Large-Scale Gene-Centric Analysis Identifies Novel Variants for Coronary Artery Disease

Adam S. Butterworth; Peter S. Braund; Martin Farrall; Robert J. Hardwick; Danish Saleheen; John F. 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 A. 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 Klueter; Kerstin Koch; Inke R. Koenig; 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 Maerz; Mieke D. Trip; Muredach P. 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; IBC 50K CAD Consortium

doi:10.1371/journal.pgen.1002260

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Large-Scale Gene-Centric Analysis Identifies Novel Variants for Coronary Artery Disease

Journal article

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Large-Scale Gene-Centric Analysis Identifies Novel Variants for Coronary Artery Disease

Adam S. Butterworth, Peter S. Braund, Martin Farrall, Robert J. Hardwick, Danish Saleheen, John F. Peden, Nicole Soranzo, John C. Chambers, Suthesh Sivapalaratnam, Marcus E. Kleber, …

PLoS genetics, Vol.7(9), pp.e1002260-e1002260

01/09/2011

DOI: https://doi.org/10.1371/journal.pgen.1002260

PMCID: PMC3178591

PMID: 21966275

Abstract

Genetics & Heredity

Life Sciences & Biomedicine

Science & Technology

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 similar to 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<10(-33); LPA:p<10(-19); 1p13.3:p<10(-17)) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5x10(-7)). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06-1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other similar to 4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes.

