Cholesteryl ester transfer protein variants have differential stability but uniform inhibition by torcetrapib.
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.
Lloyd
David B
DB
Department of Discovery Pharmacogenomics, Pfizer Global Research and Development, Groton, Connecticut 06340, USA.
Lira
Maruja E
ME
Wood
Linda S
LS
Durham
L Kathryn
LK
Freeman
Thomas B
TB
Preston
Gregory M
GM
Qiu
Xiayang
X
Sugarman
Eliot
E
Bonnette
Peter
P
Lanzetti
Anthony
A
Milos
Patrice M
PM
Thompson
John F
JF
D000328:Adult; D000368:Aged; D002318:Cardiovascular Diseases / Q000235:genetics; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics*; D002460:Cell Line; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000378:metabolism; D018360:Crystallography, X-Ray; D018076:DNA, Complementary / Q000378:metabolism; D005260:Female; D015894:Genome, Human; D005973:Glutamine / Q000737:chemistry; D006023:Glycoproteins / Q000737:chemistry* / Q000235:genetics*; D006801:Humans; D020128:Inhibitory Concentration 50; D008075:Lipoproteins, HDL / Q000737:chemistry; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D011392:Proline / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D011804:Quinolines / Q000494:pharmacology*; D014158:Transcription, Genetic
C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D018076:DNA, Complementary; D006023:Glycoproteins; D008075:Lipoproteins, HDL; D011804:Quinolines; D005973:Glutamine; C483909:torcetrapib; D011392:Proline