Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease

Nathan O. Stitziel; Kathleen E. Stirrups; Nicholas G. D. Masca; Jeanette Erdmann; Paola G. Ferrario; Inke R. Koenig; Peter E. Weeke; Thomas R. Webb; Paul L. Auer; Ursula M. Schick; Yingchang Lu; He Zhang; Marie-Pierre Dube; Anuj Goel; Martin Farrall; Gina M. Peloso; Hong-Hee Won; Ron Do; Erik van Iperen; Stavroula Kanoni; Jochen Kruppa; Anubha Mahajan; Robert A. Scott; Christina Willenborg; Peter S. Braund; Julian C. van Capelleveen; Alex S. F. Doney; Louise A. Donnelly; Rosanna Asselta; Piera A. Merlini; Stefano Duga; Nicola Marziliano; Josh C. Denny; Christian M. Shaffer; Nour Eddine El-Mokhtari; Andre Franke; Omri Gottesman; Stefanie Heilmann; Christian Hengstenberg; Per Hoffmann; Oddgeir L. Holmen; Kristian Hveem; Jan-Hakan Jansson; Karl-Heinz Joeckel; Thorsten Kessler; Jennifer Kriebel; Karl L. Laugwitz; Eirini Marouli; Nicola Martinelli; Mark I. McCarthy; Natalie R. Van Zuydam; Christa Meisinger; Tonu Esko; Evelin Mihailov; Stefan A. Escher; Maris Alver; Susanne Moebus; Andrew D. Morris; Martina Mueller-Nurasyid; Majid Nikpay; Oliviero Olivieri; Louis-Philippe Lemieux Perreault; Alaa AlQarawi; Neil R. Robertson; Karen O. Akinsanya; Dermot F. Reilly; Thomas F. Vogt; Wu Yin; Folkert W. Asselbergs; Charles Kooperberg; Rebecca D. Jackson; Eli Stahl; Konstantin Strauch; Tibor V. Varga; Melanie Waldenberger; Lingyao Zeng; Aldi T. Kraja; Chunyu Liu; Georg B. Ehret; Christopher Newton-Cheh; Daniel I. Chasman; Rajiv Chowdhury; Marco Ferrario; Ian Ford; J. Wouter Jukema; Frank Kee; Kari Kuulasmaa; Borge G. Nordestgaard; Markus Perola; Danish Saleheen; Naveed Sattar; Praveen Surendran; David Tregouet; Robin Young; Joanna M. M. Howson; Adam S. Butterworth; John Danesh; Diego Ardissino; Erwin P. Bottinger; Raimund Erbel; Paul W. Franks; Domenico Girelli; Alistair S. Hall; G. Kees Hovingh; Adnan Kastrati; Wolfgang Lieb; Thomas Meitinger; William E. Kraus; Svati H. Shah; Ruth McPherson; Marju Orho-Melander; Olle Melander; Andres Metspalu; Colin N. A. Palmer; Annette Peters; Daniel J. Rader; Muredach P. Reilly; Ruth J. F. Loos; Alex P. Reiner; Dan M. Roden; Jean-Claude Tardif; John R. Thompson; Nicholas J. Wareham; Hugh Watkins; Cristen J. Willer; Sekar Kathiresan; Panos Deloukas; Nilesh J. Samani; Heribert Schunkert; Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators

doi:10.1056/NEJMoa1507652

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Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease

Journal article

Peer reviewed

Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease

Nathan O. Stitziel, Kathleen E. Stirrups, Nicholas G. D. Masca, Jeanette Erdmann, Paola G. Ferrario, Inke R. Koenig, Peter E. Weeke, Thomas R. Webb, Paul L. Auer, Ursula M. Schick, …

The New England journal of medicine, Vol.374(12), pp.1134-1144

24/03/2016

DOI: https://doi.org/10.1056/NEJMoa1507652

PMCID: PMC4850838

PMID: 26934567

Abstract

General & Internal Medicine

Life Sciences & Biomedicine

Medicine, General & Internal

Science & Technology

BACKGROUND The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes. RESULTS We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P = 4.2x10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P = 4.0x10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P = 0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P = 0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P = 2.0x10(-4)) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P = 2.5x10(-7)). CONCLUSIONS We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease.

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Title: Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease
Creators - without role: Nathan O. Stitziel - Supreme Council Of Health
Kathleen E. Stirrups - Queen Mary University of London
Nicholas G. D. Masca - University of Leicester
Jeanette Erdmann - University of Lübeck
Paola G. Ferrario - DZHK German Ctr Cardiovasc Res, Partner Site Hamburg Lubeck Kiel, Lubeck, Germany
Inke R. Koenig - DZHK German Ctr Cardiovasc Res, Partner Site Hamburg Lubeck Kiel, Lubeck, Germany
Peter E. Weeke - Vanderbilt University
Thomas R. Webb - University of Leicester
Paul L. Auer - Supreme Council Of Health
Ursula M. Schick - University of Washington
Yingchang Lu - Supreme Council Of Health
He Zhang - College Station Medical Center
Marie-Pierre Dube - College Station Medical Center
Anuj Goel - University of Oxford
Martin Farrall - University of Oxford
Gina M. Peloso - Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA
Hong-Hee Won - Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA
Ron Do - Supreme Council Of Health
Erik van Iperen - University of Amsterdam
Stavroula Kanoni - Queen Mary University of London
Jochen Kruppa - University of Lübeck
Anubha Mahajan - University of Oxford
Robert A. Scott - Massachusetts Rehabilitation Commission
Christina Willenborg - University of Lübeck
Peter S. Braund - University of Cambridge
Julian C. van Capelleveen - University of Amsterdam
Alex S. F. Doney - University of Dundee
Louise A. Donnelly - University of Dundee
Rosanna Asselta - Humanitas University
Piera A. Merlini - Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Stefano Duga - Humanitas University
Nicola Marziliano - University of Parma
Josh C. Denny - Vanderbilt University
Christian M. Shaffer - Vanderbilt University
Nour Eddine El-Mokhtari - College Station Medical Center
Andre Franke - Univ Kiel, Inst Clin Mol Biol, Kiel, Germany
Omri Gottesman - Supreme Council Of Health
Stefanie Heilmann - University of Bonn
Christian Hengstenberg - Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany
Per Hoffmann - University of Bonn
Oddgeir L. Holmen - Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, Levanger, Norway
Kristian Hveem - Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, Levanger, Norway
Jan-Hakan Jansson - Umeå University
Karl-Heinz Joeckel - College Station Medical Center
Thorsten Kessler - Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany
Jennifer Kriebel - Helmholtz Zentrum München
Karl L. Laugwitz - DZHK Partner Site Munich Heart Alliance, Munich, Germany
Eirini Marouli - Queen Mary University of London
Nicola Martinelli
Mark I. McCarthy - University of Oxford
Natalie R. Van Zuydam - University of Oxford
Christa Meisinger - Helmholtz Zentrum München
Tonu Esko - Harvard University
Evelin Mihailov - University of Tartu
Stefan A. Escher - Lund University
Maris Alver - University of Tartu
Susanne Moebus - College Station Medical Center
Andrew D. Morris - University of Edinburgh
Martina Mueller-Nurasyid - DZHK Partner Site Munich Heart Alliance, Munich, Germany
Majid Nikpay - University of Ottawa
Oliviero Olivieri - University of Verona
Louis-Philippe Lemieux Perreault - Montreal Heart Institute
Alaa AlQarawi - King Abdulaziz University
Neil R. Robertson - University of Oxford
Karen O. Akinsanya - Merck Sharp & Dohme Ltd, Pob 2000, Rahway, NJ 07065 USA
Dermot F. Reilly - Merck Sharp & Dohme Ltd, Pob 2000, Rahway, NJ 07065 USA
Thomas F. Vogt - Merck Sharp & Dohme Ltd, Pob 2000, Rahway, NJ 07065 USA
Wu Yin - Merck Sharp & Dohme Ltd, Pob 2000, Rahway, NJ 07065 USA
Folkert W. Asselbergs - UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England
Charles Kooperberg - University of Washington
Rebecca D. Jackson - The Ohio State University
Eli Stahl - Supreme Council Of Health
Konstantin Strauch - College Station Medical Center
Tibor V. Varga - Lund University
Melanie Waldenberger - Helmholtz Zentrum München
Lingyao Zeng - Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany
Aldi T. Kraja - Supreme Council Of Health
Chunyu Liu - Framingham Heart Dis Epidemiol Study, Framingham, MA USA
Georg B. Ehret - College Station Medical Center
Christopher Newton-Cheh - Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA
Daniel I. Chasman - Brigham and Women's Hospital
Rajiv Chowdhury - University of Cambridge
Marco Ferrario - University of Insubria
Ian Ford - University of Glasgow
J. Wouter Jukema - Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands
