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

Stitziel, Nathan O.; Stirrups, Kathleen E.; Masca, Nicholas G D; Erdmann, Jeanette; Ferrario, Paola G.; König, Inke R.; Weeke, Peter E.; Webb, Thomas R.; Auer, Paul L. and Schick, Ursula M., et al. (2016) In New England Journal of Medicine 374(12). p.1134-1144
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... (More)

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).

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New England Journal of Medicine
volume
374
issue
12
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11 pages
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Massachusetts Medical Society
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  • Scopus:84962230620
ISSN
0028-4793
DOI
10.1056/NEJMoa1507652
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English
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yes
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f898cd57-135e-4de5-881b-0ff15cdc1dca
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2016-05-31 13:16:45
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2016-12-04 04:51:57
@misc{f898cd57-135e-4de5-881b-0ff15cdc1dca,
  abstract     = {<p>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<sup>-10</sup>) and ANGPTL4 (p.E40K; minorallele frequency, 2.01%; odds ratio, 0.86; P = 4.0×10<sup>-8</sup>), 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<sup>-4</sup>) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447<sup>∗</sup>; minor-allele frequency, 9.9%; odds ratio, 0.94; P = 2.5×10<sup>-7</sup>). 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).</p>},
  author       = {Stitziel, Nathan O. and Stirrups, Kathleen E. and Masca, Nicholas G D and Erdmann, Jeanette and Ferrario, Paola G. and König, Inke R. and Weeke, Peter E. and Webb, Thomas R. and Auer, Paul L. and Schick, Ursula M. and Lu, Yingchang and Zhang, He and Dube, Marie Pierre and Goel, Anuj and Farrall, Martin and Peloso, Gina M. and Won, Hong Hee and Do, Ron and Van Iperen, Erik and Kanoni, Stavroula and Kruppa, Jochen and Mahajan, Anubha and Scott, Robert A. and Willenborg, Christina and Braund, Peter S. and Van Capelleveen, Julian C. and Doney, Alex S F and Donnelly, Louise A. and Asselta, Rosanna and Merlini, Piera A. and Duga, Stefano and Marziliano, Nicola and Denny, Josh C. and Shaffer, Christian M. and El-Mokhtari, Nour Eddine and Franke, Andre and Gottesman, Omri and Heilmann, Stefanie and Hengstenberg, Christian and Hoffmann, Per and Holmen, Oddgeir L. and Hveem, Kristian and Jansson, Jan Håkan and Jöckel, Karl Heinz and Kessler, Thorsten and Kriebel, Jennifer and Laugwitz, Karl L. and Marouli, Eirini and Martinelli, Nicola and McCarthy, Mark I. and Van Zuydam, Natalie R. and Meisinger, Christa and Esko, Tõnu and Mihailov, Evelin and Escher, Stefan A. and Alver, Maris and Moebus, Susanne and Morris, Andrew D. and Müller-Nurasyid, Martina and Nikpay, Majid and Olivieri, Oliviero and Perreault, Louis Philippe Lemieux and AlQarawi, Alaa and Robertson, Neil R. and Akinsanya, Karen O. and Reilly, Dermot F. and Vogt, Thomas F. and Yin, Wu and Asselbergs, Folkert W. and Kooperberg, Charles and Jackson, Rebecca D. and Stahl, Eli and Strauch, Konstantin and Varga, Tibor V. and Waldenberger, Melanie and Zeng, Lingyao and Kraja, Aldi T. and Liu, Chunyu and Ehret, Georg B. and Newton-Cheh, Christopher and Chasman, Daniel I. and Chowdhury, Rajiv and Ferrario, Marco and Ford, Ian and Jukema, J. Wouter and Kee, Frank and Kuulasmaa, Kari and Nordestgaard, Børge G. and Perola, Markus and Saleheen, Danish and Sattar, Naveed and Surendran, Praveen and Tregouet, David and Young, Robin and Howson, Joanna M M and Butterworth, Adam S. and Danesh, John and Ardissino, Diego and Bottinger, Erwin P. and Erbel, Raimund and Franks, Paul W. and Girelli, Domenico and Hall, Alistair S. and Hovingh, G. Kees and Kastrati, Adnan and Lieb, Wolfgang and Meitinger, Thomas and Kraus, William E. and Shah, Svati H. and McPherson, Ruth and Orho-Melander, Marju and Melander, Olle and Metspalu, Andres and Palmer, Colin N A and Peters, Annette and Rader, Daniel J. and Reilly, Muredach P. and Loos, Ruth J F and Reiner, Alex P. and Roden, Dan M. and Tardif, Jean Claude and Thompson, John R. and Wareham, Nicholas J. and Watkins, Hugh and Willer, Cristen J. and Kathiresan, Sekar and Deloukas, Panos and Samani, Nilesh J. and Schunkert, Heribert},
  issn         = {0028-4793},
  language     = {eng},
  month        = {03},
  number       = {12},
  pages        = {1134--1144},
  publisher    = {ARRAY(0x88a39e8)},
  series       = {New England Journal of Medicine},
  title        = {Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease},
  url          = {http://dx.doi.org/10.1056/NEJMoa1507652},
  volume       = {374},
  year         = {2016},
}