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Title: Large-Scale Gene-Centric Analysis Identifies Novel Variants for Coronary Artery Disease
Creators - without role: Adam S. Butterworth - University of Cambridge
Peter S. Braund - University of Leicester
Martin Farrall - University of Oxford
Robert J. Hardwick - University of Leicester
Danish Saleheen - University of Cambridge
John F. Peden - University of Oxford
Nicole Soranzo - Wellcome Sanger Institute
John C. Chambers - University of London
Suthesh Sivapalaratnam - University of Amsterdam
Marcus E. Kleber - Product Innovation and Engineering (United States, Saint James) - LLC
Brendan Keating - Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA
Atif Qasim - Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania
Norman Klopp - Helmholtz Zentrum München
Jeanette Erdmann - University of Lübeck
Themistocles L. Assimes - Stanford University
Stephen G. Ball - University of Leeds
Anthony J. Balmforth - University of Leeds
Timothy A. Barnes - University of Leicester
Hanneke Basart - University of Amsterdam
Jens Baumert - Helmholtz Zentrum München
Connie R. Bezzina - University of Amsterdam
Eric Boerwinkle - Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA
Bernhard O. Boehm - University of Ulm
Jessy Brocheton - Université Paris Cité
Peter Bugert - Heidelberg Univ, Inst Transfus Med & Immunol, Germany Red Cross Blood Serv, Baden Wurttemberg Hessen gGmbH,Med Fac Mannheim, D-6800 Mannheim, Germany
Francois Cambien - Université Paris Cité
Robert Clarke - University of Oxford
Veryan Codd - University of Leicester
Rory Collins - University of Oxford
David Couper - Biostat
L. Adrienne Cupples - Boston University
Jonas S. de Jong - University of Amsterdam
Patrick Diemert - University of Lübeck
Kenechi Ejebe - Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA
Clara C. Elbers - College Station Medical Center
Paul Elliott - University of London
Myriam Fornage - College Station Medical Center
Maria-Grazia Franzosi - Ist Ric Farmacol Mario Negri, Dept Cardiovasc Res, Milan, Italy
Philippe Frossard - Ctr Noncommunicable Dis, Karachi, Pakistan
Stephen Garner - University of Cambridge
Anuj Goel - University of Oxford
Alison H. Goodall - University of Leicester
Christian Hengstenberg - University of Regensburg
Sarah E. Hunt - Wellcome Sanger Institute
John J. P. Kastelein - University of Amsterdam
Olaf H. Klungel - Utrecht Inst Pharmaceut Sci, Utrecht, Netherlands
Harald Klueter - Heidelberg Univ, Inst Transfus Med & Immunol, Germany Red Cross Blood Serv, Baden Wurttemberg Hessen gGmbH,Med Fac Mannheim, D-6800 Mannheim, Germany
Kerstin Koch - University of Cambridge
Inke R. Koenig - University of Lübeck
Angad S. Kooner - University of London
Reijo Laaksonen - Tampere University
Mark Lathrop - Evry
Mingyao Li - Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania
Kiang Liu - Northwestern University
Ruth McPherson - University of Ottawa
Muntaser D. Musameh - University of Leicester
Solomon Musani - University of Mississippi
Christopher P. Nelson - University of Leicester
Christopher J. O'Donnell - Framingham Heart Study
Halit Ongen - University of Oxford
George Papanicolaou - NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA
Annette Peters - Helmholtz Zentrum München
Bas J. M. Peters - Utrecht Inst Pharmaceut Sci, Utrecht, Netherlands
Simon Potter - Wellcome Sanger Institute
Bruce M. Psaty - University of Washington
Liming Qu - Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania
Daniel J. Rader - Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania
Asif Rasheed - Ctr Noncommunicable Dis, Karachi, Pakistan
Catherine Rice - Wellcome Sanger Institute
James Scott - University of London
Udo Seedorf - University of Münster
Joban S. Sehmi - University of London
Nona Sotoodehnia - University of Washington
Klaus Stark - University of Regensburg
Jonathan Stephens - University of Cambridge
C. Ellen van der Schoot - Sanquin
Yvonne T. van der Schouw - College Station Medical Center
Unnur Thorsteinsdottir - deCODE Genet, IS-101 Reykjavik, Iceland
Maciej Tomaszewski - University of Leicester
Pim van der Harst - University of Leicester
Ramachandran S. Vasan - Framingham Heart Dis Epidemiol Study, Echocardiog Vasc Lab, Framingham, MA USA
Arthur A. M. Wilde - University of Amsterdam
Christina Willenborg - University of Lübeck
Bernhard R. Winkelmann - Cardiol Grp Frankfurt Sachsenhausen, Frankfurt, Germany
Moazzam Zaidi - Ctr Noncommunicable Dis, Karachi, Pakistan
Weihua Zhang - University of London
Andreas Ziegler - University of Lübeck
Paul I. W. de Bakker - College Station Medical Center
Wolfgang Koenig - University of Ulm
Winfried Maerz - Synlab
Mieke D. Trip - University of Amsterdam
Muredach P. Reilly - Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania
Sekar Kathiresan - Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA
Heribert Schunkert - University of Lübeck
Anders Hamsten - Karolinska Institutet
Alistair S. Hall - University of Leeds
Jaspal S. Kooner - University of London
Simon G. Thompson - University of Cambridge
John R. Thompson
Panos Deloukas - Wellcome Sanger Institute
Willem H. Ouwehand - Wellcome Sanger Institute
Hugh Watkins - University of Oxford
John Danesh - University of Cambridge
Nilesh J. Samani - University of Leicester
IBC 50K CAD Consortium
Publication Details: PLoS genetics, Vol.7(9), pp.e1002260-e1002260
Publisher: Public Library Science
Number of pages: 14
Grant note: Leicester NIHR Biomedical Research Unit in Cardiovascular Disease German Federal Ministry of Education and Research (BMBF); Federal Ministry of Education & Research (BMBF) British Heart Foundation RP-PG-0310-1002 / National Institute for Health Research; National Institutes of Health Research (NIHR) ZonMW; Netherlands Organization for Health Research and Development AMC (The Netherlands); Netherlands Government MC_U137686857; MC_U105260792; G0700931; G0801056; MC_U106179471; G1000143; G0401527; G0701863; G0801056B; G0601966 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) Helmholtz Zentrum Munchen; Helmholtz Association UK Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) Dutch Cancer Society; KWF Kankerbestrijding World Cancer Research Fund (WCRF); World Cancer Research Fund International (WCRF) Dutch Medicines Evaluation Board German Research Center for Environmental Health European Commission (SANCO); European Commission; European Commission Joint Research Centre LSHM-CT-2004-503485 / Bloodomics Center for Translational Molecular Medicine (CTMM COHFAR) Penn Cardiovascular Institute Dutch Ministry of Health 201668; LSHM-CT-2006-037593 / European Union; European Commission; Spanish Government LSHM-CT-2007-037273 / European Community; European Commission Netherlands Organisation for Health Research and Development; Netherlands Organization for Health Research and Development Novo Nordisk; Novo Nordisk Foundation Wellcome Trust Interuniversity Cardiology Institute of The Netherlands 560283 / Stockholm County Council National Heart, Lung, and Blood Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) University of Cambridge (UK); University of Cambridge Yousef Jameel Foundation; American University Cairo Neuherberg, Germany United Kingdom Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) Karolinska Institutet and Stockholm County Council RP-PG-0310-1002; CL-2010-11-001 / National Institute for Health Research; National Institutes of Health Research (NIHR) Munich Center of Health Sciences (MC Health) LURIC (Germany) Organization for Scientific Research (NWO); Netherlands Organization for Scientific Research (NWO) RG/08/014/24067 / British Heart Foundation T6-101 / TI Pharma University of Cambridge and in Pakistan Knut and Alice Wallenberg Foundation; Knut & Alice Wallenberg Foundation AstraZeneca LSHM-CT-2004-503485 / EU Framework 6-funded Bloodomics Integrated Project Torsten and Ragnar Soderberg Foundation British Heart Foundation (BHF); British Heart Foundation Swedish Heart-Lung Foundation University of Ulm 01GS0834 / German National Genome Research Network LSHM-CT-2004-503485 / LURIC Foundation for Strategic Research RG/09/12/28096 / British Heart Foundation IGE 05012 / NL Agency Wellcome Trust Sanger Institute (UK); Wellcome Trust 2001D019; 2003T302; 2007B202 / Netherlands Heart Foundation Swedish Medical Research Council; Swedish Medical Research Council (SMRC) 05-CVD / Leducq Foundation 2001.064 / Netherlands Heart Foundation (NHS); Netherlands Heart Foundation G0601966; G0801056; MC_U137686857; G0700931; G0701863; MC_U105260792 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) GlaxoSmithKline Top Institute Pharma
Identifiers: 9938474908331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article