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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Separating the mechanism-based and off-target actions of CETP-inhibitors using <italic>CETP</italic> gene polymorphisms</title><author><name sortKey="Sofat, Reecha" sort="Sofat, Reecha" uniqKey="Sofat R" first="Reecha" last="Sofat">Reecha Sofat</name><affiliation><nlm:aff id="A1"> Centre for Clinical Pharmacology, Department of Medicine, University College London, Rayne Building, 5 University Street, London, WC1E 6JF</nlm:aff></affiliation></author><author><name sortKey="Hingorani, Aroon D" sort="Hingorani, Aroon D" uniqKey="Hingorani A" first="Aroon D" last="Hingorani">Aroon D. Hingorani</name><affiliation><nlm:aff id="A1"> Centre for Clinical Pharmacology, Department of Medicine, University College London, Rayne Building, 5 University Street, London, WC1E 6JF</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Department of Epidemiology and Public Health, 1-19 Torrington Place, University College London, WC1E 6BT</nlm:aff></affiliation></author><author><name sortKey="Smeeth, Liam" sort="Smeeth, Liam" uniqKey="Smeeth L" first="Liam" last="Smeeth">Liam Smeeth</name><affiliation><nlm:aff id="A3"> Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT</nlm:aff></affiliation></author><author><name sortKey="Humphries, Steve E" sort="Humphries, Steve E" uniqKey="Humphries S" first="Steve E" last="Humphries">Steve E. Humphries</name><affiliation><nlm:aff id="A4"> Centre for Cardiovascular Genetics, University College London Rayne Building, 5 University Street, London, WC1E 6JF</nlm:aff></affiliation></author><author><name sortKey="Talmud, Philippa J" sort="Talmud, Philippa J" uniqKey="Talmud P" first="Philippa J" last="Talmud">Philippa J. Talmud</name><affiliation><nlm:aff id="A4"> Centre for Cardiovascular Genetics, University College London Rayne Building, 5 University Street, London, WC1E 6JF</nlm:aff></affiliation></author><author><name sortKey="Cooper, Jackie" sort="Cooper, Jackie" uniqKey="Cooper J" first="Jackie" last="Cooper">Jackie Cooper</name><affiliation><nlm:aff id="A4"> Centre for Cardiovascular Genetics, University College London Rayne Building, 5 University Street, London, WC1E 6JF</nlm:aff></affiliation></author><author><name sortKey="Shah, Tina" sort="Shah, Tina" uniqKey="Shah T" first="Tina" last="Shah">Tina Shah</name><affiliation><nlm:aff id="A1"> Centre for Clinical Pharmacology, Department of Medicine, University College London, Rayne Building, 5 University Street, London, WC1E 6JF</nlm:aff></affiliation></author><author><name sortKey="Sandhu, Manjinder S" sort="Sandhu, Manjinder S" uniqKey="Sandhu M" first="Manjinder S" last="Sandhu">Manjinder S. Sandhu</name><affiliation><nlm:aff id="A5"> Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge</nlm:aff></affiliation></author><author><name sortKey="Ricketts, Sally L" sort="Ricketts, Sally L" uniqKey="Ricketts S" first="Sally L" last="Ricketts">Sally L. Ricketts</name><affiliation><nlm:aff id="A5"> Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge</nlm:aff></affiliation></author><author><name sortKey="Boekholdt, S Matthijs" sort="Boekholdt, S Matthijs" uniqKey="Boekholdt S" first="S Matthijs" last="Boekholdt">S Matthijs Boekholdt</name><affiliation><nlm:aff id="A5"> Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge</nlm:aff></affiliation><affiliation><nlm:aff id="A31"> MRC Centre of Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, UK</nlm:aff></affiliation></author><author><name sortKey="Wareham, Nicholas" sort="Wareham, Nicholas" uniqKey="Wareham N" first="Nicholas" last="Wareham">Nicholas Wareham</name><affiliation><nlm:aff id="A6"> MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge UK</nlm:aff></affiliation></author><author><name sortKey="Khaw, Kay Tee" sort="Khaw, Kay Tee" uniqKey="Khaw K" first="Kay Tee" last="Khaw">Kay Tee Khaw</name><affiliation><nlm:aff id="A7"> Department of Clinical Gerontology. University of Cambridge, Addenbrooke's Hospital, Cambridge UK</nlm:aff></affiliation></author><author><name sortKey="Kumari, Meena" sort="Kumari, Meena" uniqKey="Kumari M" first="Meena" last="Kumari">Meena Kumari</name><affiliation><nlm:aff id="A2"> Department of Epidemiology and Public Health, 1-19 Torrington Place, University College London, WC1E 6BT</nlm:aff></affiliation></author><author><name sortKey="Kivimaki, Mika" sort="Kivimaki, Mika" uniqKey="Kivimaki M" first="Mika" last="Kivimaki">Mika Kivimaki</name><affiliation><nlm:aff id="A2"> Department of Epidemiology and Public Health, 1-19 Torrington Place, University College London, WC1E 6BT</nlm:aff></affiliation></author><author><name sortKey="Marmot, Michael" sort="Marmot, Michael" uniqKey="Marmot M" first="Michael" last="Marmot">Michael Marmot</name><affiliation><nlm:aff id="A2"> Department of Epidemiology and Public Health, 1-19 Torrington Place, University College London, WC1E 6BT</nlm:aff></affiliation></author><author><name sortKey="Asselbergs, Folkert W" sort="Asselbergs, Folkert W" uniqKey="Asselbergs F" first="Folkert W" last="Asselbergs">Folkert W. Asselbergs</name><affiliation><nlm:aff id="A8"> Departments of Cardiology, Endocrinology, Nephrology University Medical Center Groningen, University of Groningen, The Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="A17"> Boston University, Department of Mathematics and School of Medicine, Boston, Mass</nlm:aff></affiliation></author><author><name sortKey="Van Der Harst, Pim" sort="Van Der Harst, Pim" uniqKey="Van Der Harst P" first="Pim" last="Van Der Harst">Pim Van Der Harst</name><affiliation><nlm:aff id="A8"> Departments of Cardiology, Endocrinology, Nephrology University Medical Center Groningen, University of Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Dullaart, Robin P F" sort="Dullaart, Robin P F" uniqKey="Dullaart R" first="Robin P F" last="Dullaart">Robin P F. Dullaart</name><affiliation><nlm:aff id="A8"> Departments of Cardiology, Endocrinology, Nephrology University Medical Center Groningen, University of Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Navis, Gerjan" sort="Navis, Gerjan" uniqKey="Navis G" first="Gerjan" last="Navis">Gerjan Navis</name><affiliation><nlm:aff id="A8"> Departments of Cardiology, Endocrinology, Nephrology University Medical Center Groningen, University of Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Van Veldhuisen, Dirk J" sort="Van Veldhuisen, Dirk J" uniqKey="Van Veldhuisen D" first="Dirk J" last="Van Veldhuisen">Dirk J. Van Veldhuisen</name><affiliation><nlm:aff id="A8"> Departments of Cardiology, Endocrinology, Nephrology University Medical Center Groningen, University of Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Van Gilst, Wiek H" sort="Van Gilst, Wiek H" uniqKey="Van Gilst W" first="Wiek H" last="Van Gilst">Wiek H. Van Gilst</name><affiliation><nlm:aff id="A8"> Departments of Cardiology, Endocrinology, Nephrology University Medical Center Groningen, University of Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Thompson, John F" sort="Thompson, John F" uniqKey="Thompson J" first="John F" last="Thompson">John F. Thompson</name><affiliation><nlm:aff id="A9"> Helicos BioSciences, One Kendall Square Bldg 700, Cambridge MA 02139 USA</nlm:aff></affiliation></author><author><name sortKey="Mccaskie, Pamela" sort="Mccaskie, Pamela" uniqKey="Mccaskie P" first="Pamela" last="Mccaskie">Pamela Mccaskie</name><affiliation><nlm:aff id="A10"> Centre for Genetic Epidemiology and Biostatistics, University of Western Australia</nlm:aff></affiliation></author><author><name sortKey="Palmer, Lyle J" sort="Palmer, Lyle J" uniqKey="Palmer L" first="Lyle J" last="Palmer">Lyle J. Palmer</name><affiliation><nlm:aff id="A10"> Centre for Genetic Epidemiology and Biostatistics, University of Western Australia</nlm:aff></affiliation></author><author><name sortKey="Arca, Marcello" sort="Arca, Marcello" uniqKey="Arca M" first="Marcello" last="Arca">Marcello Arca</name><affiliation><nlm:aff id="A11"> Dipartimento di Clinica e Terapia Medica,La Sapienza Università di Roma</nlm:aff></affiliation></author><author><name sortKey="Quagliarini, Fabiana" sort="Quagliarini, Fabiana" uniqKey="Quagliarini F" first="Fabiana" last="Quagliarini">Fabiana Quagliarini</name><affiliation><nlm:aff id="A11"> Dipartimento di Clinica e Terapia Medica,La Sapienza Università di Roma</nlm:aff></affiliation></author><author><name sortKey="Gaudio, Carlo" sort="Gaudio, Carlo" uniqKey="Gaudio C" first="Carlo" last="Gaudio">Carlo Gaudio</name><affiliation><nlm:aff id="A12"> Dipartimento Cuore e Grossi Vasi Attilio Reale, La Sapienza Università di Roma</nlm:aff></affiliation></author><author><name sortKey="Cambien, Francois" sort="Cambien, Francois" uniqKey="Cambien F" first="François" last="Cambien">François Cambien</name><affiliation><nlm:aff id="A13"> INSERM, UMRS 937, Paris, F-75634 France; Université Pierre et Marie Curie-Paris6, UMRS 937, Paris, F-75634 France</nlm:aff></affiliation></author><author><name sortKey="Nicaud, Viviane" sort="Nicaud, Viviane" uniqKey="Nicaud V" first="Viviane" last="Nicaud">Viviane Nicaud</name><affiliation><nlm:aff id="A13"> INSERM, UMRS 937, Paris, F-75634 France; Université Pierre et Marie Curie-Paris6, UMRS 937, Paris, F-75634 France</nlm:aff></affiliation></author><author><name sortKey="Poirer, Odette" sort="Poirer, Odette" uniqKey="Poirer O" first="Odette" last="Poirer">Odette Poirer</name><affiliation><nlm:aff id="A14"> INSERM, UMRS 956, Paris, F-75634 France; Université Pierre et Marie Curie-Paris6, UMRS 956, Paris, F-75634 France</nlm:aff></affiliation></author><author><name sortKey="Gudnason, Vilmundur" sort="Gudnason, Vilmundur" uniqKey="Gudnason V" first="Vilmundur" last="Gudnason">Vilmundur Gudnason</name><affiliation><nlm:aff id="A15"> University of Iceland, Reykjavik, Iceland</nlm:aff></affiliation></author><author><name sortKey="Isaacs, Aaron" sort="Isaacs, Aaron" uniqKey="Isaacs A" first="Aaron" last="Isaacs">Aaron Isaacs</name><affiliation><nlm:aff id="A16"> Department of Epidemiology and Biostatistics, Erasmus MC, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Witteman, Jacqueline C M" sort="Witteman, Jacqueline C M" uniqKey="Witteman J" first="Jacqueline C M" last="Witteman">Jacqueline C M. Witteman</name><affiliation><nlm:aff id="A16"> Department of Epidemiology and Biostatistics, Erasmus MC, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Van Duijn, Cornelia M" sort="Van Duijn, Cornelia M" uniqKey="Van Duijn C" first="Cornelia M" last="Van Duijn">Cornelia M. Van Duijn</name><affiliation><nlm:aff id="A16"> Department of Epidemiology and Biostatistics, Erasmus MC, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Pencina, Michael" sort="Pencina, Michael" uniqKey="Pencina M" first="Michael" last="Pencina">Michael Pencina</name><affiliation><nlm:aff id="A17"> Boston University, Department of Mathematics and School of Medicine, Boston, Mass</nlm:aff></affiliation></author><author><name sortKey="Vasan, Ramachandran S" sort="Vasan, Ramachandran S" uniqKey="Vasan R" first="Ramachandran. S" last="Vasan">Ramachandran. S. Vasan</name><affiliation><nlm:aff id="A17"> Boston University, Department of Mathematics and School of Medicine, Boston, Mass</nlm:aff></affiliation></author><author><name sortKey="D Agostino, Ralph B" sort="D Agostino, Ralph B" uniqKey="D Agostino R" first="Ralph B" last="D'Agostino">Ralph B. D'Agostino</name><affiliation><nlm:aff id="A17"> Boston University, Department of Mathematics and School of Medicine, Boston, Mass</nlm:aff></affiliation></author><author><name sortKey="Ordovas, Jose" sort="Ordovas, Jose" uniqKey="Ordovas J" first="Jose" last="Ordovas">Jose Ordovas</name><affiliation><nlm:aff id="A17"> Boston University, Department of Mathematics and School of Medicine, Boston, Mass</nlm:aff></affiliation></author><author><name sortKey="Li, Tricia Y" sort="Li, Tricia Y" uniqKey="Li T" first="Tricia Y." last="Li">Tricia Y. Li</name><affiliation><nlm:aff id="A18"> Department of Nutrition, Harvard School of Public Health, Boston, MA</nlm:aff></affiliation></author><author><name sortKey="Kakko, Sakari" sort="Kakko, Sakari" uniqKey="Kakko S" first="Sakari" last="Kakko">Sakari Kakko</name><affiliation><nlm:aff id="A19"> Institute of Clinical Medicine, Department of Internal Medicine, Clinical Research Center and Biocenter Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Kauma, Heikki" sort="Kauma, Heikki" uniqKey="Kauma H" first="Heikki" last="Kauma">Heikki Kauma</name><affiliation><nlm:aff id="A19"> Institute of Clinical Medicine, Department of Internal Medicine, Clinical Research Center and Biocenter Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Savolainen, Markku J" sort="Savolainen, Markku J" uniqKey="Savolainen M" first="Markku J." last="Savolainen">Markku J. Savolainen</name><affiliation><nlm:aff id="A19"> Institute of Clinical Medicine, Department of Internal Medicine, Clinical Research Center and Biocenter Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Kes Niemi, Y Antero" sort="Kes Niemi, Y Antero" uniqKey="Kes Niemi Y" first="Y. Antero" last="Kes Niemi">Y. Antero Kes Niemi</name><affiliation><nlm:aff id="A19"> Institute of Clinical Medicine, Department of Internal Medicine, Clinical Research Center and Biocenter Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Sandhofer, Anton" sort="Sandhofer, Anton" uniqKey="Sandhofer A" first="Anton" last="Sandhofer">Anton Sandhofer</name><affiliation><nlm:aff id="A20"> Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria</nlm:aff></affiliation></author><author><name sortKey="Paulweber, Bernhard" sort="Paulweber, Bernhard" uniqKey="Paulweber B" first="Bernhard" last="Paulweber">Bernhard Paulweber</name><affiliation><nlm:aff id="A21"> Department of Internal Medicine, Clinical Division of General Internal Medicine, University of Innsbruck Austria/ Department of Internal Medicine, Paracelsus Medical