Novel variants in human and monkey CETP.
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.
Lloyd
David B
DB
Department of Pharmacogenomics, Pfizer Global Research and Development, Eastern Point Road, MS8118D-3069, Groton, CT 06340, USA.
Reynolds
Jennifer M
JM
Cronan
Melissa T
MT
Williams
Suzanne P
SP
Lira
Maruja E
ME
Wood
Linda S
LS
Knight
Delvin R
DR
Thompson
John F
JF
D001741:Black or African American / Q000235:genetics; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000097:blood; D002986:Clinical Trials as Topic; D014644:Genetic Variation; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D006801:Humans; D008252:Macaca fascicularis / Q000097:blood*; D008969:Molecular Sequence Data; D002679:Pan troglodytes; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011804:Quinolines / Q000494:pharmacology; D016415:Sequence Alignment; D044465:White People / Q000235:genetics
C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D006023:Glycoproteins; D011804:Quinolines; C483909:torcetrapib