Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease

Stitziel NO, Stirrups KE, Masca NGD, Erdmann J, Ferrario PG, Koenig IR, Weeke PE, Webb TR, Auer PL, Schick UM, Lu Y, Zhang H, Dube MP, Goel A, Farrall M, Peloso GM, Won HH, Do R, Van Iperen E, Kanoni S, Kruppa J, Mahajan A, Scott RA, Willenborg C, Braund PS, Van Capelleveen JC, Doney ASF, Donnelly LA, Asselta R, Merlini PA, Duga S, Marziliano N, Denny JC, Shaffer CM, El-Mokhtari NE, Franke A, Gottesman O, Heilmann S, Hengstenberg C, Hoffmann P, Holmen OL, Hveem K, Jansson JH, Joeckel KH, Kessler T, Kriebel J, Laugwitz KL, Marouli E, Martinelli N, Mccarthy MI, Van Zuydam NR, Meisinger C, Esko T, Mihailov E, Escher SA, Alver M, Moebus S, Morris AD, Mueller-Nurasyid M, Nikpay M, Olivieri O, Perreault LPL, Alqarawi A, Robertson NR, Akinsanya KO, Reilly DF, Vogt TF, Yin W, Asselbergs FW, Kooperberg C, Jackson RD, Stahl E, Strauch K, Varga TV, Waldenberger M, Zeng L, Kraja AT, Liu C, Ehret GB, Newton-Cheh C, Chasman DI, Chowdhury R, Ferrario M, Ford I, Jukema JW, Kee F, Kuulasmaa K, Nordestgaard BG, Perola M, Saleheen D, Sattar N, Surendran P, Tregouet D, Young R, Howson JMM, Butterworth AS, Danesh J, Ardissino D, Bottinger EP, Erbel R, Franks PW, Girelli D, Hall AS, Hovingh GK, Kastrati A, Lieb W, Meitinger T, Kraus WE, Shah SH, Mcpherson R, Orho-Melander M, Melander O, Metspalu A, Palmer CNA, Peters A, Rader DJ, Reilly MP, Loos RJF, Reiner AP, Roden DM, Tardif JC, Thompson JR, Wareham NJ, Watkins H, Willer CJ, Kathiresan S, Deloukas P, Samani NJ, Schunkert H (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Book Volume: 374

Pages Range: 1134-1144

Journal Issue: 12

DOI: 10.1056/NEJMoa1507652

Abstract

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 = 4.2×10^-10) and ANGPTL4 (p.E40K; minorallele frequency, 2.01%; odds ratio, 0.86; P = 4.0×10^-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 = 2.0×10^-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 = 2.5×10^-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. (Funded by the National Institutes of Health and others).

Involved external institutions

Washington University in St. Louis United States (USA) (US) Queen Mary University of London United Kingdom (GB) University of Leicester United Kingdom (GB) Universität zu Lübeck Germany (DE) Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK e.V.) Germany (DE) Vanderbilt University United States (USA) (US) University of Wisconsin - Madison United States (USA) (US) University of Washington United States (USA) (US) Icahn School of Medicine at Mount Sinai United States (USA) (US) University of Michigan United States (USA) (US) Université de Montréal Canada (CA) University of Oxford United Kingdom (GB) Massachusetts General Hospital United States (USA) (US) University of Amsterdam Netherlands (NL) Addenbrooke's Hospital United Kingdom (GB) University of Cambridge United Kingdom (GB) University of Dundee United Kingdom (GB) Istituto Clinico Humanitas Italy (IT) Ospedale Niguarda Ca' Granda / ASST Grande Ospedale Metropolitano Niguarda Italy (IT) University of Parma / Università degli Studi di Parma Italy (IT) Kreiskrankenhaus Rendsburg Germany (DE) Christian-Albrechts-Universität zu Kiel Germany (DE) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) Technische Universität München (TUM) Germany (DE) NTNU Trondheim - Norwegian University of Science and Technology Norway (NO) Umeå University Sweden (SE) Universitätsklinikum Essen Germany (DE) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich Germany (DE) Munich Heart Alliance am Institut für Pharmakologie und Toxikologie Germany (DE) Harvard University United States (USA) (US) University of Tartu Estonia (EE) Lund University / Lunds universitet Sweden (SE) University of Edinburgh United Kingdom (GB) University of Ottawa Canada (CA) University of Verona / Università degli Studi di Verona Italy (IT) King Abdulaziz University (KAU) / جامعة الملك عبد العزيز Saudi Arabia (SA) Merck & Co., Inc. / Merck Sharp & Dohme Corp (MSD) United States (USA) (US) University College London (UCL) United Kingdom (GB) Ohio State University United States (USA) (US) Ludwig-Maximilians-Universität (LMU) Germany (DE) Framingham Heart Study United States (USA) (US) Geneva University Hospitals / Hôpitaux universitaires de Genève (HUG) Switzerland (CH) Brigham and Women's Hospital (BWH) United States (USA) (US) University of Insubria / Università degli Studi dell'Insubria Italy (IT) University of Glasgow United Kingdom (GB) Netherlands Heart Institute / Interuniversitair Cardiologisch Instituut Nederland (ICIN-NHI) Netherlands (NL) Queen's University United Kingdom (GB) University of Pennsylvania (UPenn) United States (USA) (US) National Institute for Health and Welfare (THL) Finland (FI) Copenhagen University Hospital Denmark (DK) University of Paris 6 - Pierre et Marie Curie / Université Paris VI Pierre et Marie Curie (UPMC) France (FR) University of Leeds United Kingdom (GB) Duke University United States (USA) (US)

How to cite

APA:

Stitziel, N.O., Stirrups, K.E., Masca, N.G.D., Erdmann, J., Ferrario, P.G., Koenig, I.R.,... Schunkert, H. (2016). Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease. New England Journal of Medicine, 374(12), 1134-1144. https://doi.org/10.1056/NEJMoa1507652

MLA:

Stitziel, Nathan O., et al. "Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease." New England Journal of Medicine 374.12 (2016): 1134-1144.

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