University, Salzburg Austria</nlm:aff></affiliation></author><author><name sortKey="Sorli, Jose V" sort="Sorli, Jose V" uniqKey="Sorli J" first="Jose V" last="Sorli">Jose V. Sorli</name><affiliation><nlm:aff id="A22"> Preventive Medicine Department, University of Valencia, Spain and CIBER Fisiopatologia de la Obesidad y Nutricion (ISCIII)</nlm:aff></affiliation></author><author><name sortKey="Goto, Akimoto" sort="Goto, Akimoto" uniqKey="Goto A" first="Akimoto" last="Goto">Akimoto Goto</name><affiliation><nlm:aff id="A23"> Cardiovascular Division, JA Aichi Bisai Hospital, Sobuecho, Inazawa 495-8531, Japan</nlm:aff></affiliation></author><author><name sortKey="Yokoyama, Shinji" sort="Yokoyama, Shinji" uniqKey="Yokoyama S" first="Shinji" last="Yokoyama">Shinji Yokoyama</name><affiliation><nlm:aff id="A24"> Biochemistry, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan</nlm:aff></affiliation></author><author><name sortKey="Okumura, Kenji" sort="Okumura, Kenji" uniqKey="Okumura K" first="Kenji" last="Okumura">Kenji Okumura</name><affiliation><nlm:aff id="A25"> Cardiovascular Research Medicine, Nagoya University School of Medicine 65 Tsurumai-cho, Showa-ku, Nagoya, Japan</nlm:aff></affiliation></author><author><name sortKey="Horne, Benjamin D" sort="Horne, Benjamin D" uniqKey="Horne B" first="Benjamin D" last="Horne">Benjamin D. Horne</name><affiliation><nlm:aff id="A26"> Cardiovascular Department, Intermountain Medical Centre/ Department of Biomedical Informatics, University of Utah, Murray, Utah 84157, USA</nlm:aff></affiliation></author><author><name sortKey="Packard, Chris" sort="Packard, Chris" uniqKey="Packard C" first="Chris" last="Packard">Chris Packard</name><affiliation><nlm:aff id="A27"> Glasgow Royal Infirmary, Glasgow G31 2ER</nlm:aff></affiliation></author><author><name sortKey="Freeman, Dilys" sort="Freeman, Dilys" uniqKey="Freeman D" first="Dilys" last="Freeman">Dilys Freeman</name><affiliation><nlm:aff id="A27"> Glasgow Royal Infirmary, Glasgow G31 2ER</nlm:aff></affiliation></author><author><name sortKey="Ford, Ian" sort="Ford, Ian" uniqKey="Ford I" first="Ian" last="Ford">Ian Ford</name><affiliation><nlm:aff id="A28"> Robertson Centre for Biostatistics, University of Glasgow</nlm:aff></affiliation></author><author><name sortKey="Sattar, Naveed" sort="Sattar, Naveed" uniqKey="Sattar N" first="Naveed" last="Sattar">Naveed Sattar</name><affiliation><nlm:aff id="A29"> Faculty of Medicine, BHF Glasgow Cardiovascular Research Centre, University of Glasgow</nlm:aff></affiliation></author><author><name sortKey="Mccormack, Valerie" sort="Mccormack, Valerie" uniqKey="Mccormack V" first="Valerie" last="Mccormack">Valerie Mccormack</name><affiliation><nlm:aff id="A3"> Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT</nlm:aff></affiliation><affiliation><nlm:aff id="A30"> Lifestyle and Cancer Group, International Agency for Research on Cancer, 150 cours Albert Thomas,Lyon 69008 France</nlm:aff></affiliation></author><author><name sortKey="Lawlor, Debbie A" sort="Lawlor, Debbie A" uniqKey="Lawlor D" first="Debbie A" last="Lawlor">Debbie A. Lawlor</name><affiliation><nlm:aff id="A31"> MRC Centre of Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, UK</nlm:aff></affiliation></author><author><name sortKey="Ebrahim, Shah" sort="Ebrahim, Shah" uniqKey="Ebrahim S" first="Shah" last="Ebrahim">Shah Ebrahim</name><affiliation><nlm:aff id="A3"> Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT</nlm:aff></affiliation></author><author><name sortKey="Davey Smith, George" sort="Davey Smith, George" uniqKey="Davey Smith G" first="George" last="Davey Smith">George Davey Smith</name><affiliation><nlm:aff id="A31"> MRC Centre of Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, UK</nlm:aff></affiliation></author><author><name sortKey="Kastelein, John J P" sort="Kastelein, John J P" uniqKey="Kastelein J" first="John J P" last="Kastelein">John J P. Kastelein</name><affiliation><nlm:aff id="A32"> Department of Vascular Medicine, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Deanfield, John" sort="Deanfield, John" uniqKey="Deanfield J" first="John" last="Deanfield">John Deanfield</name><affiliation><nlm:aff id="A33"> Vascular Physiology Unit, UCL Institute of Child Health, London</nlm:aff></affiliation></author><author><name sortKey="Casas, Juan P" sort="Casas, Juan P" uniqKey="Casas J" first="Juan P" last="Casas">Juan P. Casas</name><affiliation><nlm:aff id="A2"> Department of Epidemiology and Public Health, 1-19 Torrington Place, University College London, WC1E 6BT</nlm:aff></affiliation><affiliation><nlm:aff id="A3"> Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">20026784</idno><idno type="pmc">2811869</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2811869</idno><idno type="RBID">PMC:2811869</idno><idno type="doi">10.1161/CIRCULATIONAHA.109.865444</idno><date when="2009">2009</date><idno type="wicri:Area/Pmc/Corpus">001C64</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001C64</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Separating the mechanism-based and off-target actions of CETP-inhibitors using <italic>CETP</italic> gene polymorphisms</title><author><name sortKey="Sofat, Reecha" sort="Sofat, Reecha" uniqKey="Sofat R" first="Reecha" last="Sofat">Reecha Sofat</name><affiliation><nlm:aff id="A1"> Centre for Clinical Pharmacology, Department of Medicine, University College London, Rayne Building, 5 University Street, London, WC1E 6JF</nlm:aff></affiliation></author><author><name sortKey="Hingorani, Aroon D" sort="Hingorani, Aroon D" uniqKey="Hingorani A" first="Aroon D" last="Hingorani">Aroon D. Hingorani</name><affiliation><nlm:aff id="A1"> Centre for Clinical Pharmacology, Department of Medicine, University College London, Rayne Building, 5 University Street, London, WC1E 6JF</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Department of Epidemiology and Public Health, 1-19 Torrington Place, University College London, WC1E 6BT</nlm:aff></affiliation></author><author><name sortKey="Smeeth, Liam" sort="Smeeth, Liam" uniqKey="Smeeth L" first="Liam" last="Smeeth">Liam Smeeth</name><affiliation><nlm:aff id="A3"> Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT</nlm:aff></affiliation></author><author><name sortKey="Humphries, Steve E" sort="Humphries, Steve E" uniqKey="Humphries S" first="Steve E" last="Humphries">Steve E. Humphries</name><affiliation><nlm:aff id="A4"> Centre for Cardiovascular Genetics, University College London Rayne Building, 5 University Street, London, WC1E 6JF</nlm:aff></affiliation></author><author><name sortKey="Talmud, Philippa J" sort="Talmud, Philippa J" uniqKey="Talmud P" first="Philippa J" last="Talmud">Philippa J. Talmud</name><affiliation><nlm:aff id="A4"> Centre for Cardiovascular Genetics, University College London Rayne Building, 5 University Street, London, WC1E 6JF</nlm:aff></affiliation></author><author><name sortKey="Cooper, Jackie" sort="Cooper, Jackie" uniqKey="Cooper