Point: The Relationship between Cholesteryl Ester Transfer Protein and Cardiovascular Risk

Abstract

There is overwhelming epidemiologic evidence that increased concentrations of LDL cholesterol (LDL-C)2) and low concentrations of HDL cholesterol (HDL-C) are independently associated with increased cardiovascular risk. Furthermore, the risk associated with low HDL-C concentrations persists even when LDL-C has been reduced to concentrations <1.8 mmol/L (<70 mg/dL) by treatment with statins (1). It is logical, therefore, to investigate strategies designed to redistribute cholesterol away from atherogenic LDL particles in favor of potentially protective HDL particles. One such approach is to inhibit the cholesteryl ester transfer protein (CETP), a protein in human plasma that transfers cholesterol from the HDL to non-HDL fractions (2). CETP activity is prominent in humans, nonhuman primates, and rabbits (2). In contrast, there is little or no CETP activity in the plasma of most other species, including rodents (2). In general, species with CETP activity in plasma are susceptible to the development of atherosclerosis, whereas those lacking the protein tend to be naturally resistant. Furthermore, inhibiting CETP in rabbits markedly reduces the development of atherosclerosis, regardless of whether the CETP inhibition is achieved by genetic manipulation (3), by vaccination against CETP (4), or by chemical inhibitors of CETP (5). ### CETP POLYMORPHISMS AND SUSCEPTIBILITY TO ATHEROSCLEROSIS IN HUMANS Several polymorphisms of the human CETP (cholesteryl ester transfer protein, plasma) gene have been reported (2). Although many of these studies have demonstrated associations between CETP single-nucleotide polymorphisms and small changes in plasma CETP and HDL concentrations, the relationship between these polymorphisms and susceptibility to atherosclerosis is variable (2). A recent metaanalysis of 92 studies involving 113 833 participants (6) concluded, however, that those CETP genotypes associated with inhibition of CETP activity show an inverse association with coronary risk and that the magnitude of the reduction of coronary events was consistent with the reductions in risk for equivalent increases in HDL-C concentration as predicted from …