Association of CETP Gene Variants With Risk for Vascular and Nonvascular Diseases Among Chinese Adults | Cardiology | JAMA Cardiology | JAMA Network
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Original Investigation
January 2018

Association of CETP Gene Variants With Risk for Vascular and Nonvascular Diseases Among Chinese Adults

Author Affiliations
  • 1Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, England
  • 2Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, England
  • 3National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospital, Oxford, England
  • 4Chinese Academy of Medical Sciences, Dong Cheng District, Beijing, China
  • 5MRL, Merck Sharp & Dohme Corp, Boston, Masschusetts
  • 6Department of Epidemiology and Biostatistics, Nanjing Medical University School of Public Health, Nanjing, China
  • 7Department of Epidemiology and Biostatistics, Peking University Health Science Centre, Peking University, Beijing, China
JAMA Cardiol. 2018;3(1):34-43. doi:10.1001/jamacardio.2017.4177
Key Points

Question  What is the association of genetic variants in the CETP gene that lower cholesteryl ester transfer protein activity with risk for cardiovascular and other diseases?

Findings  In this biobank study of 151 217 Chinese adults, CETP gene variants were associated with higher levels of high-density lipoprotein cholesterol but not with lower levels of low-density lipoprotein cholesterol and were not associated with risk for cardiovascular disease.

Meaning  Increasing levels of high-density lipoprotein cholesterol by cholesteryl ester transfer protein inhibition in the absence of lower levels of low-density lipoprotein cholesterol may not confer significant benefits for cardiovascular disease.

Abstract

Importance  Increasing levels of high-density lipoprotein (HDL) cholesterol through pharmacologic inhibition of cholesteryl ester transfer protein (CETP) is a potentially important strategy for prevention and treatment of cardiovascular disease (CVD).

Objective  To use genetic variants in the CETP gene to assess potential risks and benefits of lifelong lower CETP activity on CVD and other outcomes.

Design, Setting, and Participants  This prospective biobank study included 151 217 individuals aged 30 to 79 years who were enrolled from 5 urban and 5 rural areas of China from June 25, 2004, through July 15, 2008. All participants had baseline genotype data, 17 854 of whom had lipid measurements and 4657 of whom had lipoprotein particle measurements. Median follow-up of 9.2 years (interquartile range, 8.2-10.1 years) was completed January 1, 2016, through linkage to health insurance records and death and disease registries.

Exposures  Five CETP variants, including an East Asian loss-of-function variant (rs2303790), combined in a genetic score weighted to associations with HDL cholesterol levels.

Main Outcomes and Measures  Baseline levels of lipids and lipoprotein particles, cardiovascular risk factors, incidence of carotid plaque and predefined major vascular and nonvascular diseases, and a phenome-wide range of diseases.

Results  Among the 151 217 individuals included in this study (58.4% women and 41.6% men), the mean (SD) age was 52.3 (10.9) years. Overall, the mean (SD) low-density lipoprotein (LDL) cholesterol level was 91 (27) mg/dL; HDL cholesterol level, 48 (12) mg/dL. CETP variants were strongly associated with higher concentrations of HDL cholesterol (eg, 6.1 [SE, 0.4] mg/dL per rs2303790 -G allele; P = 9.4 × 10−47) but were not associated with lower LDL cholesterol levels. Within HDL particles, cholesterol esters were increased and triglycerides reduced, whereas within very low-density lipoprotein particles, cholesterol esters were reduced and triglycerides increased. When scaled to 10-mg/dL higher levels of HDL cholesterol, the CETP genetic score was not associated with occlusive CVD (18 550 events; odds ratio [OR], 0.98; 95% CI, 0.91-1.06), major coronary events (5767 events; OR, 1.08; 95% CI, 0.95-1.22), myocardial infarction (3118 events; OR, 1.14; 95% CI, 0.97-1.35), ischemic stroke (13 759 events; OR, 0.94; 95% CI, 0.86-1.02), intracerebral hemorrhage (6532 events; OR, 0.94; 95% CI, 0.83-1.06), or other vascular diseases or carotid plaque. Similarly, rs2303790 was not associated with any vascular diseases or plaque. No associations with nonvascular diseases were found other than an increased risk for eye diseases with rs2303790 (4090 events; OR, 1.43; 95% CI, 1.13-1.80; P = .003).

Conclusions and Relevance  CETP variants were associated with altered HDL metabolism but did not lower LDL cholesterol levels and had no significant association with risk for CVD. These results suggest that in the absence of reduced LDL cholesterol levels, increasing HDL cholesterol levels by inhibition of CETP may not confer significant benefits for CVD.

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