J" first="Jackie" last="Cooper">Jackie Cooper</name><affiliation><nlm:aff id="A4"> Centre for Cardiovascular Genetics, University College London Rayne Building, 5 University Street, London, WC1E 6JF</nlm:aff></affiliation></author><author><name sortKey="Shah, Tina" sort="Shah, Tina" uniqKey="Shah T" first="Tina" last="Shah">Tina Shah</name><affiliation><nlm:aff id="A1"> Centre for Clinical Pharmacology, Department of Medicine, University College London, Rayne Building, 5 University Street, London, WC1E 6JF</nlm:aff></affiliation></author><author><name sortKey="Sandhu, Manjinder S" sort="Sandhu, Manjinder S" uniqKey="Sandhu M" first="Manjinder S" last="Sandhu">Manjinder S. Sandhu</name><affiliation><nlm:aff id="A5"> Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge</nlm:aff></affiliation></author><author><name sortKey="Ricketts, Sally L" sort="Ricketts, Sally L" uniqKey="Ricketts S" first="Sally L" last="Ricketts">Sally L. Ricketts</name><affiliation><nlm:aff id="A5"> Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge</nlm:aff></affiliation></author><author><name sortKey="Boekholdt, S Matthijs" sort="Boekholdt, S Matthijs" uniqKey="Boekholdt S" first="S Matthijs" last="Boekholdt">S Matthijs Boekholdt</name><affiliation><nlm:aff id="A5"> Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge</nlm:aff></affiliation><affiliation><nlm:aff id="A31"> MRC Centre of Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, UK</nlm:aff></affiliation></author><author><name sortKey="Wareham, Nicholas" sort="Wareham, Nicholas" uniqKey="Wareham N" first="Nicholas" last="Wareham">Nicholas Wareham</name><affiliation><nlm:aff id="A6"> MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge UK</nlm:aff></affiliation></author><author><name sortKey="Khaw, Kay Tee" sort="Khaw, Kay Tee" uniqKey="Khaw K" first="Kay Tee" last="Khaw">Kay Tee Khaw</name><affiliation><nlm:aff id="A7"> Department of Clinical Gerontology. University of Cambridge, Addenbrooke's Hospital, Cambridge UK</nlm:aff></affiliation></author><author><name sortKey="Kumari, Meena" sort="Kumari, Meena" uniqKey="Kumari M" first="Meena" last="Kumari">Meena Kumari</name><affiliation><nlm:aff id="A2"> Department of Epidemiology and Public Health, 1-19 Torrington Place, University College London, WC1E 6BT</nlm:aff></affiliation></author><author><name sortKey="Kivimaki, Mika" sort="Kivimaki, Mika" uniqKey="Kivimaki M" first="Mika" last="Kivimaki">Mika Kivimaki</name><affiliation><nlm:aff id="A2"> Department of Epidemiology and Public Health, 1-19 Torrington Place, University College London, WC1E 6BT</nlm:aff></affiliation></author><author><name sortKey="Marmot, Michael" sort="Marmot, Michael" uniqKey="Marmot M" first="Michael" last="Marmot">Michael Marmot</name><affiliation><nlm:aff id="A2"> Department of Epidemiology and Public Health, 1-19 Torrington Place, University College London, WC1E 6BT</nlm:aff></affiliation></author><author><name sortKey="Asselbergs, Folkert W" sort="Asselbergs, Folkert W" uniqKey="Asselbergs F" first="Folkert W" last="Asselbergs">Folkert W. Asselbergs</name><affiliation><nlm:aff id="A8"> Departments of Cardiology, Endocrinology, Nephrology University Medical Center Groningen, University of Groningen, The Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="A17"> Boston University, Department of Mathematics and School of Medicine, Boston, Mass</nlm:aff></affiliation></author><author><name sortKey="Van Der Harst, Pim" sort="Van Der Harst, Pim" uniqKey="Van Der Harst P" first="Pim" last="Van Der Harst">Pim Van Der Harst</name><affiliation><nlm:aff id="A8"> Departments of Cardiology, Endocrinology, Nephrology University Medical Center Groningen, University of Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Dullaart, Robin P F" sort="Dullaart, Robin P F" uniqKey="Dullaart R" first="Robin P F" last="Dullaart">Robin P F. Dullaart</name><affiliation><nlm:aff id="A8"> Departments of Cardiology, Endocrinology, Nephrology University Medical Center Groningen, University of Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Navis, Gerjan" sort="Navis, Gerjan" uniqKey="Navis G" first="Gerjan" last="Navis">Gerjan Navis</name><affiliation><nlm:aff id="A8"> Departments of Cardiology, Endocrinology, Nephrology University Medical Center Groningen, University of Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Van Veldhuisen, Dirk J" sort="Van Veldhuisen, Dirk J" uniqKey="Van Veldhuisen D" first="Dirk J" last="Van Veldhuisen">Dirk J. Van Veldhuisen</name><affiliation><nlm:aff id="A8"> Departments of Cardiology, Endocrinology, Nephrology University Medical Center Groningen, University of Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Van Gilst, Wiek H" sort="Van Gilst, Wiek H" uniqKey="Van Gilst W" first="Wiek H" last="Van Gilst">Wiek H. Van Gilst</name><affiliation><nlm:aff id="A8"> Departments of Cardiology, Endocrinology, Nephrology University Medical Center Groningen, University of Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Thompson, John F" sort="Thompson, John F" uniqKey="Thompson J" first="John F" last="Thompson">John F. Thompson</name><affiliation><nlm:aff id="A9"> Helicos BioSciences, One Kendall Square Bldg 700, Cambridge MA 02139 USA</nlm:aff></affiliation></author><author><name sortKey="Mccaskie, Pamela" sort="Mccaskie, Pamela" uniqKey="Mccaskie P" first="Pamela" last="Mccaskie">Pamela Mccaskie</name><affiliation><nlm:aff id="A10"> Centre for Genetic Epidemiology and Biostatistics, University of Western Australia</nlm:aff></affiliation></author><author><name sortKey="Palmer, Lyle J" sort="Palmer, Lyle J" uniqKey="Palmer L" first="Lyle J" last="Palmer">Lyle J. Palmer</name><affiliation><nlm:aff id="A10"> Centre for Genetic Epidemiology and Biostatistics, University of Western Australia</nlm:aff></affiliation></author><author><name sortKey="Arca, Marcello" sort="Arca, Marcello" uniqKey="Arca M" first="Marcello" last="Arca">Marcello Arca</name><affiliation><nlm:aff id="A11"> Dipartimento di Clinica e Terapia Medica,La Sapienza Università di Roma</nlm:aff></affiliation></author><author><name sortKey="Quagliarini, Fabiana" sort="Quagliarini, Fabiana" uniqKey="Quagliarini F" first="Fabiana" last="Quagliarini">Fabiana Quagliarini</name><affiliation><nlm:aff id="A11"> Dipartimento di Clinica e Terapia Medica,La Sapienza Università di Roma</nlm:aff></affiliation></author><author><name sortKey="Gaudio, Carlo" sort="Gaudio, Carlo" uniqKey="Gaudio C" first="Carlo" last="Gaudio">Carlo Gaudio</name><affiliation><nlm:aff id="A12"> Dipartimento Cuore e Grossi Vasi Attilio Reale, La Sapienza Università di Roma</nlm:aff></affiliation></author><author><name sortKey="Cambien, Francois" sort="Cambien, Francois" uniqKey="Cambien F" first="François" last="Cambien">François Cambien</name><affiliation><nlm:aff id="A13"> INSERM, UMRS 937, Paris, F-75634 France; Université Pierre et Marie Curie-Paris6, UMRS 937, Paris, F-75634 France</nlm:aff></affiliation></author><author><name