@article{e2ebd8613f1c43d4b1eca50a511b8a6f,
title = "Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart Disease",
abstract = "Rationale: Therapies that inhibit CETP (cholesteryl ester transfer protein) have failed to demonstrate a reduction in risk for coronary heart disease (CHD). Human DNA sequence variants that truncate the CETP gene may provide insight into the efficacy of CETP inhibition. Objective: To test whether protein-truncating variants (PTVs) at the CETP gene were associated with plasma lipid levels and CHD. Methods and Results: We sequenced the exons of the CETP gene in 58 469 participants from 12 case-control studies (18 817 CHD cases, 39 652 CHD-free controls). We defined PTV as those that lead to a premature stop, disrupt canonical splice sites, or lead to insertions/deletions that shift frame. We also genotyped 1 Japanese-specific PTV in 27561 participants from 3 case-control studies (14 286 CHD cases, 13 275 CHD-free controls). We tested association of CETP PTV carrier status with both plasma lipids and CHD. Among 58 469 participants with CETP gene-sequencing data available, average age was 51.5 years and 43% were women; 1 in 975 participants carried a PTV at the CETP gene. Compared with noncarriers, carriers of PTV at CETP had higher high-density lipoprotein cholesterol (effect size, 22.6 mg/dL; 95% confidence interval, 18-27; P<1.0×10-4), lower low-density lipoprotein cholesterol (-12.2 mg/dL; 95% confidence interval, -23 to -0.98; P=0.033), and lower triglycerides (-6.3%; 95% confidence interval, -12 to -0.22; P=0.043). CETP PTV carrier status was associated with reduced risk for CHD (summary odds ratio, 0.70; 95% confidence interval, 0.54-0.90; P=5.1×10-3). Conclusions: Compared with noncarriers, carriers of PTV at CETP displayed higher high-density lipoprotein cholesterol, lower low-density lipoprotein cholesterol, lower triglycerides, and lower risk for CHD.",
author = "{DiscovEHR Study Group} and {TAICHI Consortium} and Akihiro Nomura and Won, {Hong Hee} and Khera, {Amit V.} and Fumihiko Takeuchi and Kaoru Ito and Shane McCarthy and Emdin, {Connor A.} and Derek Klarin and Pradeep Natarajan and Zekavat, {Seyedeh M.} and Namrata Gupta and Peloso, {Gina M.} and Borecki, {Ingrid B.} and Teslovich, {Tanya M.} and Rosanna Asselta and Stefano Duga and Merlini, {Piera A.} and Adolfo Correa and Thorsten Kessler and Wilson, {James G.} and Bown, {Matthew J.} and Hall, {Alistair S.} and Braund, {Peter S.} and Carey, {David J.} and Murray, {Michael F.} and Kirchner, {H. Lester} and Leader, {Joseph B.} and Lavage, {Daniel R.} and Manus, {J. Neil} and Hartze, {Dustin N.} and Samani, {Nilesh J.} and Heribert Schunkert and Jaume Marrugat and Roberto Elosua and Ruth McPherson and Martin Farrall and Hugh Watkins and Juang, {Jyh Ming J.} and Hsiung, {Chao A.} and Lin, {Shih Yi} and Wang, {Jun Sing} and Hayato Tada and Kawashiri, {Masa Aki} and Akihiro Inazu and Masakazu Yamagishi and Tomohiro Katsuya and Eitaro Nakashima and Masahiro Nakatochi and Ken Yamamoto and Michiaki Kubo",
note = "Funding Information: A. Nomura was funded by the Yoshida Scholarship Foundation. H.-H. Won was funded by the National Research Foundation of Korea (NRF) grant funded by the Korea government (Ministry of Science, ICT and Future Planning; no. 2016R1C1B2007920). A.V. Khera is supported by a KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst funded by the National Institutes of Health (NIH; TR001100). D. Klarin is supported by the National Heart, Lung, and Blood Institute (NHLBI) of NIH under award number T32 HL007734. P. Natarajan is supported by the John S. LaDue Memorial Fellowship in Cardiology from Harvard Medical School. S. Kathiresan is supported by the Ofer and Shelly Nemirovsky Research Scholar Award from the Massachusetts General Hospital, the Donovan Family Foundation, and R01 HL127564. Exome sequencing in ATVB (Atherosclerosis Thrombosis and Vascular Biology), DHM (Deutsches Herzzentrum M{\"u}nchen Myocardial Infarction Study), JHS (Jackson Heart Study), OHS (Ottawa Heart Study), PROCARDIS (Precocious Coronary Artery Disease Study), and PROMIS (Pakistan Risk of Myocardial Infarction Study) was supported by 5U54HG003067 (to E.S. Lander and S. Gabriel). The JHS is supported and conducted in collaboration with Jackson State University (HHSN268201300049C and HHSN268201300050C), Tougaloo College (HHSN268201300048C), and the University of Mississippi Medical Center (HHSN268201300046C and HHSN268201300047C) contracts from the NHLBI and the National Institute for Minority Health and Health Disparities. Samples for the Leicester study were collected as part of projects funded by the British Heart Foundation (British Heart Foundation Family Heart Study, RG2000010; UK Aneurysm Growth Study, CS/14/2/30841) and the National Institute for Health Research (NIHR Leicester Cardiovascular Biomedical Research Unit Biomedical Research Informatics Centre for Cardiovascular Science, IS-BRU-0211-20033). The DiscovEHR (DiscovEHR project of the Regeneron Genetics Center and the Geisinger Health System) project is funded by Regeneron Pharmaceuticals. Publisher Copyright: {\textcopyright} 2017 American Heart Association, Inc.",
year = "2017",
month = jun,
day = "23",
doi = "10.1161/CIRCRESAHA.117.311145",
language = "English",
volume = "121",
pages = "81--88",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "1",
}