Torcetrapib
Two novel CETP gene variants are found in humans, and torcetrapib inhibits both variant and normal CETP equally (Biochim Biophys Acta 2005)
Original title: Novel variants in human and monkey CETP
To better characterize CETP genetic variation, researchers resequenced the CETP promoter and exonic DNA in 189 individuals with extreme HDL cholesterol or age, identifying two novel amino acid variants (V-12D and Y361C) plus expressing a previously unstudied variant (R137W). The D-12 variant was not secreted and showed no detectable activity in cells, while C361 and W137 retained near-normal cholesteryl ester transfer activity when purified but were less well secreted than wild type. Torcetrapib, a CETP inhibitor then in clinical development with atorvastatin, inhibited wild-type CETP and the W137 and C361 variants uniformly. Resequencing DNA from nine cynomolgus monkeys found numerous intronic and silent SNPs plus two variable amino acids; genotyping these amino-acid-altering SNPs in 29 monkeys found no significant association with HDL cholesterol levels, and three monkey SNPs matched human SNPs, all at CpG sites.
Original abstract
Variation in CETP has been shown to play an important role in HDL-C levels and cardiovascular disease. To better characterize this variation, the promoter and exonic DNA for CETP was resequenced in 189 individuals with extreme HDL-C or age. Two novel amino acid variants were found in humans (V-12D and Y361C) and an additional variant (R137W) not previously studied in vitro were expressed. D-12 was not secreted and had no detectable activity in cells. C361 and W137 retained near normal amounts of cholesteryl ester transfer activity when purified but were less well secreted than wild type. Torcetrapib, a CETP inhibitor in clinical development with atorvastatin, was found to have a uniform effect on inhibition of wild type CETP versus W137 or C361. In addition, the level of variation in other species was assessed by resequencing DNA from nine cynomolgus monkeys. Numerous intronic and silent SNPs were found as well as two variable amino acids. The amino acid altering SNPs were genotyped in 29 monkeys and not found to be significantly associated with HDL-C levels. Three SNPs found in monkeys were identical to three found in humans with these SNPs all occurring at CpG sites.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.