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

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posted on 2019-02-11, 14:42 authored by Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators, NO Stitziel, KE Stirrups, NGD Masca, J Erdmann, PG Ferrario, IR König, PE Weeke, TR Webb, PL Auer, UM Schick, Y Lu, H Zhang, M-P Dube, A Goel, M Farrall, GM Peloso, H-H Won, R Do, E van Iperen, S Kanoni, J Kruppa, A Mahajan, RA Scott, C Willenberg, PS Braund, JC van Capelleveen, ASF Doney, LA Donnelly, R Asselta, PA Merlini, S Duga, N Marziliano, JC Denny, CM Shaffer, NE El-Mokhtari, A Franke, O Gottesman, S Heilmann, C Hengstenberg, P Hoffman, OL Holmen, K Hveem, J-H Jansson, K-H Jöckel, T Kessler, J Kriebel, KL Laugwitz, E Marouli, N Martinelli, MI McCarthy, NR Van Zuydam, C Meisinger, T Esko, E Mihailov, SA Escher, M Alver, S Moebus, AD Morris, M Müller-Nurasyid, M Nikpay, O Olivieri, L-P Lemieux Perreault, A AlQarawi, NR Robertson, KO Akinsanya, DF Reilly, TF Vogt, W Yin, FW Asselbergs, C Kooperberg, RD Jackson, E Stahl, K Strauch, TV Varga, M Waldenberger, L Zeng, AT Kraja, C Liu, GB Ehret, C Newton-Cheh, DI Chasman, R Chowdhury, M Ferrario, I Ford, JW Jukema, F Kee, K Kuulasmaa, BG Nordestgaard, M Perola, D Saleheen, N Sattar, P Surendran, D Tregouet, R Young, JMM Howson, AS Butterworth, J Danesh, D Ardissino, EP Bottinger, R Erbel, PW Franks, D Girelli, AS Hall, GK Hovingh, A Kastrati, W Lieb, T Meitinger, WE Kraus, SH Shah, R McPherson, M Orho-Melander, O Melander, A Metspalu, CNA Palmer, A Peters, D Rader, MP Reilly, RJF Loos, AP Reiner, DM Roden, J-C Tardif, JR Thompson, NJ Wareham, H Watkins, CJ Willer, S Kathiresan, P Deloukas, NJ Samani, H Schunkert
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; minor-allele 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.).


Supported by a career development award from the National Heart, Lung, and Blood Institute, National Institutes of Health (NIH) (K08HL114642 to Dr. Stitziel) and by the Foundation for Barnes–Jewish Hospital. Dr. Peloso is supported by the National Heart, Lung, and Blood Institute of the NIH (award number K01HL125751). Dr. Kathiresan is supported by a Research Scholar award from the Massachusetts General Hospital, the Donovan Family Foundation, grants from the NIH (R01HL107816 and R01HL127564), a grant from Fondation Leducq, and an investigator-initiated grant from Merck. Dr. Merlini was supported by a grant from the Italian Ministry of Health (RFPS-2007-3-644382). Drs. Ardissino and Marziliano were supported by Regione Emilia Romagna Area 1 Grants. Drs. Farrall and Watkins acknowledge the support of the Wellcome Trust core award (090532/Z/09/Z), the British Heart Foundation (BHF) Centre of Research Excellence. Dr. Schick is supported in part by a grant from the National Cancer Institute (R25CA094880). Dr. Goel acknowledges EU FP7 & Wellcome Trust Institutional strategic support fund. Dr. Deloukas’s work forms part of the research themes contributing to the translational research portfolio of Barts Cardiovascular Biomedical Research Unit, which is supported and funded by the National Institute for Health Research (NIHR). Drs. Webb and Samani are funded by the British Heart Foundation, and Dr. Samani is an NIHR Senior Investigator. Dr. Masca was supported by the NIHR Leicester Cardiovascular Biomedical Research Unit (BRU), and this work forms part of the portfolio of research supported by the BRU. Dr. Won was supported by a postdoctoral award from the American Heart Association (15POST23280019). Dr. McCarthy is a Wellcome Trust Senior Investigator (098381) and an NIHR Senior Investigator. Dr. Danesh is a British Heart Foundation Professor, European Research Council Senior Investigator, and NIHR Senior Investigator. Drs. Erdmann, Webb, Samani, and Schunkert are sup



New England Journal of Medicine, 2016, 374 (12), pp. 1134-1144

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