title: Meta-analysis of genome-wide association studies of HDL cholesterol response to statins.
abstract: In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation.
  
  
  
  We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1×10-4from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5×10-8) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment.
  
  
  
  Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.
authors: Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
authors: Iris
authors: I
authors: Postmus
authors: Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.|Barts NIHR Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, EC1M 6BQ, UK.
authors: Helen R
authors: HR
authors: Warren
authors: Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.|Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Stella
authors: S
authors: Trompet
authors: Montreal Heart Institute, Université de Montréal, Montreal, Canada.
authors: Benoit J
authors: BJ
authors: Arsenault
authors: Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.
authors: Christy L
authors: CL
authors: Avery
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors: Joshua C
authors: JC
authors: Bis
authors: Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
authors: Daniel I
authors: DI
authors: Chasman
authors: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Catherine E
authors: CE
authors: de Keyser
authors: Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
authors: Harshal A
authors: HA
authors: Deshmukh
authors: California Pacific Medical Center Research Institute, San Francisco, California, USA.
authors: Daniel S
authors: DS
authors: Evans
authors: Department of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee, USA.
authors: QiPing
authors: Q
authors: Feng
authors: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Departments of Pediatrics and Medicine at Harbor-UCLA Medical Center, Torrance, California, USA.
authors: Xiaohui
authors: X
authors: Li
authors: Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Roelof A J
authors: RA
authors: Smit
authors: Icelandic Heart Association, Kopavogur, Iceland.|Department of Medicine, University of Iceland, Reykjavik, Iceland.
authors: Albert V
authors: AV
authors: Smith
authors: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
authors: Fangui
authors: F
authors: Sun
authors: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Departments of Pediatrics and Medicine at Harbor-UCLA Medical Center, Torrance, California, USA.
authors: Kent D
authors: KD
authors: Taylor
authors: Department of Biostatistics, University of Washington, Seattle, Washington, USA.
authors: Alice M
authors: AM
authors: Arnold
authors: Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.|Barts NIHR Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, EC1M 6BQ, UK.
authors: Michael R
authors: MR
authors: Barnes
authors: Personalised Healthcare and Biomarkers AstraZeneca Research and Development, Alderley Park, UK.
authors: Bryan J
authors: BJ
authors: Barratt
authors: University College London Hospital, London, UK.
authors: John
authors: J
authors: Betteridge
authors: Department of Cardiology, Academic Medical Center, Amsterdam, North Holland, Netherlands.
authors: S Matthijs
authors: SM
authors: Boekholdt
authors: Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors: Eric
authors: E
authors: Boerwinkle
authors: Department of Pharmacology and Therapeutics, University College Cork, Western Road, Cork, Ireland.
authors: Brendan M
authors: BM
authors: Buckley
authors: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Departments of Pediatrics and Medicine at Harbor-UCLA Medical Center, Torrance, California, USA.
authors: Y-D Ida
authors: YI
authors: Chen
authors: Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
authors: Anton J M
authors: AJ
authors: de Craen
authors: California Pacific Medical Center Research Institute, San Francisco, California, USA.
authors: Steven R
authors: SR
authors: Cummings
authors: Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, USA.|Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors: Joshua C
authors: JC
authors: Denny
authors: Montreal Heart Institute, Université de Montréal, Montreal, Canada.
authors: Marie Pierre
authors: MP
authors: Dubé
authors: Cardiovascular Research Group, School of Biosciences, University of Manchester, Manchester, UK.
authors: Paul N
authors: PN
authors: Durrington
authors: Icelandic Heart Association, Kopavogur, Iceland.
authors: Gudny
authors: G
authors: Eiriksdottir
authors: Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK.
authors: Ian
authors: I
authors: Ford
authors: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Departments of Pediatrics and Medicine at Harbor-UCLA Medical Center, Torrance, California, USA.
authors: Xiuqing
authors: X
authors: Guo
authors: Laboratory of Epidemiology, Demography, Biometry, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
authors: Tamara B
authors: TB
authors: Harris
authors: Department of Epidemiology, University of Washington, Seattle, Washington, USA.|Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA.|Group Health Research Institute, Group Health Cooperative, Seattle, Washington, USA.
authors: Susan R
authors: SR
authors: Heckbert
authors: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.|The Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands.
authors: Albert
authors: A
authors: Hofman
authors: Department of Vascular Medicine, Academic Medical Center, Amsterdam, North Holland, Netherlands.
authors: G Kees
authors: GK
authors: Hovingh
authors: Department of Vascular Medicine, Academic Medical Center, Amsterdam, North Holland, Netherlands.
authors: John J P
authors: JJ
authors: Kastelein
authors: Laboratory of Epidemiology, Demography, Biometry, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
authors: Leonore J
authors: LJ
authors: Launer
authors: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
authors: Ching-Ti
authors: CT
authors: Liu
authors: Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors: Yongmei
authors: Y
authors: Liu
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.|Department of Statistic, University of Auckland, Auckland, New Zealand.
authors: Thomas
authors: T
authors: Lumley
authors: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
authors: Paul M
authors: PM
authors: McKeigue
authors: Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.|Barts NIHR Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, EC1M 6BQ, UK.
authors: Patricia B
authors: PB
authors: Munroe
authors: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.
authors: Andrew
authors: A
authors: Neil
authors: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors: Deborah A
authors: DA
authors: Nickerson
authors: Medical Evidence and Observational Research, AstraZeneca Gothenburg, Mölndal, Sweden.|Unit of Occupational and Environmental Medicine, University of Gothenburg, Gothenburg, Sweden.
authors: Fredrik
authors: F
authors: Nyberg
authors: The Conway Institute, University College Dublin, Dublin 4, Ireland.
