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J. Biol. Chem., Vol. 280, Issue 15, 14918-14922, April 15, 2005

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Cholesteryl Ester Transfer Protein Variants Have Differential Stability but Uniform Inhibition by Torcetrapib^*

David B. Lloyd, Maruja E. Lira, Linda S. Wood, L. Kathryn Durham, Thomas B. Freeman¶, Gregory M. Preston¶, Xiayang Qiu||, Eliot Sugarman**, Peter Bonnette**, Anthony Lanzetti||, Patrice M. Milos, and John F. Thompson

From the Departments of Discovery Pharmacogenomics, Clinical Biostatistics, ^¶Translational Biomarkers, ^||Protein Expression and Structure, and ^**Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton, Connecticut 06340

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.

Received for publication, January 14, 2005

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: MS8118D-3069, Eastern Point Rd., Pfizer Global Research and Development, Groton, CT 06340. Tel.: 860-441-5139; Fax: 860-441-0436; E-mail: john.f.thompson{at}pfizer.com.

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