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Review | Clinician's Corner

Association of Cholesteryl Ester Transfer Protein Genotypes With CETP Mass and Activity, Lipid Levels, and Coronary Risk

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. doi:10.1001/jama.299.23.2777.
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Published online

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.

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Figure 1. Study Flow Diagram
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CETP indicates cholesteryl ester transfer protein.
aBecause these studies tended to be smaller, they comprised a total of only approximately 3% of the overall number of coronary cases included in this review, and a total of only approximately 8% of the overall number of participants included in the analysis of lipid concentrations.

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Figure 2. Associations of CETP Genotypes With CETP Phenotypes and Lipid Levels
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CETP indicates cholesteryl ester transfer protein; CI, confidence interval; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. To convert apolipoproteins A-I and B to mg/dL, divide by 0.01; to convert HDL-C and LDL-C to mg/dL, divide by 0.0259; and to convert triglyercides to mg/dL, divide by 0.0113. Assessment of heterogeneity: I2 (95% CI) for CETP mass, CETP activity, HDL-C, apolipoprotein A-I, LDL-C, apolipoprotein B, and triglycerides, respectively, were 66% (39%-81%), 71% (44%-86%), 75% (69%-80%), 66% (46%-78%), 51% (32%-65%), 14% (0%-51%), and 49% (30%-62%) for TaqIB; 0% (0%-71%), NA*, 56% (33%-71%), 0% (0%-68%), 24% (0%-58%), 16% (0%-60%), and 0% (0%-49%) for I405V; and 71% (17%-90%), NA*, 37% (0%-61%), 36% (0%-78%), 29% (0%-63%), 0% (0%-90%), and 0% (0%-57%) for −629C>A. NA* indicates I2 statistics were not calculated when there were only 2 studies.
aPooled estimates calculated by random-effects models. Estimates calculated by fixed-effect models are shown in eTable 3.
bStandardized mean differences.
cCalculated with reference to the weighted mean level of each marker in common homozygotes.

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Figure 3. Mean Differences in HDL-C Levels Associated With CETP Genotypes, Grouped by Recorded Study Characteristics
Graphic Jump Location

CETP indicates cholesteryl ester transfer protein; CI, confidence interval; HDL-C, high-density lipoprotein cholesterol. To convert HDL-C to mg/dL, divide by 0.0259. Sizes of data markers are proportional to the inverse of the variance of the weighted mean difference. For sex and ethnicity, studies may have contributed data to more than 1 category. Overall estimates were calculated using random-effects models (fixed-effect estimates are provided in eTable 3). Several recorded characteristics explained part of the heterogeneity observed, including ethnicity (P = .008), population source (P = .04), and data source (P < .001) for TaqIB; study size (P = .02) for I405V; and ethnicity (P < .001) and population source (P = .007) for −629C>A.

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Figure 4. CETP Genotypes and Coronary Risk, Grouped by Recorded Study Characteristics
Graphic Jump Location

CETP indicates cholesteryl ester transfer protein; CI, confidence interval. Sizes of data markers are proportional to the inverse of the variance of the loge odds ratio. For ethnicity, source of controls, and outcome assessed, studies may have contributed data to more than 1 category. For ethnicity, results are not presented for 4 studies of TaqIB and 2 studies of I405V and −629C>A that were predominantly based in nonwhite, non−East Asian individuals. For outcome assessed in TaqIB, results are not presented for 1 study that did not provide genotype frequencies separately for cases of myocardial infarction and coronary stenosis. Assessment of heterogeneity: TaqIB (I2 = 18%; 95% CI, 0%-45%), I405V (I2 = 39%; 95% CI, 0%-66%), or −629C>A (I2 = 32%; 95% CI, 0%-62%). Observed heterogeneity could be partially explained by study size (P = .01) and data source (P = .003) for TaqIB and by source of controls (P < .001) for I405V (other comparisons P = .05 for each). Overall estimates were calculated using random-effects models; those calculated using fixed-effect models were 0.96 (95% CI, 0.93-0.99) for TaqIB, 0.95 (95% CI, 0.92-0.99) for I405V, and 0.95 (95% CI, 0.91-0.99) for −629C>A.

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Figure 5. Observed Per-Allele Odds Ratios for Coronary Disease With CETP Variants vs Odds Ratios Derived From Available Prospective Studies of HDL-C Levels
Graphic Jump Location

CETP indicates cholesteryl ester transfer protein; CI, confidence interval; HDL-C, high-density lipoprotein cholesterol. Sizes of data markers are proportional to the inverse of the variance of the loge risk estimate. χ2 Test for difference: P = .11 for TaqIB, P = .72 for I405V, and P = .19 for −629C>A.
aPer-allele odds ratio for coronary disease as shown in Figure 4.
bHazard ratios for coronary heart disease calculated by using risk estimates from 153 798 participants in 61 studies1 for an increase in usual HDL-C levels equal to those observed per allele for TaqIB, I405V, and −629C>A (Figure 2).

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