Abstract
Cholesteryl ester transfer protein (CETP) is an important modulator of high density lipoprotein cholesterol in humans and thus considered to be a therapeutic target for preventing cardiovascular disease. The gene encoding CETP has been shown to be highly variable, with multiple single nucleotide polymorphisms responsible for altering both its transcription and sequence. Examining nine missense variants of CETP, we found some had significant associations with CETP mass and high density lipoprotein cholesterol levels. Two variants, Pro-373 and Gln-451, appear to be more stable in vivo, an observation mirrored by partial proteolysis studies performed in vitro. Because these naturally occurring variant proteins are potentially present in clinical populations that will be treated with CETP inhibitors, all commonly occurring haplotypes were tested to determine whether the proteins they encode could be inhibited by torcetrapib, a compound currently in clinical trials in combination with atorvastatin. Torcetrapib behaved similarly with all variants, with no significant differences in inhibition.
Highlights
Despite tremendous advances in lifestyle interventions and drug treatments, cardiovascular disease remains the most significant cause of mortality in the developed world
Because these naturally occurring variant proteins are potentially present in clinical populations that will be treated with Cholesteryl ester transfer protein (CETP) inhibitors, all commonly occurring haplotypes were tested to determine whether the proteins they encode could be inhibited by torcetrapib, a compound currently in clinical trials in combination with atorvastatin
Clinical populations in which both High density lipoprotein cholesterol (HDL-C), an indirect measure of CETP activity, and CETP mass had been determined provide a valuable tool for estimating the specific activity of the protein under physiological conditions
Summary
Clinical Trials—The ACCESS (Atorvastatin Comparative Cholesterol Efficacy and Safety Study) clinical trial from which 2913 DNA samples were genotyped has been described previously [11]. Data from two smaller Phase II clinical trials in which torcetrapib was examined were used because of the availability of baseline CETP mass measurements. DNA preparation was as described previously [8]. TaqMan assays obtained from ABI were used for all genotyping except for I405V and R451Q, which were analyzed by fluorescence polarization as described previously [8]. In Vitro Methods—Wild type CETP was cloned via PCR amplification of cDNA from HepG2 cells and inserted into a modified version of pSecTag2/Hygro (Invitrogen) that produces amino-terminal His and V5 tags.
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