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N Engl J Med DOI:10.1056/NEJMoa1507652

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

Publication TypeJournal Article
Year of Publication2016
AuthorsStitziel, NO, Stirrups, KE, Masca, NGD, Erdmann, J, Ferrario, PG, König, IR, Weeke, PE, Webb, TR, Auer, PL, Schick, UM, Lu, Y, Zhang, H, Dube, M-P, Goel, A, Farrall, M, Peloso, GM, Won, H-H, Do, R, van Iperen, E, Kanoni, S, Kruppa, J, Mahajan, A, Scott, RA, Willenberg, C, Braund, PS, van Capelleveen, JC, Doney, ASF, Donnelly, LA, Asselta, R, Merlini, PA, Duga, S, Marziliano, N, Denny, JC, Shaffer, CM, El-Mokhtari, NEddine, Franke, A, Gottesman, O, Heilmann, S, Hengstenberg, C, Hoffman, P, Holmen, OL, Hveem, K, Jansson, J-H, Jöckel, K-H, Kessler, T, Kriebel, J, Laugwitz, KL, Marouli, E, Martinelli, N, McCarthy, MI, van Zuydam, NR, Meisinger, C, Esko, T, Mihailov, E, Escher, SA, Alvar, M, Moebus, S, Morris, AD, Müller-Nurasyid, M, Nikpay, M, Olivieri, O, Perreault, L-PLemieux, 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, J Jukema, W, Kee, F, Kuulasmaa, K, Nordestgaard, BG, Perola, M, Saleheen, D, Sattar, N, Surendran, P, Trégouët, D, Young, R, Howson, JMM, Butterworth, AS, Danesh, J, Ardissino, D, Bottinger, EP, Erbel, R, Franks, PW, Girelli, D, Hall, AS, G Hovingh, K, Kastrati, A, Lieb, W, Meitinger, T, Kraus, WE, Shah, SH, McPherson, R, Orho-Melander, M, Melander, O, Metspalu, A, Palmer, CNA, Peters, A, Rader, D, Reilly, MP, Loos, RJF, Reiner, AP, Roden, DM, Tardif, J-C, Thompson, JR, Wareham, NJ, Watkins, H, Willer, CJ, Kathiresan, S, Deloukas, P, Samani, NJ, Schunkert, H
Corporate AuthorsMyocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators
JournalN Engl J Med
Date Published2016 Mar 24
KeywordsAged, Angiopoietins, Cell Adhesion Molecules, Coronary Artery Disease, Female, Genotyping Techniques, Humans, Lipoprotein Lipase, Male, Middle Aged, Mutation, Mutation, Missense, Risk Factors, Sequence Analysis, DNA, Triglycerides

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.).


Alternate JournalN. Engl. J. Med.
PubMed ID26934567
PubMed Central IDPMC4850838
Grant List090532/Z/09/Z / / Wellcome Trust / United Kingdom
098381 / / Wellcome Trust / United Kingdom
K01HL125751 / HL / NHLBI NIH HHS / United States
K08 HL114642 / HL / NHLBI NIH HHS / United States
K08HL114642 / HL / NHLBI NIH HHS / United States
R01HL107816 / HL / NHLBI NIH HHS / United States
R01HL127564 / HL / NHLBI NIH HHS / United States
R25CA094880 / CA / NCI NIH HHS / United States
RG/14/5/30893 / / British Heart Foundation / United Kingdom
U01 HG008672 / HG / NHGRI NIH HHS / United States