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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Loss-of-function mutations in APOC3, triglycerides, and coronary disease
New England Journal of Medicine, Volume 371, No. 1, Year 2014
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Description
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<1×10-20), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P=8×10 -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=4×10-6). 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. Copyright © 2014 Massachusetts Medical Society.
Authors & Co-Authors
Crosby, Jacy
Unknown Affiliation
Peloso, Gina Marie
Unknown Affiliation
Auer, Paul Livermore
Unknown Affiliation
Crosslin, David R.
Unknown Affiliation
Stitziel, Nathan Oliver
Unknown Affiliation
Lange, Leslie A.
Unknown Affiliation
Lu, Yingchang
Unknown Affiliation
Tang, Zheng Zheng
Unknown Affiliation
Zhang, He
Unknown Affiliation
Hindy, George
Unknown Affiliation
Masca, Nicholas G.D.
Unknown Affiliation
Stirrups, Kathleen E.
Unknown Affiliation
Kanoni, Stavroula
Unknown Affiliation
Do, Ron
Unknown Affiliation
Jun, Goo
Unknown Affiliation
Hu, Youna
Unknown Affiliation
Kang, Hyun-min
Unknown Affiliation
Xue, Chenyi
Unknown Affiliation
Goel, Anuj
Unknown Affiliation
Farrall, Martin
Unknown Affiliation
Duga, Stefano
Unknown Affiliation
Merlini, Piera Angelica
Unknown Affiliation
Asselta, Rosanna
Unknown Affiliation
Girelli, Domenico
Unknown Affiliation
Olivieri, Oliviero
Unknown Affiliation
Martinelli, Nicola
Unknown Affiliation
Yin, Wu
Unknown Affiliation
Reilly, Dermot F.
Unknown Affiliation
Speliotes, Elizabeth K.
Unknown Affiliation
Fox, Caroline S.
Unknown Affiliation
Hveem, Kristian
Unknown Affiliation
Holmen, Oddgeir Lingaas
Unknown Affiliation
Nikpay, Majid
Unknown Affiliation
Farlow, Deborah N.
Unknown Affiliation
Assimes, Themistocles L.
Unknown Affiliation
Franceschini, Nora
Unknown Affiliation
Robinson, Jennifer G.
Unknown Affiliation
North, Kari E.
Unknown Affiliation
Martin, Lisa W.
Unknown Affiliation
DePristo, Mark
Unknown Affiliation
Gupta, Namrata
Unknown Affiliation
Escher, Stefan A.
Unknown Affiliation
Jansson, Jan Håkan
Unknown Affiliation
van Zuydam, Natalie R.
Unknown Affiliation
Palmer, Colin Neil Alexander
Unknown Affiliation
Wareham, Nicholas J.
Unknown Affiliation
Koch, Werner
Unknown Affiliation
Meitinger, Thomas A.
Unknown Affiliation
Peters, Annette Michael
Unknown Affiliation
Lieb, Wolfgang S.
Unknown Affiliation
Erbel, Raimund D.
Unknown Affiliation
König, I. R.
Unknown Affiliation
Kruppa, Jochen
Unknown Affiliation
Degenhardt, Franziska A.
Unknown Affiliation
Gottesman, Omri
Unknown Affiliation
Böttinger, Erwin P.
Unknown Affiliation
O'Donnell, Christopher J.
Unknown Affiliation
Psaty, Bruce M.
Unknown Affiliation
Ballantyne, Christie Mitchell
Unknown Affiliation
Abecasis, Gonçalo R.
Unknown Affiliation
Ordovas, J. M.
Unknown Affiliation
Melander, Olle
Unknown Affiliation
Watkins, Hugh C.
Unknown Affiliation
Orho-Melander, Marju
Unknown Affiliation
Ardissino, Diego
Unknown Affiliation
Loos, Ruth J.F.
Unknown Affiliation
McPherson, Ruth M.
Unknown Affiliation
Willer, Cristen J.
Unknown Affiliation
Erdmann, Jeanette
Unknown Affiliation
Hall, Alistair Scott
Unknown Affiliation
Samani, Nilesh J.
Unknown Affiliation
Deloukas, Panos
Unknown Affiliation
Schunkert, Heribert
Unknown Affiliation
Wilson, James Gaines
Unknown Affiliation
Kooperberg, Charles B.
Unknown Affiliation
Rich, Stephen S.
Unknown Affiliation
Tracy, Russell P.
Unknown Affiliation
Lin, Dan Yu
Unknown Affiliation
Altshuler, David M.
Unknown Affiliation
Gabriel, Stacey Bolk
Unknown Affiliation
Nickerson, Deborah A.
Unknown Affiliation
Jarvik, Gail Pairitz
Unknown Affiliation
Cupples, Laura Adrienne
Unknown Affiliation
Reiner, Alex P.
Unknown Affiliation
Boerwinkle, Eric A.
Unknown Affiliation
Kathiresan, Sekar
Unknown Affiliation
Statistics
Citations: 819
Authors: 86
Affiliations: 57
Identifiers
Doi:
10.1056/NEJMoa1307095
ISSN:
00284793
e-ISSN:
15334406
Research Areas
Cancer
Genetics And Genomics
Noncommunicable Diseases
Study Design
Case-Control Study