Frank Kee - Queens University
Kari Kuulasmaa - Natl Inst Hlth & Welf, Helsinki, Finland
Borge G. Nordestgaard - Copenhagen Univ Hosp, Copenhagen, Denmark
Markus Perola - Natl Inst Hlth & Welf, Helsinki, Finland
Danish Saleheen - Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA
Naveed Sattar - University of Glasgow
Praveen Surendran
David Tregouet - Sorbonne Université
Robin Young - University of Cambridge
Joanna M. M. Howson - University of Cambridge
Adam S. Butterworth - University of Cambridge
John Danesh - University of Cambridge
Diego Ardissino - University of Parma
Erwin P. Bottinger - Supreme Council Of Health
Raimund Erbel - College Station Medical Center
Paul W. Franks - Harvard University
Domenico Girelli - University of Verona
Alistair S. Hall - University of Leeds
G. Kees Hovingh - University of Amsterdam
Adnan Kastrati - Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany
Wolfgang Lieb - Univ Kiel, Inst Epidemiol & Biobank Popgen, Kiel, Germany
Thomas Meitinger - Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany
William E. Kraus - Duke University
Svati H. Shah - Duke University
Ruth McPherson - University of Ottawa
Marju Orho-Melander - Lund University
Olle Melander - Lund University
Andres Metspalu - University of Tartu
Colin N. A. Palmer - University of Dundee
Annette Peters - DZHK Partner Site Munich Heart Alliance, Munich, Germany
Daniel J. Rader - Supreme Council Of Health
Muredach P. Reilly - Supreme Council Of Health
Ruth J. F. Loos - Supreme Council Of Health
Alex P. Reiner - University of Washington
Dan M. Roden - Vanderbilt University
Jean-Claude Tardif - College Station Medical Center
John R. Thompson - University of Leicester
Nicholas J. Wareham - Massachusetts Rehabilitation Commission
Hugh Watkins - University of Oxford
Cristen J. Willer - College Station Medical Center
Sekar Kathiresan - Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA
Panos Deloukas - Queen Mary University of London
Nilesh J. Samani - University of Leicester
Heribert Schunkert - Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany
Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators
Publication Details: The New England journal of medicine, Vol.374(12), pp.1134-1144
Publisher: Massachusetts Medical Soc
Number of pages: 11
Grant note: 15POST23280019 / American Heart Association British Heart Foundation Deutsche Forschungsgemeinschaft cluster of excellence "Inflammation at Interfaces"; German Research Foundation (DFG) DZHK German Federal Ministry of Education and Research e:Med program (e:AtheroSysMed and sysINFLAME) K08HL114642 / National Heart, Lung, and Blood Institute, National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) G0800270; MC_UU_12015/1; MC_PC_13048; MR/L003120/1; MR/N005813/1 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) Foundation for Barnes Jewish Hospital 090532/Z/09/Z; 098381 / Wellcome Trust National Institute for Health Research (NIHR); National Institutes of Health Research (NIHR) Merck; Merck & Company Fondation Leducq; Leducq Foundation R01HL107816; R01HL127564 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 261123 / European Union; European Commission; Spanish Government K01HL125751 / National Heart, Lung, and Blood Institute of the NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) RFPS-2007-3-644382 / Italian Ministry of Health; Ministry of Health, Italy Regione Emilia Romagna Area EU FP7 AMP; Wellcome Trust Institutional BRU MR/N005813/1; G0800270; MC_UU_12015/1; MR/L003120/1 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) 1123 / SFB; Austrian Science Fund (FWF) NIHR Leicester Cardiovascular Biomedical Research Unit (BRU) NNF14OC0011049; NNF15OC0016320; NNF16OC0021370 / Novo Nordisk Fonden; Novo Nordisk Foundation RG/08/014/24067; RG/13/13/30194; RG/14/5/30893 / British Heart Foundation RG/14/5/30893 / BHF; British Heart Foundation Donovan Family Foundation R25CA094880 / National Cancer Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) NF-SI-0512-10165; NF-SI-0611-10170; NF-SI-0611-10099 / National Institute for Health Research; National Institutes of Health Research (NIHR) Massachusetts General Hospital; General Electric British Heart Foundation (BHF) Centre of Research Excellence; British Heart Foundation 12CVD02 / Fondation Leducq (CADgenomics); Leducq Foundation
Identifiers: 9934166308331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article