Journal article
Loss-of-function mutations in APOC3, triglycerides, and coronary disease
The New England journal of medicine, Vol.371(1), pp.22-31
07/03/2014
DOI: 10.1056/NEJMoa1307095
PMCID: PMC4180269
PMID: 24941081
Abstract
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.
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.
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)).
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.).
Details
- Title: Subtitle
- Loss-of-function mutations in APOC3, triglycerides, and coronary disease
- Creators
- Jacy CrosbyGina M PelosoPaul L AuerDavid R CrosslinNathan O StitzielLeslie A LangeYingchang LuZheng-zheng TangHe ZhangGeorge HindyNicholas MascaKathleen StirrupsStavroula KanoniRon DoGoo JunYouna HuHyun Min KangChenyi XueAnuj GoelMartin FarrallStefano DugaPier Angelica MerliniRosanna AsseltaDomenico GirelliOliviero OlivieriNicola MartinelliWu YinDermot ReillyElizabeth SpeliotesCaroline S FoxKristian HveemOddgeir L HolmenMajid NikpayDeborah N FarlowThemistocles L AssimesNora FranceschiniJennifer RobinsonKari E NorthLisa W MartinMark DePristoStefan A EscherJan-Håkan JanssonNatalie Van ZuydamColin N A PalmerNicholas WarehamWerner KochThomas MeitingerAnnette PetersWolfgang LiebRaimund ErbelInke R KonigJochen KruppaFranziska DegenhardtOmri GottesmanErwin P BottingerChristopher J O'DonnellBruce M PsatyChristie M BallantyneGoncalo AbecasisJose M OrdovasOlle MelanderHugh WatkinsMarju Orho-MelanderDiego ArdissinoRuth J F LoosRuth McPhersonCristen J WillerJeanette ErdmannAlistair S HallNilesh J SamaniPanos DeloukasHeribert SchunkertJames G WilsonCharles KooperbergStephen S RichRussell P TracyDan-Yu LinDavid AltshulerStacey GabrielDeborah A NickersonGail P JarvikL Adrienne CupplesAlex P ReinerEric BoerwinkleSekar KathiresanTG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood InstituteNamrata Gupta
- Resource Type
- Journal article
- Publication Details
- The New England journal of medicine, Vol.371(1), pp.22-31
- Publisher
- United States
- DOI
- 10.1056/NEJMoa1307095
- PMID
- 24941081
- PMCID
- PMC4180269
- ISSN
- 1533-4406
- eISSN
- 1533-4406
- Grant note
- RC2 HL103010 / NHLBI NIH HHS RC2 HL-102923 / NHLBI NIH HHS K08-HL114642 / NHLBI NIH HHS K08 HL114642 / NHLBI NIH HHS R01HL107816 / NHLBI NIH HHS RC2 HL102924 / NHLBI NIH HHS CIHR U01 AG049505 / NIA NIH HHS British Heart Foundation R01 HL107816 / NHLBI NIH HHS R01 NS017950 / NINDS NIH HHS RC2 HL-103010 / NHLBI NIH HHS RC2 HL102923 / NHLBI NIH HHS R01 HL109946 / NHLBI NIH HHS RC2 HL102926 / NHLBI NIH HHS RC2 HL-102925 / NHLBI NIH HHS R01 CA082659 / NCI NIH HHS RC2 HL-102926 / NHLBI NIH HHS T32 HL007208 / NHLBI NIH HHS RC2 HL-102924 / NHLBI NIH HHS P30 AG010129 / NIA NIH HHS RC2 HL102925 / NHLBI NIH HHS T32HL007208 / NHLBI NIH HHS
- Language
- English
- Date published
- 07/03/2014
- Academic Unit
- Epidemiology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9983995019002771
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