Journal
CIRCULATION RESEARCH
Volume 121, Issue 1, Pages 81-+Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.117.311145
Keywords
case-control studies; cholesteryl ester transfer protein; coronary disease; lipids
Funding
- Yoshida Scholarship Foundation
- National Research Foundation of Korea (NRF) - Korea government (Ministry of Science, ICT and Future Planning) [2016R1C1B2007920]
- KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst - National Institutes of Health (NIH) [TR001100]
- National Heart, Lung, and Blood Institute (NHLBI) of NIH [T32 HL007734]
- John S. LaDue Memorial Fellowship in Cardiology from Harvard Medical School
- Ofer and Shelly Nemirovsky Research Scholar Award from the Massachusetts General Hospital
- Donovan Family Foundation
- Jackson State University [HHSN268201300049C, HHSN268201300050C]
- Tougaloo College [HHSN268201300048C]
- University of Mississippi Medical Center from the NHLBI [HHSN268201300046C, HHSN268201300047C]
- National Institute for Minority Health and Health Disparities
- British Heart Foundation (British Heart Foundation Family Heart Study) [RG2000010]
- British Heart Foundation (UK Aneurysm Growth Study) [CS/14/2/30841]
- National Institute for Health Research (NIHR Leicester Cardiovascular Biomedical Research Unit Biomedical Research Informatics Centre for Cardiovascular Science) [IS_BRU_0211_20033]
- Regeneron Pharmaceuticals
- [R01 HL127564]
- [5U54HG003067]
- National Research Foundation of Korea [2016R1C1B2007920] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- British Heart Foundation [CS/14/2/30841, RG/08/014/24067] Funding Source: researchfish
- Medical Research Council [MR/L003120/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10165] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [16H05250, 15K05577] Funding Source: KAKEN
- MRC [MR/L003120/1] Funding Source: UKRI
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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<1.0x10(-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=5.1x10(-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.
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