CETP genotypes, HDL cholesterol and coronary risk

A meta-analysis including data from nearly 114,000 healthy subjects and over 27,000 coronary cases reported in the Journal of the American Medical Association showed an association between three genotypes of cholesteryl ester transfer protein (CETP), moderate increases in high-density lipoprotein (HDL) cholesterol and coronary risk. These data suggest that the presence of these CETP genetic variants may confer slightly reduced coronary risk. The study was reviewed by HDL Forum Editor, Professor John Chapman.

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;299:2777-88.

The authors included studies published between 1970 and 2008 on CETP genotype associations with data on CETP mass, CETP activity, levels of HDL cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides or apolipoproteins A-I and B, or with risk of myocardial infarction or angiographic coronary stenosis. Only lipid data from healthy individuals (i.e. without known coronary or other diseases or clinical lipid abnormalities) were included. Data were collected on three common (TaqIB, I405V and -629C>A) and three less common (D442G, -631C>A and R451Q) CETP genotypes.

In total, 92 studies with data on CETP phenotypes and/or lipid levels in 113,833 healthy subjects and 46 studies with data on 27,196 coronary cases and 55,338 controls were identified. Most of these studies related to the three common CETP genotypes.

The three common CETP genotypes were associated with moderate inhibition of CETP activity and modest increases in HDL cholesterol, as well as a weak inverse association with coronary risk.

For carriers of the TaqIB variant, each A allele inherited was associated with about 5-10% lower CETP mass and activity, 3-5% higher mean HDL cholesterol and apoA-I levels, marginally lower LDL cholesterol and apoB levels and about 2% lower triglyceride levels (Table 1) compared with individuals who were homozygous for common alleles. Results were similar for the other two common alleles (I405V and -629C>A).

Table 1. Association of TaqIB genotype with CETP mass, activity and lipid levels

 Total no. of studiesTotal no. of subjects% mean difference (95%CI)
per A allele*
CETP mass 13 4603 -9.7% (-11.7 to -7.8%)
CETP activity 9 4532 -8.6% (-13.0 to -4.1%)
HDL cholesterol 72 68134 +4.5% (3.8 to 5.2%)
ApoA-I 21 26712 +2.4% (1.6 to 3.2%)
LDL cholesterol 50 53879 -0.9% (-1.6 to -0.3%)
ApoB 16 23594 -0.5% (-1.1 to 0.1%)
Triglycerides 56 57372 -2.0% (-3.2 to -0.7%)

* Compared with the weighted mean of each marker in common homozygotes

The combined odds ratio for coronary disease was 0.95 (95% CI, 0.92-0.99) per A allele of the TaqIB variant, 0.94 (95%CI, 0.89 to 1.00) per G allele of the I405V variant and 0.95 (95%CI, 0.91-1.00) per A allele of the -629C>A allele. The researchers did indicate that there was possible modest heterogeneity among the available studies for each of these polymorphisms which may have influenced these results.

The size of the per allele-risk reductions was consistent with that expected on the basis of associations observed between HDL cholesterol and coronary risk in prospective studies.1 The analysis findings are also consistent with the genome wide analyses for cardiovascular risk genes recently published in Nature.2
The authors concluded that their findings warrant the need for larger studies to evaluate the impact that single CETP variants have on coronary risk, also taking into account lifestyle factors.

Reference

1. Prospective Studies Collaboration, Lewington S, Whitlock G, Clark R et al. 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;370:1829-39.
2. Chien KR. Regenerative medicine and human models of human disease. Nature 2008;453:302-5. Published online 14 May 2008.

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