sortKey="Nicaud, Viviane" sort="Nicaud, Viviane" uniqKey="Nicaud V" first="Viviane" last="Nicaud">Viviane Nicaud</name><affiliation><nlm:aff id="A13"> INSERM, UMRS 937, Paris, F-75634 France; Université Pierre et Marie Curie-Paris6, UMRS 937, Paris, F-75634 France</nlm:aff></affiliation></author><author><name sortKey="Poirer, Odette" sort="Poirer, Odette" uniqKey="Poirer O" first="Odette" last="Poirer">Odette Poirer</name><affiliation><nlm:aff id="A14"> INSERM, UMRS 956, Paris, F-75634 France; Université Pierre et Marie Curie-Paris6, UMRS 956, Paris, F-75634 France</nlm:aff></affiliation></author><author><name sortKey="Gudnason, Vilmundur" sort="Gudnason, Vilmundur" uniqKey="Gudnason V" first="Vilmundur" last="Gudnason">Vilmundur Gudnason</name><affiliation><nlm:aff id="A15"> University of Iceland, Reykjavik, Iceland</nlm:aff></affiliation></author><author><name sortKey="Isaacs, Aaron" sort="Isaacs, Aaron" uniqKey="Isaacs A" first="Aaron" last="Isaacs">Aaron Isaacs</name><affiliation><nlm:aff id="A16"> Department of Epidemiology and Biostatistics, Erasmus MC, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Witteman, Jacqueline C M" sort="Witteman, Jacqueline C M" uniqKey="Witteman J" first="Jacqueline C M" last="Witteman">Jacqueline C M. Witteman</name><affiliation><nlm:aff id="A16"> Department of Epidemiology and Biostatistics, Erasmus MC, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Van Duijn, Cornelia M" sort="Van Duijn, Cornelia M" uniqKey="Van Duijn C" first="Cornelia M" last="Van Duijn">Cornelia M. Van Duijn</name><affiliation><nlm:aff id="A16"> Department of Epidemiology and Biostatistics, Erasmus MC, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Pencina, Michael" sort="Pencina, Michael" uniqKey="Pencina M" first="Michael" last="Pencina">Michael Pencina</name><affiliation><nlm:aff id="A17"> Boston University, Department of Mathematics and School of Medicine, Boston, Mass</nlm:aff></affiliation></author><author><name sortKey="Vasan, Ramachandran S" sort="Vasan, Ramachandran S" uniqKey="Vasan R" first="Ramachandran. S" last="Vasan">Ramachandran. S. Vasan</name><affiliation><nlm:aff id="A17"> Boston University, Department of Mathematics and School of Medicine, Boston, Mass</nlm:aff></affiliation></author><author><name sortKey="D Agostino, Ralph B" sort="D Agostino, Ralph B" uniqKey="D Agostino R" first="Ralph B" last="D'Agostino">Ralph B. D'Agostino</name><affiliation><nlm:aff id="A17"> Boston University, Department of Mathematics and School of Medicine, Boston, Mass</nlm:aff></affiliation></author><author><name sortKey="Ordovas, Jose" sort="Ordovas, Jose" uniqKey="Ordovas J" first="Jose" last="Ordovas">Jose Ordovas</name><affiliation><nlm:aff id="A17"> Boston University, Department of Mathematics and School of Medicine, Boston, Mass</nlm:aff></affiliation></author><author><name sortKey="Li, Tricia Y" sort="Li, Tricia Y" uniqKey="Li T" first="Tricia Y." last="Li">Tricia Y. Li</name><affiliation><nlm:aff id="A18"> Department of Nutrition, Harvard School of Public Health, Boston, MA</nlm:aff></affiliation></author><author><name sortKey="Kakko, Sakari" sort="Kakko, Sakari" uniqKey="Kakko S" first="Sakari" last="Kakko">Sakari Kakko</name><affiliation><nlm:aff id="A19"> Institute of Clinical Medicine, Department of Internal Medicine, Clinical Research Center and Biocenter Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Kauma, Heikki" sort="Kauma, Heikki" uniqKey="Kauma H" first="Heikki" last="Kauma">Heikki Kauma</name><affiliation><nlm:aff id="A19"> Institute of Clinical Medicine, Department of Internal Medicine, Clinical Research Center and Biocenter Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Savolainen, Markku J" sort="Savolainen, Markku J" uniqKey="Savolainen M" first="Markku J." last="Savolainen">Markku J. Savolainen</name><affiliation><nlm:aff id="A19"> Institute of Clinical Medicine, Department of Internal Medicine, Clinical Research Center and Biocenter Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Kes Niemi, Y Antero" sort="Kes Niemi, Y Antero" uniqKey="Kes Niemi Y" first="Y. Antero" last="Kes Niemi">Y. Antero Kes Niemi</name><affiliation><nlm:aff id="A19"> Institute of Clinical Medicine, Department of Internal Medicine, Clinical Research Center and Biocenter Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland</nlm:aff></affiliation></author><author><name sortKey="Sandhofer, Anton" sort="Sandhofer, Anton" uniqKey="Sandhofer A" first="Anton" last="Sandhofer">Anton Sandhofer</name><affiliation><nlm:aff id="A20"> Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria</nlm:aff></affiliation></author><author><name sortKey="Paulweber, Bernhard" sort="Paulweber, Bernhard" uniqKey="Paulweber B" first="Bernhard" last="Paulweber">Bernhard Paulweber</name><affiliation><nlm:aff id="A21"> Department of Internal Medicine, Clinical Division of General Internal Medicine, University of Innsbruck Austria/ Department of Internal Medicine, Paracelsus Medical University, Salzburg Austria</nlm:aff></affiliation></author><author><name sortKey="Sorli, Jose V" sort="Sorli, Jose V" uniqKey="Sorli J" first="Jose V" last="Sorli">Jose V. Sorli</name><affiliation><nlm:aff id="A22"> Preventive Medicine Department, University of Valencia, Spain and CIBER Fisiopatologia de la Obesidad y Nutricion (ISCIII)</nlm:aff></affiliation></author><author><name sortKey="Goto, Akimoto" sort="Goto, Akimoto" uniqKey="Goto A" first="Akimoto" last="Goto">Akimoto Goto</name><affiliation><nlm:aff id="A23"> Cardiovascular Division, JA Aichi Bisai Hospital, Sobuecho, Inazawa 495-8531, Japan</nlm:aff></affiliation></author><author><name sortKey="Yokoyama, Shinji" sort="Yokoyama, Shinji" uniqKey="Yokoyama S" first="Shinji" last="Yokoyama">Shinji Yokoyama</name><affiliation><nlm:aff id="A24"> Biochemistry, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan</nlm:aff></affiliation></author><author><name sortKey="Okumura, Kenji" sort="Okumura, Kenji" uniqKey="Okumura K" first="Kenji" last="Okumura">Kenji Okumura</name><affiliation><nlm:aff id="A25"> Cardiovascular Research Medicine, Nagoya University School of Medicine 65 Tsurumai-cho, Showa-ku, Nagoya, Japan</nlm:aff></affiliation></author><author><name sortKey="Horne, Benjamin D" sort="Horne, Benjamin D" uniqKey="Horne B" first="Benjamin D" last="Horne">Benjamin D. Horne</name><affiliation><nlm:aff id="A26"> Cardiovascular Department, Intermountain Medical Centre/ Department of Biomedical Informatics, University of Utah, Murray, Utah 84157, USA</nlm:aff></affiliation></author><author><name sortKey="Packard, Chris" sort="Packard, Chris" uniqKey="Packard C" first="Chris" last="Packard">Chris Packard</name><affiliation><nlm:aff id="A27"> Glasgow Royal Infirmary, Glasgow G31 2ER</nlm:aff></affiliation></author><author><name sortKey="Freeman, Dilys" sort="Freeman, Dilys" uniqKey="Freeman D" first="Dilys" last="Freeman">Dilys Freeman</name><affiliation><nlm:aff id="A27"> Glasgow Royal