Application of Genetic Epidemiology to CETP (Cholesteryl Ester Transfer Protein) Concentration and Risk of Cardiovascular Disease
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- cholesteryl ester transfer proteins
- genome-wide association study
See Article by Blauw et al
In the current issue of Circulation: Genomic and Precision Medicine, the primary aim of Blauw et al1 was to assess the causal effects of variation in circulating CETP (cholesteryl ester transfer protein) levels on the risk of cardiovascular disease. The approach used was the genetic epidemiological technique Mendelian randomization that was preceded by the systematic identification (by a genome-wide association study) of genetic variants associated with CETP levels that could be used as instruments in the Mendelian randomization approach to test for association with cardiovascular disease.
Cholesteryl ester transfer protein, also known as plasma lipid transfer protein, facilitates the transfer of cholesteryl esters from HDL (high-density lipoprotein) to V/LDL (low- and very-low-density lipoprotein) in exchange for triglycerides. Thus CETP contributes to the ratio of HDL to V/LDL, to the atherosclerotic profile, and to the risk of cardiovascular disease. Observational data indicate an association of increased CETP levels with increased risk of cardiovascular disease.2 This has lead to the development of CETP inhibitors and 4 published phase III clinical trials testing the effect of CETP inhibition on increasing HDL-cholesterol and decreasing non-HDL-cholesterol levels, with the primary end point being a reduction of cardiovascular disease risk. These clinical trials have had mixed results with only one (anacetrapib) meeting its primary end point, a 9% reduction in the incidence of major coronary events.3 At the midpoint of this study, there was an 18% reduction in circulating non-HDL-cholesterol levels and 25% reduction in apolipoprotein B (marker of V/LDL) levels in those exposed to anacetrapib with a considerably higher (104%) increase in HDL-cholesterol (a pattern consistent with other CETP inhibitors4–6). Owing to its high lipophilicity anacetrapib accumulates in adipose tissue.7 Although no safety problems have been reported in clinical studies, anacetrapib …