Separating the Mechanism-Based and Off-Target Actions of Cholesteryl Ester Transfer Protein Inhibitors With CETP Gene Polymorphisms
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Separating the Mechanism-Based and Off-Target Actions of Cholesteryl Ester Transfer Protein Inhibitors With CETP Gene Polymorphisms

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Separating the Mechanism-Based and Off-Target Actions of Cholesteryl Ester Transfer Protein Inhibitors With CETP Gene Polymorphisms

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dc.contributor.author Sofat, Reecha
dc.contributor.author Hingorani, Aroon D.
dc.contributor.author Smeeth, Liam
dc.contributor.author Humphries, Steve E.
dc.contributor.author Talmud, Philippa J.
dc.contributor.author Cooper, Jackie
dc.contributor.author Shah, Tina
dc.contributor.author Sandhu, Manjinder S.
dc.contributor.author Ricketts, Sally L.
dc.contributor.author Boekholdt, S. Matthijs
dc.contributor.author Wareham, Nicholas
dc.contributor.author Khaw, Kay Tee
dc.contributor.author Kumari, Meena
dc.contributor.author Kivimaki, Mika
dc.contributor.author Marmot, Michael
dc.contributor.author Asselbergs, Folkert W.
dc.contributor.author van der Harst, Pim
dc.contributor.author Dullaart, Robin P.F.
dc.contributor.author Navis, Gerjan
dc.contributor.author van Veldhuisen, Dirk J.
dc.contributor.author Van Gilst, Wiek H.
dc.contributor.author Thompson, John F.
dc.contributor.author McCaskie, Pamela
dc.contributor.author Palmer, Lyle J.
dc.contributor.author Arca, Marcello
dc.contributor.author Quagliarini, Fabiana
dc.contributor.author Gaudio, Carlo
dc.contributor.author Cambien, François
dc.contributor.author Nicaud, Viviane
dc.contributor.author Poirer, Odette
dc.contributor.author Gudnason, Vilmundur
dc.contributor.author Isaacs, Aaron
dc.contributor.author Witteman, Jacqueline C.M.
dc.contributor.author van Duijn, Cornelia M.
dc.contributor.author Pencina, Michael
dc.contributor.author Vasan, Ramachandran S.
dc.contributor.author D'Agostino, Ralph B.
dc.contributor.author Ordovas, Jose M.
dc.contributor.author Li, Tricia Y.
dc.contributor.author Kakko, Sakari
dc.contributor.author Kauma, Heikki
dc.contributor.author Savolainen, Markku J.
dc.contributor.author Kesäniemi, Antero
dc.contributor.author Sandhofer, Anton
dc.contributor.author Paulweber, Bernhard
dc.contributor.author Sorlí Guerola, José Vicente
dc.contributor.author Goto, Akimoto
dc.contributor.author Yokoyama, Shinji
dc.contributor.author Okumura, Kenji
dc.contributor.author Horne, Benjamin D.
dc.contributor.author Packard, Chris
dc.contributor.author Freeman, Dilys
dc.contributor.author Ford, Ian
dc.contributor.author Sattar, Naveed
dc.contributor.author McCormack, Valerie
dc.contributor.author Lawlor, Debbie A.
dc.contributor.author Ebrahim, Shah
dc.contributor.author Smith, George Davey
dc.contributor.author Kastelein, John J.P.
dc.contributor.author Deanfield, John
dc.contributor.author Casas, Juan P.
dc.date.accessioned 2011-06-02T09:27:56Z
dc.date.available 2011-06-02T09:27:56Z
dc.date.issued 2010
dc.identifier.uri http://hdl.handle.net/10550/18830