Infirmary, Glasgow G31 2ER</nlm:aff></affiliation></author><author><name sortKey="Ford, Ian" sort="Ford, Ian" uniqKey="Ford I" first="Ian" last="Ford">Ian Ford</name><affiliation><nlm:aff id="A28"> Robertson Centre for Biostatistics, University of Glasgow</nlm:aff></affiliation></author><author><name sortKey="Sattar, Naveed" sort="Sattar, Naveed" uniqKey="Sattar N" first="Naveed" last="Sattar">Naveed Sattar</name><affiliation><nlm:aff id="A29"> Faculty of Medicine, BHF Glasgow Cardiovascular Research Centre, University of Glasgow</nlm:aff></affiliation></author><author><name sortKey="Mccormack, Valerie" sort="Mccormack, Valerie" uniqKey="Mccormack V" first="Valerie" last="Mccormack">Valerie Mccormack</name><affiliation><nlm:aff id="A3"> Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT</nlm:aff></affiliation><affiliation><nlm:aff id="A30"> Lifestyle and Cancer Group, International Agency for Research on Cancer, 150 cours Albert Thomas,Lyon 69008 France</nlm:aff></affiliation></author><author><name sortKey="Lawlor, Debbie A" sort="Lawlor, Debbie A" uniqKey="Lawlor D" first="Debbie A" last="Lawlor">Debbie A. Lawlor</name><affiliation><nlm:aff id="A31"> MRC Centre of Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, UK</nlm:aff></affiliation></author><author><name sortKey="Ebrahim, Shah" sort="Ebrahim, Shah" uniqKey="Ebrahim S" first="Shah" last="Ebrahim">Shah Ebrahim</name><affiliation><nlm:aff id="A3"> Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT</nlm:aff></affiliation></author><author><name sortKey="Davey Smith, George" sort="Davey Smith, George" uniqKey="Davey Smith G" first="George" last="Davey Smith">George Davey Smith</name><affiliation><nlm:aff id="A31"> MRC Centre of Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, UK</nlm:aff></affiliation></author><author><name sortKey="Kastelein, John J P" sort="Kastelein, John J P" uniqKey="Kastelein J" first="John J P" last="Kastelein">John J P. Kastelein</name><affiliation><nlm:aff id="A32"> Department of Vascular Medicine, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Deanfield, John" sort="Deanfield, John" uniqKey="Deanfield J" first="John" last="Deanfield">John Deanfield</name><affiliation><nlm:aff id="A33"> Vascular Physiology Unit, UCL Institute of Child Health, London</nlm:aff></affiliation></author><author><name sortKey="Casas, Juan P" sort="Casas, Juan P" uniqKey="Casas J" first="Juan P" last="Casas">Juan P. Casas</name><affiliation><nlm:aff id="A2"> Department of Epidemiology and Public Health, 1-19 Torrington Place, University College London, WC1E 6BT</nlm:aff></affiliation><affiliation><nlm:aff id="A3"> Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT</nlm:aff></affiliation></author></analytic><series><title level="j">Circulation</title><idno type="ISSN">0009-7322</idno><idno type="eISSN">1524-4539</idno><imprint><date when="2009">2009</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="S1"><title>Background:</title><p id="P2">Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-cholesterol but torcetrapib, the first-in-class inhibitor tested in a large outcome trial caused 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 hypothesised that common single nucleotide polymorphisms (SNPs) in the <italic>CETP-</italic>gene could help distinguish mechanism-based from off-target actions of CETP-inhibitors to inform on the validity of CETP as a therapeutic target.</p></sec><sec id="S2"><title>Methods and Results</title><p id="P3">We compared the effect of <italic>CETP</italic> SNPs and torcetrapib treatment on lipid fractions, blood pressure and electrolytes in up to 67,687 individuals from genetic studies and 17,911 from randomised trials. <italic>CETP</italic> SNPs <italic>and</italic> torcetrapib treatment reduced CETP activity and had directionally concordant effect on eight lipid and lipoprotein traits (total-, LDL- and HDL-cholesterol, HDL2, HDL3, apolipoproteins A-I, -B, and triglycerides), with the genetic effect on HDL-cholesterol (0.13 mmol/L; 95% CI: 0.11, 0.14) being consistent with that expected of a 10 mg dose of torcetrapib (0.13 mmol/L; 0.10, 0.15). In trials, 60mg torcetrapib elevated systolic and diastolic blood pressure by 4.47mmHg (4.10, 4.84) and 2.08mmHg (1.84, 2.31) respectively. However, the effect of CETP SNPs on systolic 0.16mmHg (−0.28, 0.60) and diastolic blood pressure −0.04mmHg (−0.36, 0.28) was null and significantly different from that expected of 10 mg torcetrapib.</p></sec><sec id="S3"><title>Conclusions:</title><p id="P4">Discordance in the effects of <italic>CETP</italic> SNPs 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 use in drug development programmes as a new source of randomised evidence for drug target validation in man.</p></sec></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">0147763</journal-id><journal-id journal-id-type="pubmed-jr-id">2979</journal-id><journal-id journal-id-type="nlm-ta">Circulation</journal-id><journal-id journal-id-type="iso-abbrev">Circulation</journal-id><journal-title-group><journal-title>Circulation</journal-title></journal-title-group><issn pub-type="ppub">0009-7322</issn><issn pub-type="epub">1524-4539</issn></journal-meta><article-meta><article-id pub-id-type="pmid">20026784</article-id><article-id pub-id-type="pmc">2811869</article-id><article-id pub-id-type="doi">10.1161/CIRCULATIONAHA.109.865444</article-id><article-id pub-id-type="manuscript">UKMS28287</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Separating the mechanism-based and off-target actions of CETP-inhibitors using <italic>CETP</italic> gene polymorphisms</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Sofat</surname><given-names>Reecha</given-names></name><degrees>MRCP</degrees><xref ref-type="aff" rid="A1">1</xref><xref ref-type="author-notes" rid="FN1">†</xref></contrib><contrib contrib-type="author"><name><surname>Hingorani</surname><given-names>Aroon D</given-names></name><degrees>PhD, FRCP</degrees><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref><xref ref-type="author-notes" rid="FN1">†</xref></contrib><contrib contrib-type="author"><name><surname>Smeeth</surname><given-names>Liam</given-names></name><degrees>MRCGP, PhD</degrees><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Humphries</surname><given-names>Steve E</given-names></name><degrees>PhD, MRCP, FRCPath</degrees><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Talmud</surname><given-names>Philippa 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rid="A31">31</xref></contrib><contrib contrib-type="author"><name><surname>Wareham</surname><given-names>Nicholas</given-names></name><degrees>MBBS FRCP</degrees><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Khaw</surname><given-names>Kay