Landmark JAMA meta-analysis of over 190,000 people finds CETP genotypes that inhibit CETP activity only weakly reduce coronary risk (JAMA 2008)

Original title: Association of cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels, and coronary risk

JAMA · 18 June 2008 · 9

Thompson A, Di Angelantonio E, Sarwar N, Erqou S, Saleheen D, Dullaart RP, Keavney B, Ye Z, Danesh J

This meta-analysis assessed associations of CETP genotypes with CETP phenotypes, lipid levels, and coronary risk, searching studies published between January 1970 and January 2008 across five databases and through correspondence with investigators, covering three common (TaqIB, I405V, -629C>A) and three uncommon (D442G, -631C>A, R451Q) CETP polymorphisms. Ninety-two studies provided data on CETP phenotypes or lipid levels in 113,833 healthy participants, and 46 studies provided data on 27,196 coronary cases and 55,338 controls. Per A allele, TaqIB carriers had lower mean CETP mass (-9.7%), lower CETP activity (-8.6%), higher HDL-cholesterol (4.5%), and higher apolipoprotein A-I (2.4%), with similar patterns for I405V and -629C>A. Combined per-allele odds ratios for coronary disease were only weakly protective: 0.95 for TaqIB, 0.94 for I405V, and 0.95 for -629C>A. The authors conclude these CETP genotypes show weakly inverse coronary risk associations compatible with the expected benefit of their modest HDL-cholesterol increases.

Original abstract

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.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.