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N Engl J Med DOI:10.1056/NEJMoa1307095

Loss-of-function mutations in APOC3, triglycerides, and coronary disease.

Publication TypeJournal Article
Year of Publication2014
AuthorsCrosby, J, Peloso, GM, Auer, PL, Crosslin, DR, Stitziel, NO, Lange, LA, Lu, Y, Tang, Z-zheng, Zhang, H, Hindy, G, Masca, N, Stirrups, K, Kanoni, S, Do, R, Jun, G, Hu, Y, Kang, HMin, Xue, C, Goel, A, Farrall, M, Duga, S, Merlini, PAngelica, Asselta, R, Girelli, D, Olivieri, O, Martinelli, N, Yin, W, Reilly, D, Speliotes, E, Fox, CS, Hveem, K, Holmen, OL, Nikpay, M, Farlow, DN, Assimes, TL, Franceschini, N, Robinson, J, North, KE, Martin, LW, DePristo, M, Gupta, N, Escher, SA, Jansson, J-H, Van Zuydam, N, Palmer, CNA, Wareham, N, Koch, W, Meitinger, T, Peters, A, Lieb, W, Erbel, R, König, IR, Kruppa, J, Degenhardt, F, Gottesman, O, Bottinger, EP, O'Donnell, CJ, Psaty, BM, Ballantyne, CM, Abecasis, G, Ordovas, JM, Melander, O, Watkins, H, Orho-Melander, M, Ardissino, D, Loos, RJF, McPherson, R, Willer, CJ, Erdmann, J, Hall, AS, Samani, NJ, Deloukas, P, Schunkert, H, Wilson, JG, Kooperberg, C, Rich, SS, Tracy, RP, Lin, D-Y, Altshuler, D, Gabriel, S, Nickerson, DA, Jarvik, GP, L Cupples, A, Reiner, AP, Boerwinkle, E, Kathiresan, S
Corporate AuthorsTG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute
JournalN Engl J Med
Volume371
Issue1
Pages22-31
Date Published2014 Jul 03
ISSN1533-4406
KeywordsAfrican Continental Ancestry Group, Apolipoprotein C-III, Coronary Disease, European Continental Ancestry Group, Exome, Genotype, Heterozygote, Humans, Liver, Mutation, Risk Factors, Sequence Analysis, DNA, Triglycerides
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→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

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.).

URLhttp://www.nejm.org/doi/abs/10.1056/NEJMoa1307095?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed
DOI10.1056/NEJMoa1307095
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24941081?dopt=Abstract

Alternate JournalN. Engl. J. Med.
PubMed ID24941081
PubMed Central IDPMC4180269
Grant ListR01 CA082659 / CA / NCI NIH HHS / United States
RC2 HL102923 / HL / NHLBI NIH HHS / United States
/ / British Heart Foundation / United Kingdom
R01 NS017950 / NS / NINDS NIH HHS / United States
R01 HL107816 / HL / NHLBI NIH HHS / United States
R01 HL109946 / HL / NHLBI NIH HHS / United States
RC2 HL102926 / HL / NHLBI NIH HHS / United States
RC2 HL-102926 / HL / NHLBI NIH HHS / United States
R01HL107816 / HL / NHLBI NIH HHS / United States
RC2 HL-102923 / HL / NHLBI NIH HHS / United States
T32 HL007208 / HL / NHLBI NIH HHS / United States
K08 HL114642 / HL / NHLBI NIH HHS / United States
RC2 HL-102924 / HL / NHLBI NIH HHS / United States
RC2 HL102924 / HL / NHLBI NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
RC2 HL-102925 / HL / NHLBI NIH HHS / United States
T32HL007208 / HL / NHLBI NIH HHS / United States
RC2 HL103010 / HL / NHLBI NIH HHS / United States
K08-HL114642 / HL / NHLBI NIH HHS / United States
RC2 HL-103010 / HL / NHLBI NIH HHS / United States
RC2 HL102925 / HL / NHLBI NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States