authors: Eoin
authors: E
authors: O'Brien
authors: Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, USA.|Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.|NHLBI Division of Intramural Research, Bethesda, Maryland, USA.
authors: Christopher J
authors: CJ
authors: O'Donnell
authors: Department of Cardiology, Johns Hopkins University, Baltimore, Maryland, USA.
authors: Wendy
authors: W
authors: Post
authors: International Centre for Circulatory Health, Imperial College London, London, UK.
authors: Neil
authors: N
authors: Poulter
authors: Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston University School of Medicine, and the Framingham Heart Study, Framingham, Massachusetts, USA.
authors: Ramachandran S
authors: RS
authors: Vasan
authors: Department of Biostatistics, University of Washington, Seattle, Washington, USA.
authors: Kenneth
authors: K
authors: Rice
authors: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
authors: Stephen S
authors: SS
authors: Rich
authors: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Fernando
authors: F
authors: Rivadeneira
authors: Institute of Cardiovascular and Medical Science, University of Glasgow, Glasgow, Scotland.
authors: Naveed
authors: N
authors: Sattar
authors: International Centre for Circulatory Health, Imperial College London, London, UK.
authors: Peter
authors: P
authors: Sever
authors: Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.|Barts NIHR Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, EC1M 6BQ, UK.
authors: Sue
authors: S
authors: Shaw-Hawkins
authors: The Conway Institute, University College Dublin, Dublin 4, Ireland.|School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland.
authors: Denis C
authors: DC
authors: Shields
authors: Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors: P Eline
authors: PE
authors: Slagboom
authors: Department of Epidemiology, University of Washington, Seattle, Washington, USA.|Group Health Research Institute, Group Health Cooperative, Seattle, Washington, USA.|Department of Veterans Affairs Office of Research and Development, Seattle Epidemiologic Research and Information Center, Seattle, Washington, USA.
authors: Nicholas L
authors: NL
authors: Smith
authors: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors: Joshua D
authors: JD
authors: Smith
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.|Division of Cardiology, Harborview Medical Center, University of Washington, Seattle, Washington, USA.
authors: Nona
authors: N
authors: Sotoodehnia
authors: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.|Beaumont Hospital, Dublin, Ireland.
authors: Alice
authors: A
authors: Stanton
authors: Faculty of Medicine, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
authors: David J
authors: DJ
authors: Stott
authors: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.|Inspectorate of Health Care, the Hague, the Netherlands.
authors: Bruno H
authors: BH
authors: Stricker
authors: Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.
authors: Til
authors: T
authors: Stürmer
authors: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.|The Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands.|Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: André G
authors: AG
authors: Uitterlinden
authors: Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, USA.
authors: Wei-Qi
authors: WQ
authors: Wei
authors: Department of Public Health, Center for Healthy Ageing, University of Copenhagen, Copenhagen, Denmark.
authors: Rudi G J
authors: RG
authors: Westendorp
authors: Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.|Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
authors: Eric A
authors: EA
authors: Whitsel
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors: Kerri L
authors: 0000-0003-2749-1279
authors: KL
authors: Wiggins
authors: Department of Internal Medicine, Sanford Healthcare, Sioux Falls, South Dakota, USA.|Department of Medicine, University of South Dakota, Sioux Falls, South Dakota, USA.
authors: Russell A
authors: RA
authors: Wilke
authors: Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
authors: Christie M
authors: CM
authors: Ballantyne
authors: Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.|Department of Public Health, University of Dundee, Dundee, UK.
authors: Helen M
authors: HM
authors: Colhoun
authors: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.|Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, USA.
authors: L Adrienne
authors: LA
authors: Cupples
authors: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Oscar H
authors: OH
authors: Franco
authors: Icelandic Heart Association, Kopavogur, Iceland.|Department of Medicine, University of Iceland, Reykjavik, Iceland.
authors: Vilmundur
authors: V
authors: Gudnason
authors: Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors: Graham
authors: G
authors: Hitman
authors: Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
authors: Colin N A
authors: CN
authors: Palmer
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.|Department of Epidemiology, University of Washington, Seattle, Washington, USA.|Group Health Research Institute, Group Health Cooperative, Seattle, Washington, USA.|Department of Health Services, University of Washington, Seattle, Washington, USA.
authors: Bruce M
authors: BM
authors: Psaty
authors: Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors: Paul M
authors: PM
authors: Ridker
authors: Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors: Jeanette M
authors: JM
authors: Stafford
authors: Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.|Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA.
authors: Charles M
authors: CM
authors: Stein
authors: Montreal Heart Institute, Université de Montréal, Montreal, Canada.
authors: Jean-Claude
authors: JC
authors: Tardif
authors: Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.|Barts NIHR Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, EC1M 6BQ, UK.
authors: Mark J
authors: MJ
authors: Caulfield
authors: Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.|Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands.|Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
authors: J Wouter
authors: JW
authors: Jukema
authors: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Departments of Pediatrics and Medicine at Harbor-UCLA Medical Center, Torrance, California, USA.
authors: Jerome I
authors: JI
authors: Rotter
authors: Department of Atherosclerosis Research, Children's Hospital Oakland Research Institute, Oakland, California, USA.
authors: Ronald M
authors: RM
authors: Krauss
mesh_terms: D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics*; D008076:Cholesterol, HDL / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008297:Male; D000071184:Pharmacogenomic Variants; D020641:Polymorphism, Single Nucleotide; D016896:Treatment Outcome; D044465:White People / Q000235:genetics
chemical_list: C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors
keywords: Genome-wide association study; HDL-cholesterol; Statins; pharmacogenetics