Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease

Jacy Crosby; Gina M. Peloso; Paul L. Auer; David R. Crosslin; Nathan O. Stitziel; Leslie A. Lange; Yingchang Lu; Zheng-zheng Tang; He Zhang; George Hindy; Nicholas Masca; Kathleen Stirrups; Stavroula Kanoni; Ron Do; Goo Jun; Youna Hu; Hyun Min Kang; Chenyi Xue; Anuj Goel; Martin Farrall; Stefano Duga; Pier Angelica Merlini; Rosanna Asselta; Domenico Girelli; Oliviero Olivieri; Nicola Martinelli; Wu Yin; Dermot Reilly; Elizabeth Speliotes; Caroline S. Fox; Kristian Hveem; Oddgeir L. Holmen; Majid Nikpay; Deborah N. Farlow; Themistocles L. Assimes; Nora Franceschini; Jennifer Robinson; Kari E. North; Lisa W. Martin; Mark DePristo; Namrata Gupta; Stefan A. Escher; Jan-Hakan Jansson; Natalie Van Zuydam; Colin N. A. Palmer; Nicholas Wareham; Werner Koch; Thomas Meitinger; Annette Peters; Wolfgang Lieb; Raimund Erbel; Inke R. Konig; Jochen Kruppa; Franziska Degenhardt; Omri Gottesman; Erwin P. Bottinger; Christopher J. O'Donnell; Bruce M. Psaty; Christie M. Ballantyne; Goncalo Abecasis; Jose M. Ordovas; Olle Melander; Hugh Watkins; Marju Orho-Melander; Diego Ardissino; Ruth J. F. Loos; Ruth McPherson; Cristen J. Willer; Jeanette Erdmann; Alistair S. Hall; Nilesh J. Samani; Panos Deloukas; Heribert Schunkert; James G. Wilson; Charles Kooperberg; Stephen S. Rich; Russell P. Tracy; Dan-Yu Lin; David Altshuler; Stacey Gabriel; Deborah A. Nickerson; Gail P. Jarvik; L. Adrienne Cupples; Alex P. Reiner; Eric Boerwinkle; Sekar Kathiresan; Natl Heart Lung Blood Inst

doi:10.1056/NEJMoa1307095

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Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease

Journal article

Peer reviewed

Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease

Jacy Crosby, Gina M. Peloso, Paul L. Auer, David R. Crosslin, Nathan O. Stitziel, Leslie A. Lange, Yingchang Lu, Zheng-zheng Tang, He Zhang, George Hindy, …

The New England journal of medicine, Vol.371(1), pp.22-31

03/07/2014

DOI: https://doi.org/10.1056/NEJMoa1307095

PMCID: PMC4180269

PMID: 24941081

Abstract

General & Internal Medicine

Life Sciences & Biomedicine

Medicine, General & Internal

Science & Technology

Background Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype. Methods We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons. Results An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G -> A and IVS3+1G -> T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1x10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P = 8x10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P = 4x10(-6)). Conclusions Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.)

