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

Crosby, Jacy; Peloso, Gina M.; Auer, Paul L.; Crosslin, David R.; Stitziel, Nathan O.; Lange, Leslie A.; Lu, Yingchang; Tang, Zheng-zheng; Zhang, He and Hindy, George LU , et al. (2014) In New England Journal of Medicine 371(1). p.22-31
Abstract
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.... (More)
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.) (Less)
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New England Journal of Medicine
volume
371
issue
1
pages
22 - 31
publisher
Massachusetts Medical Society
external identifiers
  • wos:000338265700006
  • scopus:84903727023
ISSN
0028-4793
DOI
10.1056/NEJMoa1307095
language
English
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yes
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fafa9f3d-3670-4bd9-a44d-110e3c713f0f (old id 4602645)
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2014-09-01 07:47:05
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2017-11-05 03:25:30
@article{fafa9f3d-3670-4bd9-a44d-110e3c713f0f,
  abstract     = {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 -&gt; A and IVS3+1G -&gt; 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&lt;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.)},
  author       = {Crosby, Jacy and Peloso, Gina M. and Auer, Paul L. and Crosslin, David R. and Stitziel, Nathan O. and Lange, Leslie A. and Lu, Yingchang and Tang, Zheng-zheng and Zhang, He and Hindy, George and Masca, Nicholas and Stirrups, Kathleen and Kanoni, Stavroula and Do, Ron and Jun, Goo and Hu, Youna and Kang, Hyun Min and Xue, Chenyi and Goel, Anuj and Farrall, Martin and Duga, Stefano and Merlini, Pier Angelica and Asselta, Rosanna and Girelli, Domenico and Olivieri, Oliviero and Martinelli, Nicola and Yin, Wu and Reilly, Dermot and Speliotes, Elizabeth and Fox, Caroline S. and Hveem, Kristian and Holmen, Oddgeir L. and Nikpay, Majid and Farlow, Deborah N. and Assimes, Themistocles L. and Franceschini, Nora and Robinson, Jennifer and North, Kari E. and Martin, Lisa W. and DePristo, Mark and Gupta, Namrata and Escher, Stefan A. and Jansson, Jan-Hakan and Van Zuydam, Natalie and Palmer, Colin N. A. and Wareham, Nicholas and Koch, Werner and Meitinger, Thomas and Peters, Annette and Lieb, Wolfgang and Erbel, Raimund and Konig, Inke R. and Kruppa, Jochen and Degenhardt, Franziska and Gottesman, Omri and Bottinger, Erwin P. and O'Donnell, Christopher J. and Psaty, Bruce M. and Ballantyne, Christie M. and Abecasis, Goncalo and Ordovas, Jose M. and Melander, Olle and Watkins, Hugh and Orho-Melander, Marju and Ardissino, Diego and Loos, Ruth J. F. and McPherson, Ruth and Willer, Cristen J. and Erdmann, Jeanette and Hall, Alistair S. and Samani, Nilesh J. and Deloukas, Panos and Schunkert, Heribert and Wilson, James G. and Kooperberg, Charles and Rich, Stephen S. and Tracy, Russell P. and Lin, Dan-Yu and Altshuler, David and Gabriel, Stacey and Nickerson, Deborah A. and Jarvik, Gail P. and Cupples, L. Adrienne and Reiner, Alex P. and Boerwinkle, Eric and Kathiresan, Sekar},
  issn         = {0028-4793},
  language     = {eng},
  number       = {1},
  pages        = {22--31},
  publisher    = {Massachusetts Medical Society},
  series       = {New England Journal of Medicine},
  title        = {Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease},
  url          = {http://dx.doi.org/10.1056/NEJMoa1307095},
  volume       = {371},
  year         = {2014},
}