Association of CETP Gene Variants With Risk for Vascular and Nonvascular Diseases Among Chinese Adults | Cardiology | JAMA Cardiology | JAMA Network
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Lewington  S, Whitlock  G, Clarke  R,  et al; Prospective Studies Collaboration.  Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths.  Lancet. 2007;370(9602):1829-1839.PubMedGoogle ScholarCrossref
Di Angelantonio  E, Sarwar  N, Perry  P,  et al; Emerging Risk Factors Collaboration.  Major lipids, apolipoproteins, and risk of vascular disease.  JAMA. 2009;302(18):1993-2000.PubMedGoogle ScholarCrossref
Tall  AR.  Plasma cholesteryl ester transfer protein.  J Lipid Res. 1993;34(8):1255-1274.PubMedGoogle Scholar
Barter  PJ, Caulfield  M, Eriksson  M,  et al; ILLUMINATE Investigators.  Effects of torcetrapib in patients at high risk for coronary events.  N Engl J Med. 2007;357(21):2109-2122.PubMedGoogle ScholarCrossref
Johns  DG, Duffy  J, Fisher  T, Hubbard  BK, Forrest  MJ.  On- and off-target pharmacology of torcetrapib: current understanding and implications for the structure activity relationships (SAR), discovery and development of cholesteryl ester-transfer protein (CETP) inhibitors.  Drugs. 2012;72(4):491-507.PubMedGoogle ScholarCrossref
Schwartz  GG, Olsson  AG, Abt  M,  et al; dal-OUTCOMES Investigators.  Effects of dalcetrapib in patients with a recent acute coronary syndrome.  N Engl J Med. 2012;367(22):2089-2099.PubMedGoogle ScholarCrossref
Lincoff  AM, Nicholls  SJ, Riesmeyer  JS,  et al; ACCELERATE Investigators.  Evacetrapib and cardiovascular outcomes in high-risk vascular disease.  N Engl J Med. 2017;376(20):1933-1942.PubMedGoogle ScholarCrossref
HPS3/TIMI55-REVEAL Collaborative Group.  Effects of anacetrapib in patients with atherosclerotic vascular disease.  N Engl J Med. 2017;377(13):1217-1227.PubMedGoogle Scholar
Evans  DM, Davey Smith  G.  Mendelian randomization: new applications in the coming age of hypothesis-free causality.  Annu Rev Genomics Hum Genet. 2015;16:327-350.PubMedGoogle ScholarCrossref
Plenge  RM, Scolnick  EM, Altshuler  D.  Validating therapeutic targets through human genetics.  Nat Rev Drug Discov. 2013;12(8):581-594.PubMedGoogle ScholarCrossref
Thompson  A, Di Angelantonio  E, Sarwar  N,  et al.  Association of cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels, and coronary risk.  JAMA. 2008;299(23):2777-2788.PubMedGoogle ScholarCrossref
Voight  BF, Peloso  GM, Orho-Melander  M,  et al.  Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study.  Lancet. 2012;380(9841):572-580.PubMedGoogle ScholarCrossref
Johannsen  TH, Frikke-Schmidt  R, Schou  J, Nordestgaard  BG, Tybjærg-Hansen  A.  Genetic inhibition of CETP, ischemic vascular disease and mortality, and possible adverse effects.  J Am Coll Cardiol. 2012;60(20):2041-2048.PubMedGoogle ScholarCrossref
Anderson  CD, Falcone  GJ, Phuah  CL,  et al; Global Lipids Genetics Consortium and International Stroke Genetics Consortium.  Genetic variants in CETP increase risk of intracerebral hemorrhage.  Ann Neurol. 2016;80(5):730-740.PubMedGoogle ScholarCrossref
Webb  TR, Erdmann  J, Stirrups  KE,  et al; Wellcome Trust Case Control Consortium; MORGAM Investigators; Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators.  Systematic evaluation of pleiotropy identifies 6 further loci associated with coronary artery disease.  J Am Coll Cardiol. 2017;69(7):823-836.PubMedGoogle ScholarCrossref
Ference  BA, Kastelein  JJP, Ginsberg  HN,  et al.  Association of genetic variants related to CETP inhibitors and statins with lipoprotein levels and cardiovascular risk.  JAMA. 2017;318(10):947-956.PubMedGoogle ScholarCrossref
Willer  CJ, Schmidt  EM, Sengupta  S,  et al; Global Lipids Genetics Consortium.  Discovery and refinement of loci associated with lipid levels.  Nat Genet. 2013;45(11):1274-1283.PubMedGoogle ScholarCrossref
Rader  DJ, deGoma  EM.  Future of cholesteryl ester transfer protein inhibitors.  Annu Rev Med. 2014;65:385-403.PubMedGoogle ScholarCrossref
Takahashi  K, Jiang  XC, Sakai  N,  et al.  A missense mutation in the cholesteryl ester transfer protein gene with possible dominant effects on plasma high density lipoproteins.  J Clin Invest. 1993;92(4):2060-2064.PubMedGoogle ScholarCrossref
Inazu  A, Jiang  XC, Haraki  T,  et al.  Genetic cholesteryl ester transfer protein deficiency caused by two prevalent mutations as a major determinant of increased levels of high density lipoprotein cholesterol.  J Clin Invest. 1994;94(5):1872-1882.PubMedGoogle ScholarCrossref
Nagano  M, Yamashita  S, Hirano  K,  et al.  Molecular mechanisms of cholesteryl ester transfer protein deficiency in Japanese.  J Atheroscler Thromb. 2004;11(3):110-121.PubMedGoogle ScholarCrossref
Zhong  S, Sharp  DS, Grove  JS,  et al.  Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels.  J Clin Invest. 1996;97(12):2917-2923.PubMedGoogle ScholarCrossref
Takeuchi  F, Isono  M, Katsuya  T,  et al.  Association of genetic variants influencing lipid levels with coronary artery disease in Japanese individuals.  PLoS One. 2012;7(9):e46385.PubMedGoogle ScholarCrossref
Cheng  CY, Yamashiro  K, Chen  LJ,  et al.  New loci and coding variants confer risk for age-related macular degeneration in East Asians.  Nat Commun. 2015;6:6063.PubMedGoogle ScholarCrossref
Nomura  A, Won  HH, Khera  AV,  et al.  Protein-truncating variants at the cholesteryl ester transfer protein gene and risk for coronary heart disease.  Circ Res. 2017;121(1):81-88.PubMedGoogle ScholarCrossref
Chen  Z, Lee  L, Chen  J,  et al.  Cohort profile: the Kadoorie Study of Chronic Disease in China (KSCDC).  Int J Epidemiol. 2005;34(6):1243-1249.PubMedGoogle ScholarCrossref
Chen  Z, Chen  J, Collins  R,  et al; China Kadoorie Biobank (CKB) Collaborative Group.  China Kadoorie Biobank of 0.5 million people: survey methods, baseline characteristics and long-term follow-up.  Int J Epidemiol. 2011;40(6):1652-1666.PubMedGoogle ScholarCrossref
Teslovich  TM, Musunuru  K, Smith  AV,  et al.  Biological, clinical and population relevance of 95 loci for blood lipids.  Nature. 2010;466(7307):707-713.PubMedGoogle ScholarCrossref
Soininen  P, Kangas  AJ, Würtz  P,  et al.  High-throughput serum NMR metabonomics for cost-effective holistic studies on systemic metabolism.  Analyst. 2009;134(9):1781-1785.PubMedGoogle ScholarCrossref
Millwood  IY, Bennett  DA, Walters  RG,  et al; China Kadoorie Biobank Collaborative Group.  A phenome-wide association study of a lipoprotein-associated phospholipase A2 loss-of-function variant in 90 000 Chinese adults.  Int J Epidemiol. 2016;45(5):1588-1599.PubMedGoogle ScholarCrossref
Burgess  S, Thompson  SG.  Use of allele scores as instrumental variables for Mendelian randomization.  Int J Epidemiol. 2013;42(4):1134-1144.PubMedGoogle ScholarCrossref
Momozawa  Y, Akiyama  M, Kamatani  Y,  et al.  Low-frequency coding variants in CETP and CFB are associated with susceptibility of exudative age-related macular degeneration in the Japanese population.  Hum Mol Genet. 2016;25(22):5027-5034.PubMedGoogle Scholar
Burgess  S, Davey Smith  G.  Mendelian randomization implicates high-density lipoprotein cholesterol–associated mechanisms in etiology of age-related macular degeneration.  Ophthalmology. 2017;124(8):1165-1174.PubMedGoogle ScholarCrossref
Davidson  M, Liu  SX, Barter  P,  et al.  Measurement of LDL-C after treatment with the CETP inhibitor anacetrapib.  J Lipid Res. 2013;54(2):467-472.PubMedGoogle ScholarCrossref
Holmes  MV, Millwood  IY, Kartsonaki  C,  et al.  Serum NMR metabolomics identifies similar associations of lipoproteins and lipids with risk of myocardial infarction and ischemic stroke but not with hemorrhagic stroke.  Circulation. 2016;134:A14009.Google Scholar
Holmes  MV, Asselbergs  FW, Palmer  TM,  et al; UCLEB Consortium.  Mendelian randomization of blood lipids for coronary heart disease.  Eur Heart J. 2015;36(9):539-550.PubMedGoogle ScholarCrossref
White  J, Swerdlow  DI, Preiss  D,  et al.  Association of lipid fractions with risks for coronary artery disease and diabetes.  JAMA Cardiol. 2016;1(6):692-699.PubMedGoogle ScholarCrossref
Rohatgi  A, Khera  A, Berry  JD,  et al.  HDL cholesterol efflux capacity and incident cardiovascular events.  N Engl J Med. 2014;371(25):2383-2393.PubMedGoogle ScholarCrossref
Zanoni  P, Khetarpal  SA, Larach  DB,  et al; CHD Exome+ Consortium; CARDIoGRAM Exome Consortium; Global Lipids Genetics Consortium.  Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease.  Science. 2016;351(6278):1166-1171.PubMedGoogle ScholarCrossref
Chen  W, Stambolian  D, Edwards  AO,  et al; Complications of Age-Related Macular Degeneration Prevention Trial Research Group.  Genetic variants near TIMP3 and high-density lipoprotein–associated loci influence susceptibility to age-related macular degeneration.  Proc Natl Acad Sci U S A. 2010;107(16):7401-7406.PubMedGoogle ScholarCrossref
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.


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.