dc.description.abstract Background— Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the hypertensive effect resulted from CETP inhibition or an off-target action of torcetrapib has been debated. We hypothesized that common single-nucleotide polymorphisms in the CETP gene could help distinguish mechanism-based from off-target actions of CETP inhibitors to inform on the validity of CETP as a therapeutic target. Methods and Results— We compared the effect of CETP single-nucleotide polymorphisms and torcetrapib treatment on lipid fractions, blood pressure, and electrolytes in up to 67 687 individuals from genetic studies and 17 911 from randomized trials. CETP single-nucleotide polymorphisms and torcetrapib treatment reduced CETP activity and had a directionally concordant effect on 8 lipid and lipoprotein traits (total, low-density lipoprotein, and HDL cholesterol; HDL2; HDL3; apolipoproteins A-I and B; and triglycerides), with the genetic effect on HDL cholesterol (0.13 mmol/L, 95% confidence interval [CI] 0.11 to 0.14 mmol/L) being consistent with that expected of a 10-mg dose of torcetrapib (0.13 mmol/L, 95% CI 0.10 to 0.15). In trials, 60 mg of torcetrapib elevated systolic and diastolic blood pressure by 4.47 mm Hg (95% CI 4.10 to 4.84 mm Hg) and 2.08 mm Hg (95% CI 1.84 to 2.31 mm Hg), respectively. However, the effect of CETP single-nucleotide polymorphisms on systolic blood pressure (0.16 mm Hg, 95% CI –0.28 to 0.60 mm Hg) and diastolic blood pressure (–0.04 mm Hg, 95% CI –0.36 to 0.28 mm Hg) was null and significantly different from that expected of 10 mg of torcetrapib. Conclusions— Discordance in the effects of CETP single-nucleotide polymorphisms and torcetrapib treatment on blood pressure despite the concordant effects on lipids indicates the hypertensive action of torcetrapib is unlikely to be due to CETP inhibition or shared by chemically dissimilar CETP inhibitors. Genetic studies could find a place in drug-development programs as a new source of randomized evidence for drug-target validation in humans. en
dc.language.iso en en
dc.relation http://circ.ahajournals.org/cgi/reprint/121/1/52 en
dc.source SOFAT, Reecha ; Hingorani, Aroon D. ; Smeeth, Liam ; Humphries, Steve E. ; Talmud, Philippa J. ; Cooper, Jackie ; Shah, Tina ; Sandhu, Manjinder S. ; Ricketts, Sally L. ; Boekholdt, S. Matthijs ; Wareham, Nicholas ; Khaw Kay, Tee ; Kumari, Meena ; Kivimaki, Mika ; Marmot, Michael ; Asselbergs, Folkert W. ; Van der Harst, Pim ; Dullaart, Robin P.F. ; Navis, Gerjanvan ; Veldhuisen, Dirk J. ; Van Gilst, Wiek H. ; Thompson, John F. ; McCaskie, Pamela ; Palmer, Lyle J. ; Arca, Marcello ; Quagliarini, Fabiana ; Gaudio, Carlo ; Cambien, François ; Nicaud, Viviane ; Poirer, Odette ; Gudnason, Vilmundur ; Isaacs, Aaron ; Witteman, Jacqueline C.M. ; van Duijn, Cornelia M. , Pencina, Michael ; Vasan, Ramachandran S. ; D'Agostino, Ralph B. ; Ordovas, Jose ; Li, Tricia Y. ; Kakko, Sakari ; Kauma, Heikki ; Savolainen, Markku J. ; Kesäniemi, Antero ; Sandhofer, Anton ; Paulweber, Bernhard ; Sorli Guerola, Jose Vicente ; Goto, Akimoto ; Yokoyama, Shinji ; Okumura, Kenji ; Horne, Benjamin D. ; Packard, Chris ; Freeman, Dilys ; Ford, Ian ; Sattar, Naveed ; McCormack, Valerie ; Lawlor, Debbie A. ; Ebrahim, Shah ; Smith, George Davey ; Kastelein, John J.P. ; Deanfield, John ; Casas, Juan P., 2010, Separating the Mechanism-Based and Off-Target Actions of Cholesteryl Ester Transfer Protein Inhibitors With CETP Gene Polymorphisms, Circulation, vol. 121, no. 1, p. 52-62 en
dc.subject Genetics ; Pharmacology ; Epidemiology ; High-density lipoproteins en
dc.title Separating the Mechanism-Based and Off-Target Actions of Cholesteryl Ester Transfer Protein Inhibitors With CETP Gene Polymorphisms en
dc.type info:eu-repo/semantics/article en
dc.type info:eu-repo/semantics/publishedVersion en
dc.subject.unesco UNESCO::CIENCIAS MÉDICAS en
dc.subject.unesco UNESCO::CIENCIAS MÉDICAS ::Medicina interna en
dc.identifier.doi 10.1161/CIRCULATIONAHA.109.865444 en
dc.description.private Sorli Guerola, Jose Vicente, Jose.Sorli@uv.es en
dc.identifier.idgrec 055068 en

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