Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

Postmus, Iris; Trompet, Stella; Deshmukh, Harshal A.; Barnes, Michael R.; Li, Xiaohui; Warren, Helen R.; Chasman, Daniel I.; Zhou, Kaixin; Arsenault, Benoit J.; Donnelly, Louise A.; Wiggins, Kerri L.; Avery, Christy L.; Griffin, Paula; Feng, QiPing; Taylor, Kent D.; Li, Guo; Evans, Daniel S.; Smith, Albert V.; de Keyser, Catherine E.; Johnson, Andrew D.; de Craen, Anton J. M.; Stott, David J.; Buckley, Brendan M.; Ford, Ian; Westendorp, Rudi G. J.; Slagboom, P. Eline; Sattar, Naveed; Munroe, Patricia B.; Sever, Peter; Poulter, Neil; Stanton, Alice; Shields, Denis C.; O’Brien, Eoin; Shaw-Hawkins, Sue; Chen, Y.-D. Ida; Nickerson, Deborah A.; Smith, Joshua D.; Dubé, Marie Pierre; Boekholdt, S. Matthijs; Hovingh, G. Kees; Kastelein, John J. P.; McKeigue, Paul M.; Betteridge, John; Neil, Andrew; Durrington, Paul N.; Doney, Alex; Carr, Fiona; Morris, Andrew; McCarthy, Mark I.; Groop, Leif; Ahlqvist, Emma; Bis, Joshua C.; Rice, Kenneth; Smith, Nicholas L.; Lumley, Thomas; Whitsel, Eric A.; Stürmer, Til; Boerwinkle, Eric; Ngwa, Julius S.; O’Donnell, Christopher J.; Vasan, Ramachandran S.; Wei, Wei-Qi; Wilke, Russell A.; Liu, Ching-Ti; Sun, Fangui; Guo, Xiuqing; Heckbert, Susan R; Post, Wendy; Sotoodehnia, Nona; Arnold, Alice M.; Stafford, Jeanette M.; Ding, Jingzhong; Herrington, David M.; Kritchevsky, Stephen B.; Eiriksdottir, Gudny; Launer, Leonore J.; Harris, Tamara B.; Chu, Audrey Y.; Giulianini, Franco; MacFadyen, Jean G.; Barratt, Bryan J.; Nyberg, Fredrik; Stricker, Bruno H.; Uitterlinden, André G.; Hofman, Albert; Rivadeneira, Fernando; Emilsson, Valur; Franco, Oscar H.; Ridker, Paul M.; Gudnason, Vilmundur; Liu, Yongmei; Denny, Joshua C.; Ballantyne, Christie M.; Rotter, Jerome I.; Cupples, L. Adrienne; Psaty, Bruce M.; Palmer, Colin N. A.; Tardif, Jean-Claude; Colhoun, Helen M.; Hitman, Graham; Krauss, Ronald M.; Jukema, J Wouter; Caulfield, Mark J.

Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

Iris Postmus, Stella Trompet, Harshal A. Deshmukh, Michael R. Barnes, Xiaohui Li, Helen R. Warren, Daniel I. Chasman, Kaixin Zhou, Benoit J. Arsenault, Louise A. Donnelly, Kerri L. Wiggins, Christy L. Avery, Paula Griffin, QiPing Feng, Kent D. Taylor, Guo Li, Daniel S. Evans, Albert V. Smith, Catherine E. de Keyser, Andrew D. Johnson, Anton J. M. de Craen, David J. Stott, Brendan M. Buckley, Ian Ford, Rudi G. J. Westendorp, P. Eline Slagboom, Naveed Sattar, Patricia B. Munroe, Peter Sever, Neil Poulter, Alice Stanton, Denis C. Shields, Eoin O’Brien, Sue Shaw-Hawkins, Y.-D. Ida Chen, Deborah A. Nickerson, Joshua D. Smith, Marie Pierre Dubé, S. Matthijs Boekholdt, G. Kees Hovingh, John J. P. Kastelein, Paul M. McKeigue, John Betteridge, Andrew Neil, Paul N. Durrington, Alex Doney, Fiona Carr, Andrew Morris, Mark I. McCarthy, Leif Groop, Emma Ahlqvist, Joshua C. Bis, Kenneth Rice, Nicholas L. Smith, Thomas Lumley, Eric A. Whitsel, Til Stürmer, Eric Boerwinkle, Julius S. Ngwa, Christopher J. O’Donnell, Ramachandran S. Vasan, Wei-Qi Wei, Russell A. Wilke, Ching-Ti Liu, Fangui Sun, Xiuqing Guo, Susan R Heckbert, Wendy Post, Nona Sotoodehnia, Alice M. Arnold, Jeanette M. Stafford, Jingzhong Ding, David M. Herrington, Stephen B. Kritchevsky, Gudny Eiriksdottir, Leonore J. Launer, Tamara B. Harris, Audrey Y. Chu, Franco Giulianini, Jean G. MacFadyen, Bryan J. Barratt, Fredrik Nyberg, Bruno H. Stricker, André G. Uitterlinden, Albert Hofman, Fernando Rivadeneira, Valur Emilsson, Oscar H. Franco, Paul M. Ridker, Vilmundur Gudnason, Yongmei Liu, Joshua C. Denny, Christie M. Ballantyne, Jerome I. Rotter, L. Adrienne Cupples, Bruce M. Psaty, Colin N. A. Palmer, Jean-Claude Tardif, Helen M. Colhoun, Graham Hitman, Ronald M. Krauss, J Wouter Jukema () and Mark J. Caulfield ()
Additional contact information
Iris Postmus: Leiden University Medical Center
Stella Trompet: Leiden University Medical Center
Harshal A. Deshmukh: Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee
Michael R. Barnes: Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London
Xiaohui Li: Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center
Helen R. Warren: NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London
Daniel I. Chasman: Brigham and Women's Hospital
Kaixin Zhou: Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee
Benoit J. Arsenault: Montreal Heart Institute, Universite de Montreal
Louise A. Donnelly: Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee
Kerri L. Wiggins: Cardiovascular Health Research Unit, University of Washington
Christy L. Avery: University of North Carolina
Paula Griffin: Boston University School of Public Health
QiPing Feng: Vanderbilt University
Kent D. Taylor: Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center
Guo Li: Cardiovascular Health Research Unit, University of Washington
Daniel S. Evans: California Pacific Medical Center Research Institute
Albert V. Smith: Icelandic Heart Association
Catherine E. de Keyser: Erasmus Medical Center
Andrew D. Johnson: Framingham Heart Study (FHS) of the National Heart, Lung and Blood Institute, Cardiovascular Epidemiology and Human Genomics
Anton J. M. de Craen: Leiden University Medical Center
David J. Stott: Faculty of Medicine, Institute of Cardiovascular and Medical Sciences, University of Glasgow
Brendan M. Buckley: University College Cork
Ian Ford: Robertson Center for Biostatistics, University of Glasgow
Rudi G. J. Westendorp: Leiden University Medical Center
P. Eline Slagboom: The Netherlands Consortium for Healthy Ageing
Naveed Sattar: Faculty of Medicine, BHF Glasgow Cardiovascular Research Centre
Patricia B. Munroe: NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London
Peter Sever: International Centre for Circulatory Health, Imperial College
Neil Poulter: International Centre for Circulatory Health, Imperial College
Alice Stanton: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland
Denis C. Shields: The Conway Institute, University College Dublin
Eoin O’Brien: The Conway Institute, University College Dublin
Sue Shaw-Hawkins: Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London
Y.-D. Ida Chen: Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center
