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

Summary, in English

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).

• Author: Nathan O. Stitziel; Kathleen E. Stirrups; Nicholas G D Masca; Jeanette Erdmann; Paola G. Ferrario; Inke R. König; 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 Håkan Jansson; Karl Heinz Jöckel; Thorsten Kessler; Jennifer Kriebel; Karl L. Laugwitz; Eirini Marouli; Nicola Martinelli; Mark I. McCarthy; Natalie R. Van Zuydam; Christa Meisinger; Tõnu Esko; Evelin Mihailov; Stefan A. Escher; Maris Alver; Susanne Moebus; Andrew D. Morris; Martina Müller-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; Børge 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
• Department/s: EXODIAB: Excellence of Diabetes Research in Sweden; EpiHealth: Epidemiology for Health; Genetic and Molecular Epidemiology; Department of Food Technology, Engineering and Nutrition; Diabetes - Cardiovascular Disease; Cardiovascular Research - Hypertension; Department of Clinical Sciences, Malmö
• Publishing year: 2016-03-24
• Language: English
• Pages: 1134-1144
• Publication/Series: New England Journal of Medicine
• Volume: 374
• Issue: 12
• Links: http://dx.doi.org/10.1056/NEJMoa1507652
• Document type: Journal article
• Publisher: Massachusetts Medical Society
• Topic: Medical Genetics
• Status: Published
• Research group: Genetic and Molecular Epidemiology; Diabetes - Cardiovascular Disease; Cardiovascular Research - Hypertension
• ISBN/ISSN/Other: ISSN: 0028-4793