovascular Institute, University of Pennsylvania Medical Center
  • Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health
  • Universität zu Lübeck, Medizinische Klinik II
  • Department of Medicine, Stanford University School of Medicine
  • LIGHT Research Institute, University of Leeds
  • Division of Cardiovascular and Diabetes Research, Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds
  • Heart Failure Research Centre, Department of Clinical and Experimental Cardiology, Academic Medical Center
  • Human Genetics Center and Institute of Molecular Medicine, The University of Texas Health Science Center at Houston
  • Division of Endocrinology and Diabetes, Centre of excellence 'Metabolic Diseases', Department of Internal Medicine, University of Ulm
  • INSERM UMRS 937, Pierre and Marie Curie University (UPMC, Paris 6)and Medical School
  • Institute of Transfusion Medicine and Immunology, Heidelberg University, Germany Red Cross Blood Service of Baden-Württemberg - Hessen gGmbH
  • Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford
  • Department of Biostatistics, University of North Carolina
  • National Heart, Lung and Blood Institute's Framingham Heart Study
  • Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School
  • University Medical Center Utrecht
  • MRC-HPA Centre for Environment and Health, Imperial College London
  • Institute of Molecular Medicine, The University of Texas Health Science Center at Houston
  • Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche Mario Negri
  • NHS Blood and Transplant
  • Klinik und Poliklinik für Innere Medizin II, Universität Regensburg
  • Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck
  • Hammersmith Hospital, National Heart and Lung Institute, Imperial College London
  • Science Center, Tampere University Hospital
  • Fondation Jean Dausset - CEPH
  • Department of Biostatistics and Epidemiology, University of Pennsylvania Medical Center
  • Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University
  • The John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa
  • University of Mississippi Medical Center
  • National Heart, Lung and Blood Institute
  • Division of Prevention and Population Sciences, National Heart, Lung and Blood Institute, National Institutes of Health
  • Group Health Research Institute, Group Health Cooperative
  • Institute of Translational Medicine and Therapeutics, University of Pennsylvania Medical Center
  • Leibniz-Institut für Arterioskleroseforschung, Universität Münster
  • Division of Cardiology, University of Washington
  • Department of Experimental Immunohematology, Sanquin Research
  • deCODE Genetics
  • Section of Preventive Medicine and Epidemiology, Dept of Medicine, Framingham Heart Study
  • Cardiology Group Frankfurt-Sachsenhausen, Frankfurt and Clin- Phenomics GmbH
  • Division of Genetics, Department of Medicine, Brigham's and Women's Hospital, Harvard Medical School
  • Department of Internal Medicine II-Cardiology, University of Ulm Medical Center
  • Institute of Public Heath, Social Medicine and Epidemiology, University of Heidelberg
  • Broad Institute of Harvard and MIT
  • Karolinska Institutet
  • Division of Cardiovascular and Neuronal Remodelling, Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds
  • Medical Research Council Biostatistics Unit
  • Department of Health Sciences, University of Leicester

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ~2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p
Original languageEnglish
JournalPLoS Genetics
Volume7
Issue number9
DOIs
Publication statusPublished - 1 Sept 2011

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

  1. SDG 3 - Good Health and Well-being
    SDG 3 Good Health and Well-being

Keywords

  • lipid
  • ABCG5 gene
  • ABCG8 gene
  • adult
  • article
  • Asian
  • cardiovascular risk
  • case control study
  • chromosome 9p
  • COL4A1 gene
  • COL4A2 gene
  • controlled study
  • coronary artery disease
  • CYP17A1 gene
  • Europe
  • female
  • gene
  • gene expression
  • gene frequency
  • genetic analysis
  • genetic association
  • genetic predisposition
  • genetic variability
  • human
  • IL5 gene
  • large scale gene centric analysis
  • LIPA gene
  • major clinical study
  • male
  • race difference
  • risk assessment
  • risk factor
  • TRIB1 gene
  • ZC3HC1 gene

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