Tee</given-names></name><degrees>MBBChir, FRCP</degrees><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Kumari</surname><given-names>Meena</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Kivimaki</surname><given-names>Mika</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Marmot</surname><given-names>Michael</given-names></name><degrees>PhD, FRCP</degrees><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Asselbergs</surname><given-names>Folkert 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contrib-type="author"><name><surname>Gaudio</surname><given-names>Carlo</given-names></name><degrees>MD</degrees><xref ref-type="aff" rid="A12">12</xref></contrib><contrib contrib-type="author"><name><surname>Cambien</surname><given-names>François</given-names></name><degrees>MD</degrees><xref ref-type="aff" rid="A13">13</xref></contrib><contrib contrib-type="author"><name><surname>Nicaud</surname><given-names>Viviane</given-names></name><degrees>MA</degrees><xref ref-type="aff" rid="A13">13</xref></contrib><contrib contrib-type="author"><name><surname>Poirer</surname><given-names>Odette</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A14">14</xref></contrib><contrib contrib-type="author"><name><surname>Gudnason</surname><given-names>Vilmundur</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="A15">15</xref></contrib><contrib contrib-type="author"><name><surname>Isaacs</surname><given-names>Aaron</given-names></name><degrees>PhD</degrees><xref 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S</given-names></name><degrees>MD</degrees><xref ref-type="aff" rid="A17">17</xref></contrib><contrib contrib-type="author"><name><surname>D'Agostino</surname><given-names>Ralph B</given-names><suffix>Sr</suffix></name><degrees>PhD</degrees><xref ref-type="aff" rid="A17">17</xref></contrib><contrib contrib-type="author"><name><surname>Ordovas</surname><given-names>Jose</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A17">17</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Tricia Y.</given-names></name><degrees>MSc</degrees><xref ref-type="aff" rid="A18">18</xref></contrib><contrib contrib-type="author"><name><surname>Kakko</surname><given-names>Sakari</given-names></name><degrees>MD PhD</degrees><xref ref-type="aff" rid="A19">19</xref></contrib><contrib contrib-type="author"><name><surname>Kauma</surname><given-names>Heikki</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="A19">19</xref></contrib><contrib contrib-type="author"><name><surname>Savolainen</surname><given-names>Markku J.</given-names></name><degrees>MD PhD</degrees><xref ref-type="aff" rid="A19">19</xref></contrib><contrib contrib-type="author"><name><surname>Kesäniemi</surname><given-names>Y.Antero</given-names></name><degrees>MD, PhD, FAHA</degrees><xref ref-type="aff" rid="A19">19</xref></contrib><contrib contrib-type="author"><name><surname>Sandhofer</surname><given-names>Anton</given-names></name><degrees>MD</degrees><xref ref-type="aff" rid="A20">20</xref></contrib><contrib contrib-type="author"><name><surname>Paulweber</surname><given-names>Bernhard</given-names></name><degrees>MD</degrees><xref ref-type="aff" rid="A21">21</xref></contrib><contrib contrib-type="author"><name><surname>Sorli</surname><given-names>Jose V</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="A22">22</xref></contrib><contrib contrib-type="author"><name><surname>Goto</surname><given-names>Akimoto</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="A23">23</xref></contrib><contrib contrib-type="author"><name><surname>Yokoyama</surname><given-names>Shinji</given-names></name><degrees>MD, PhD, FRCPC</degrees><xref ref-type="aff" rid="A24">24</xref></contrib><contrib contrib-type="author"><name><surname>Okumura</surname><given-names>Kenji</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="A25">25</xref></contrib><contrib contrib-type="author"><name><surname>Horne</surname><given-names>Benjamin D</given-names></name><degrees>PhD, MPH</degrees><xref ref-type="aff" rid="A26">26</xref></contrib><contrib contrib-type="author"><name><surname>Packard</surname><given-names>Chris</given-names></name><degrees>DSc</degrees><xref ref-type="aff" rid="A27">27</xref></contrib><contrib contrib-type="author"><name><surname>Freeman</surname><given-names>Dilys</given-names></name><degrees>BSc, PhD</degrees><xref ref-type="aff" rid="A27">27</xref></contrib><contrib contrib-type="author"><name><surname>Ford</surname><given-names>Ian</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A28">28</xref></contrib><contrib contrib-type="author"><name><surname>Sattar</surname><given-names>Naveed</given-names></name><degrees>PhD, FRCPath</degrees><xref ref-type="aff" rid="A29">29</xref></contrib><contrib contrib-type="author"><name><surname>McCormack</surname><given-names>Valerie</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A3">3</xref><xref ref-type="aff" rid="A30">30</xref></contrib><contrib contrib-type="author"><name><surname>Lawlor</surname><given-names>Debbie A</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A31">31</xref></contrib><contrib contrib-type="author"><name><surname>Ebrahim</surname><given-names>Shah</given-names></name><degrees>Dm, MSc, FFPHM</degrees><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Davey Smith</surname><given-names>George</given-names></name><degrees>MD, DSc, FFPHM</degrees><xref ref-type="aff" rid="A31">31</xref></contrib><contrib contrib-type="author"><name><surname>Kastelein</surname><given-names>John J P</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="A32">32</xref></contrib><contrib contrib-type="author"><name><surname>Deanfield</surname><given-names>John</given-names></name><degrees>BA, BCh, MB, FRCP</degrees><xref ref-type="aff" rid="A33">33</xref></contrib><contrib contrib-type="author"><name><surname>Casas</surname><given-names>Juan P</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A3">3</xref></contrib></contrib-group><aff id="A1"><label>1</label> Centre for Clinical Pharmacology, Department of Medicine, University College London, Rayne Building, 5 University Street, London, WC1E 6JF</aff><aff id="A2"><label>2</label> Department of Epidemiology and Public Health, 1-19 Torrington Place, University College London, WC1E 6BT</aff><aff id="A3"><label>3</label> Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT</aff><aff id="A4"><label>4</label> Centre for Cardiovascular Genetics, University College London Rayne Building, 5 University Street, London, WC1E 6JF</aff><aff id="A5"><label>5</label> Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge</aff><aff id="A6"><label>6</label> MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge UK</aff><aff id="A7"><label>7</label> Department of Clinical Gerontology. University of Cambridge, Addenbrooke's Hospital, Cambridge UK</aff><aff id="A8"><label>8</label> Departments of Cardiology, Endocrinology, Nephrology University Medical Center Groningen, University of Groningen, The Netherlands</aff><aff id="A9"><label>9</label> Helicos BioSciences, One Kendall Square Bldg 700, Cambridge MA 02139 USA</aff><aff id="A10"><label>10</label> Centre for Genetic