Dataset Information

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

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<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. (Funded by the National Heart, Lung, and Blood Institute and others.).

SUBMITTER: TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute

PROVIDER: S-EPMC4180269 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Crosby Jacy J Peloso Gina M GM Auer Paul L PL Crosslin David R DR Stitziel Nathan O NO Lange Leslie A LA Lu Yingchang Y Tang Zheng-zheng ZZ Zhang He H Hindy George G Masca Nicholas N Stirrups Kathleen K Kanoni Stavroula S Do Ron R Jun Goo G Hu Youna Y Kang Hyun Min HM Xue Chenyi C Goel Anuj A Farrall Martin M Duga Stefano S Merlini Pier Angelica PA Asselta Rosanna R Girelli Domenico D Olivieri Oliviero O Martinelli Nicola N Yin Wu W Reilly Dermot D Speliotes Elizabeth E Fox Caroline S CS Hveem Kristian K Holmen Oddgeir L OL Nikpay Majid M Farlow Deborah N DN Assimes Themistocles L TL Franceschini Nora N Robinson Jennifer J North Kari E KE Martin Lisa W LW DePristo Mark M Gupta Namrata N Escher Stefan A SA Jansson Jan-Håkan JH Van Zuydam Natalie N Palmer Colin N A CN Wareham Nicholas N Koch Werner W Meitinger Thomas T Peters Annette A Lieb Wolfgang W Erbel Raimund R Konig Inke R IR Kruppa Jochen J Degenhardt Franziska F Gottesman Omri O Bottinger Erwin P EP O'Donnell Christopher J CJ Psaty Bruce M BM Ballantyne Christie M CM Abecasis Goncalo G Ordovas Jose M JM Melander Olle O Watkins Hugh H Orho-Melander Marju M Ardissino Diego D Loos Ruth J F RJ McPherson Ruth R Willer Cristen J CJ Erdmann Jeanette J Hall Alistair S AS Samani Nilesh J NJ Deloukas Panos P Schunkert Heribert H Wilson James G JG Kooperberg Charles C Rich Stephen S SS Tracy Russell P RP Lin Dan-Yu DY Altshuler David D Gabriel Stacey S Nickerson Deborah A DA Jarvik Gail P GP Cupples L Adrienne LA Reiner Alex P AP Boerwinkle Eric E Kathiresan Sekar S

The New England journal of medicine 20140618 1

<h4>Background</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 24941081

Similar Datasets

Project description:BackgroundHypertriglyceridemia has emerged as a critical coronary artery disease (CAD) risk factor. Rare loss-of-function (LoF) variants in apolipoprotein C-III have been reported to reduce triglycerides (TG) and are cardioprotective in American Indians and Europeans. However, there is a lack of data in other Europeans and non-Europeans. Also, whether genetically increased plasma TG due to ApoC-III is causally associated with increased CAD risk is still unclear and inconsistent. The objectives of this study were to verify the cardioprotective role of earlier reported six LoF variants of APOC3 in South Asians and other multi-ethnic cohorts and to evaluate the causal association of TG raising common variants for increasing CAD risk.MethodsWe performed gene-centric and Mendelian randomization analyses and evaluated the role of genetic variation encompassing APOC3 for affecting circulating TG and the risk for developing CAD.ResultsOne rare LoF variant (rs138326449) with a 37% reduction in TG was associated with lowered risk for CAD in Europeans (p = 0.007), but we could not confirm this association in Asian Indians (p = 0.641). Our data could not validate the cardioprotective role of other five LoF variants analysed. A common variant rs5128 in the APOC3 was strongly associated with elevated TG levels showing a p-value 2.8 × 10- 424. Measures of plasma ApoC-III in a small subset of Sikhs revealed a 37% increase in ApoC-III concentrations among homozygous mutant carriers than the wild-type carriers of rs5128. A genetically instrumented per 1SD increment of plasma TG level of 15 mg/dL would cause a mild increase (3%) in the risk for CAD (p = 0.042).ConclusionsOur results highlight the challenges of inclusion of rare variant information in clinical risk assessment and the generalizability of implementation of ApoC-III inhibition for treating atherosclerotic disease. More studies would be needed to confirm whether genetically raised TG and ApoC-III concentrations would increase CAD risk.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets