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Alexander Thompson, MRes, MPhil; Emanuele Di Angelantonio, MD, MSc; Nadeem Sarwar, MRPharmS, MPhil; Sebhat Erqou, MD, MPhil; Danish Saleheen, MBBS, MPhil; Robin P. F. Dullaart, MD, PhD; Bernard Keavney, MD, FRCP; Zheng Ye, PhD; John Danesh, DPhil, FRCP

JAMA. 2008;299(23):2777-2788.

Context  The importance of the cholesteryl ester transfer protein (CETP) pathway in coronary disease is uncertain. Study of CETP genotypes can help better understand the relevance of this pathway to lipid metabolism and disease risk.

Objective  To assess associations of CETP genotypes with CETP phenotypes, lipid levels, and coronary risk.

Data Sources  Studies published between January 1970 and January 2008 were identified through computer-based and manual searches using MEDLINE, EMBASE, BIOSIS, Science Citation Index, and the Chinese National Knowledge Infrastructure Database. Previously unreported studies were sought through correspondence with investigators.

Study Selection  Relevant studies related principally to 3 common (TaqIB [rs708272], I405V [rs5882], and –629C>A [rs1800775]) and 3 uncommon (D442G [rs2303790], –631C>A [rs1800776], and R451Q [rs1800777]) CETP polymorphisms.

Data Extraction  Information on CETP genotypes, CETP phenotypes, lipid levels, coronary disease, and study characteristics was abstracted from publications, supplied by investigators, or both.

Results  Ninety-two studies had data on CETP phenotypes, lipid levels, or both in 113 833 healthy participants, and 46 studies had data on 27 196 coronary cases and 55 338 controls. For each A allele inherited, individuals with the TaqIB polymorphism had lower mean CETP mass (–9.7%; 95% confidence interval [CI], –11.7% to –7.8%), lower mean CETP activity (–8.6%; 95% CI, –13.0% to –4.1%), higher mean high-density lipoprotein cholesterol (HDL-C) concentrations (4.5%; 95% CI, 3.8%-5.2%), and higher mean apolipoprotein A-I concentrations (2.4%; 95% CI, 1.6%-3.2%). The pattern of findings was very similar with the I405V and –629C>A polymorphisms. The combined per-allele odds ratios (ORs) for coronary disease were 0.95 (95% CI, 0.92-0.99) for TaqIB, 0.94 (95% CI, 0.89-1.00) for I405V, and 0.95 (95% CI, 0.91-1.00) for –629C>A.

Conclusions  Three CETP genotypes that are associated with moderate inhibition of CETP activity (and, therefore, modestly higher HDL-C levels) show weakly inverse associations with coronary risk. The ORs for coronary disease were compatible with the expected reductions in risk for equivalent increases in HDL-C concentration in available prospective studies.

Author Affiliations: Department of Public Health and Primary Care, University of Cambridge, Cambridge, England (Drs Di Angelantonio, Erqou, Saleheen, Ye, and Danesh, and Messrs Thompson and Sarwar); Department of Endocrinology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (Dr Dullaart); and Institute of Human Genetics, Newcastle University, Newcastle, England (Dr Keavney).

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