Deborah A. Nickerson: University of Washington
Joshua D. Smith: University of Washington
Marie Pierre Dubé: Montreal Heart Institute, Universite de Montreal
S. Matthijs Boekholdt: Academic Medical Center
G. Kees Hovingh: Academic Medical Center
John J. P. Kastelein: Academic Medical Center
Paul M. McKeigue: University of Edinburgh
Andrew Neil: University of Oxford
Paul N. Durrington: Cardiovascular Research Group, School of Biosciences, University of Manchester
Alex Doney: Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee
Fiona Carr: Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee
Andrew Morris: Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee
Mark I. McCarthy: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Old Road
Leif Groop: Lund University
Emma Ahlqvist: Lund University
Joshua C. Bis: Cardiovascular Health Research Unit, University of Washington
Kenneth Rice: University of Washington
Nicholas L. Smith: University of Washington
Thomas Lumley: Cardiovascular Health Research Unit, University of Washington
Eric A. Whitsel: University of North Carolina
Til Stürmer: University of North Carolina
Eric Boerwinkle: Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston
Julius S. Ngwa: Boston University School of Public Health
Christopher J. O’Donnell: NHLBI Framingham Heart Study
Ramachandran S. Vasan: Section of Preventive Medicine and Epidemiology, Boston University School of Medicine, and the Framingham Heart Study
Wei-Qi Wei: Vanderbilt University
Russell A. Wilke: Center for IMAGENETICS, Sanford Healthcare
Ching-Ti Liu: Boston University School of Public Health
Fangui Sun: Boston University School of Public Health
Xiuqing Guo: Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center
Susan R Heckbert: University of Washington
Wendy Post: Johns Hopkins University
Nona Sotoodehnia: Cardiovascular Health Research Unit, University of Washington
Alice M. Arnold: University of Washington
Jeanette M. Stafford: Wake Forest School of Medicine
Jingzhong Ding: Wake Forest School of Medicine
David M. Herrington: Section on Cardiology, Wake Forest School of Medicine
Stephen B. Kritchevsky: Wake Forest School of Medicine
Gudny Eiriksdottir: Icelandic Heart Association
Leonore J. Launer: Laboratory of Epidemiology, Demography, Biometry, National Institute on Aging, National Institutes of Health
Tamara B. Harris: Laboratory of Epidemiology, Demography, Biometry, National Institute on Aging, National Institutes of Health
Audrey Y. Chu: Brigham and Women's Hospital
Franco Giulianini: Brigham and Women's Hospital
Jean G. MacFadyen: Brigham and Women's Hospital
Bryan J. Barratt: Personalised Healthcare and Biomarkers, AstraZeneca
Fredrik Nyberg: AstraZeneca Research and Development
Bruno H. Stricker: Erasmus Medical Center
André G. Uitterlinden: The Netherlands Consortium for Healthy Ageing
Albert Hofman: The Netherlands Consortium for Healthy Ageing
Fernando Rivadeneira: Erasmus Medical Center
Valur Emilsson: Icelandic Heart Association
Oscar H. Franco: Erasmus Medical Center
Paul M. Ridker: Brigham and Women's Hospital
Vilmundur Gudnason: Icelandic Heart Association
Yongmei Liu: Wake Forest School of Medicine
Joshua C. Denny: Vanderbilt University
Christie M. Ballantyne: Baylor College of Medicine
Jerome I. Rotter: Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center
L. Adrienne Cupples: Boston University School of Public Health
Bruce M. Psaty: Cardiovascular Health Research Unit, University of Washington
Colin N. A. Palmer: Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee
Jean-Claude Tardif: Montreal Heart Institute, Universite de Montreal
Helen M. Colhoun: Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee
Graham Hitman: Barts and the London School of Medicine and Dentistry, Queen Mary University of London
Ronald M. Krauss: Children’s Hospital Oakland Research Institute
J Wouter Jukema: Leiden University Medical Center
Mark J. Caulfield: NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London

Nature Communications, 2014, vol. 5, issue 1, 1-10

Abstract: Abstract Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.

Date: 2014
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DOI: 10.1038/ncomms6068

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