Epidemiology and Biostatistics, University of Western Australia</aff><aff id="A11"><label>11</label> Dipartimento di Clinica e Terapia Medica,La Sapienza Università di Roma</aff><aff id="A12"><label>12</label> Dipartimento Cuore e Grossi Vasi Attilio Reale, La Sapienza Università di Roma</aff><aff id="A13"><label>13</label> INSERM, UMRS 937, Paris, F-75634 France; Université Pierre et Marie Curie-Paris6, UMRS 937, Paris, F-75634 France</aff><aff id="A14"><label>14</label> INSERM, UMRS 956, Paris, F-75634 France; Université Pierre et Marie Curie-Paris6, UMRS 956, Paris, F-75634 France</aff><aff id="A15"><label>15</label> University of Iceland, Reykjavik, Iceland</aff><aff id="A16"><label>16</label> Department of Epidemiology and Biostatistics, Erasmus MC, Rotterdam, The Netherlands</aff><aff id="A17"><label>17</label> Boston University, Department of Mathematics and School of Medicine, Boston, Mass</aff><aff id="A18"><label>18</label> Department of Nutrition, Harvard School of Public Health, Boston, MA</aff><aff id="A19"><label>19</label> Institute of Clinical Medicine, Department of Internal Medicine, Clinical Research Center and Biocenter Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland</aff><aff id="A20"><label>20</label> Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria</aff><aff id="A21"><label>21</label> Department of Internal Medicine, Clinical Division of General Internal Medicine, University of Innsbruck Austria/ Department of Internal Medicine, Paracelsus Medical University, Salzburg Austria</aff><aff id="A22"><label>22</label> Preventive Medicine Department, University of Valencia, Spain and CIBER Fisiopatologia de la Obesidad y Nutricion (ISCIII)</aff><aff id="A23"><label>23</label> Cardiovascular Division, JA Aichi Bisai Hospital, Sobuecho, Inazawa 495-8531, Japan</aff><aff id="A24"><label>24</label> Biochemistry, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan</aff><aff id="A25"><label>25</label> Cardiovascular Research Medicine, Nagoya University School of Medicine 65 Tsurumai-cho, Showa-ku, Nagoya, Japan</aff><aff id="A26"><label>26</label> Cardiovascular Department, Intermountain Medical Centre/ Department of Biomedical Informatics, University of Utah, Murray, Utah 84157, USA</aff><aff id="A27"><label>27</label> Glasgow Royal Infirmary, Glasgow G31 2ER</aff><aff id="A28"><label>28</label> Robertson Centre for Biostatistics, University of Glasgow</aff><aff id="A29"><label>29</label> Faculty of Medicine, BHF Glasgow Cardiovascular Research Centre, University of Glasgow</aff><aff id="A30"><label>30</label> Lifestyle and Cancer Group, International Agency for Research on Cancer, 150 cours Albert Thomas,Lyon 69008 France</aff><aff id="A31"><label>31</label> MRC Centre of Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, UK</aff><aff id="A32"><label>32</label> Department of Vascular Medicine, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands</aff><aff id="A33"><label>33</label> Vascular Physiology Unit, UCL Institute of Child Health, London</aff><author-notes><corresp id="CR1"><bold>Name and Address for Correspondence:</bold> Professor Aroon Hingorani, Department of Epidemiology and Public Health, University College London, 1-19 Torrington Place, London WC1E 6BT <bold>Fax Number:</bold> +44(0)20 7679 6211, <bold>Telephone:</bold> +44(0)20 7679 6612, <email>a.hingorani@ucl.ac.uk</email></corresp><corresp id="CR2">Dr Juan P Casas, Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT <bold>Fax Number:</bold> +(44) 207 580 6897 <bold>Telephone:</bold> +(44) 207 927 2163 <email>Juan.Pablo-Casas@lshtm.ac.uk</email></corresp><fn fn-type="equal" id="FN1"><label>†</label><p id="P1">Contributed equally</p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>6</day><month>1</month><year>2010</year></pub-date><pub-date pub-type="epub"><day>21</day><month>12</month><year>2009</year></pub-date><pub-date pub-type="ppub"><day>5</day><month>1</month><year>2010</year></pub-date><pub-date pub-type="pmc-release"><day>05</day><month>7</month><year>2010</year></pub-date><volume>121</volume><issue>1</issue><fpage>52</fpage><lpage>62</lpage><abstract><sec id="S1"><title>Background:</title><p id="P2">Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-cholesterol but torcetrapib, the first-in-class inhibitor tested in a large outcome trial caused 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 hypothesised that common single nucleotide polymorphisms (SNPs) in the <italic>CETP-</italic>gene could help distinguish mechanism-based from off-target actions of CETP-inhibitors to inform on the validity of CETP as a therapeutic target.</p></sec><sec id="S2"><title>Methods and Results</title><p id="P3">We compared the effect of <italic>CETP</italic> SNPs and torcetrapib treatment on lipid fractions, blood pressure and electrolytes in up to 67,687 individuals from genetic studies and 17,911 from randomised trials. <italic>CETP</italic> SNPs <italic>and</italic> torcetrapib treatment reduced CETP activity and had directionally concordant effect on eight lipid and lipoprotein traits (total-, LDL- and HDL-cholesterol, HDL2, HDL3, apolipoproteins A-I, -B, and triglycerides), with the genetic effect on HDL-cholesterol (0.13 mmol/L; 95% CI: 0.11, 0.14) being consistent with that expected of a 10 mg dose of torcetrapib (0.13 mmol/L; 0.10, 0.15). In trials, 60mg torcetrapib elevated systolic and diastolic blood pressure by 4.47mmHg (4.10, 4.84) and 2.08mmHg (1.84, 2.31) respectively. However, the effect of CETP SNPs on systolic 0.16mmHg (−0.28, 0.60) and diastolic blood pressure −0.04mmHg (−0.36, 0.28) was null and significantly different from that expected of 10 mg torcetrapib.</p></sec><sec id="S3"><title>Conclusions:</title><p id="P4">Discordance in the effects of <italic>CETP</italic> SNPs 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 use in drug development programmes as a new source of randomised evidence for drug target validation in man.</p></sec></abstract><kwd-group><kwd>genetics</kwd><kwd>pharmacology</kwd><kwd>epidemiology</kwd></kwd-group><funding-group><award-group><funding-source country="United Kingdom">Wellcome Trust : </funding-source><award-id>082178 || WT</award-id></award-group><award-group><funding-source country="United Kingdom">Medical Research Council : </funding-source><award-id>G19/35(70654) || MRC_</award-id></award-group><award-group><funding-source country="United Kingdom">British Heart Foundation : </funding-source><award-id>PG/04/110/17827 || BHF_</award-id></award-group><award-group><funding-source country="United Kingdom">British Heart Foundation : </funding-source><award-id>FS/07/011/22085 || BHF_</award-id></award-group><award-group><funding-source country="United Kingdom">British Heart Foundation : </funding-source><award-id>FS/05/125/19379 || BHF_</award-id></award-group></funding-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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