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Title: Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease
Creators - without role: Jacy Crosby - The University of Texas Health Science Center at Houston
Gina M. Peloso - Broad Institute
Paul L. Auer - University of Wisconsin–Milwaukee
David R. Crosslin - University of Washington
Nathan O. Stitziel - Washington University in St. Louis
Leslie A. Lange - University of North Carolina at Chapel Hill
Yingchang Lu - Icahn School of Medicine at Mount Sinai
Zheng-zheng Tang - University of North Carolina at Chapel Hill
He Zhang - University of Michigan–Ann Arbor
George Hindy - Lund University
Nicholas Masca - University of Leicester
Kathleen Stirrups - Queen Mary University of London
Stavroula Kanoni - Queen Mary University of London
Ron Do - Broad Institute
Goo Jun - University of Michigan–Ann Arbor
Youna Hu - University of Michigan–Ann Arbor
Hyun Min Kang - University of Michigan–Ann Arbor
Chenyi Xue - University of Michigan–Ann Arbor
Anuj Goel - University of Oxford
Martin Farrall - University of Oxford
Stefano Duga - University of Milan
Pier Angelica Merlini - Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Rosanna Asselta - University of Milan
Domenico Girelli - University of Verona
Oliviero Olivieri - University of Verona
Nicola Martinelli - University of Verona
Wu Yin - Merck Sharp & Dohme Ltd, Boston, MA USA
Dermot Reilly - MSD
Elizabeth Speliotes - University of Michigan–Ann Arbor
Caroline S. Fox - National Institutes of Health
Kristian Hveem - Levanger Hospital
Oddgeir L. Holmen - Norwegian University of Science and Technology
Majid Nikpay - University of Ottawa
Deborah N. Farlow - Broad Institute
Themistocles L. Assimes - Stanford University
Nora Franceschini - University of North Carolina at Chapel Hill
Jennifer Robinson - University of Iowa
Kari E. North - University of North Carolina at Chapel Hill
Lisa W. Martin - Supreme Council Of Health
Mark DePristo - Broad Institute
Namrata Gupta - Broad Institute
Stefan A. Escher - Lund University
Jan-Hakan Jansson - Umeå University
Natalie Van Zuydam - University of Dundee
Colin N. A. Palmer - University of Dundee
Nicholas Wareham - Cambridge University Hospitals NHS Foundation Trust
Werner Koch - Technical University of Munich
Thomas Meitinger - Technical University of Munich
Annette Peters - German Ctr Cardiovasc Res, Munich, Germany
Wolfgang Lieb - Kiel University
Raimund Erbel - West German Heart Ctr, Dept Cardiol, Essen, Germany
Inke R. Konig - University of Lübeck
Jochen Kruppa - University of Lübeck
Franziska Degenhardt - University of Bonn
Omri Gottesman - Icahn School of Medicine at Mount Sinai
Erwin P. Bottinger - Icahn School of Medicine at Mount Sinai
Christopher J. O'Donnell - National Institutes of Health
Bruce M. Psaty - University of Washington
Christie M. Ballantyne - Baylor College of Medicine
Goncalo Abecasis - University of Michigan–Ann Arbor
Jose M. Ordovas - Madrid Institute for Advanced Studies
Olle Melander - Lund University
Hugh Watkins - University of Oxford
Marju Orho-Melander - Lund University
Diego Ardissino - University of Parma
Ruth J. F. Loos - Icahn School of Medicine at Mount Sinai
Ruth McPherson - University of Ottawa
Cristen J. Willer - University of Michigan–Ann Arbor
Jeanette Erdmann - University of Lübeck
Alistair S. Hall - University of Leeds
Nilesh J. Samani - University of Leicester
Panos Deloukas - Queen Mary University of London
Heribert Schunkert - Technical University of Munich
James G. Wilson - University of Mississippi
Charles Kooperberg - Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa
Stephen S. Rich - University of Virginia
Russell P. Tracy - University of Vermont
Dan-Yu Lin - Biostat
David Altshuler - Broad Institute
Stacey Gabriel - Broad Institute
Deborah A. Nickerson - University of Washington
Gail P. Jarvik - University of Washington
L. Adrienne Cupples - Boston University
Alex P. Reiner - University of Washington
Eric Boerwinkle - Baylor College of Medicine
Sekar Kathiresan - Broad Institute
Natl Heart Lung Blood Inst
Publication Details: The New England journal of medicine, Vol.371(1), pp.22-31
Publisher: Massachusetts Medical Soc
Number of pages: 10
Grant note: NNF13OC0005339 / Novo Nordisk Fonden; Novo Nordisk Foundation National Heart, Lung, and Blood Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) NF-SI-0611-10170 / National Institute for Health Research; National Institute for Health Research (NIHR) R01NS017950 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) R01CA082659 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) U01AG049505 / NATIONAL INSTITUTE ON AGING; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) RC2HL102926 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI)
Identifiers: 9938343808331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article