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Original article
Meta-analysis of genome-wide association studies of HDL cholesterol response to statins
  1. Iris Postmus1,
  2. Helen R Warren2,3,
  3. Stella Trompet1,4,
  4. Benoit J Arsenault5,
  5. Christy L Avery6,
  6. Joshua C Bis7,
  7. Daniel I Chasman8,9,
  8. Catherine E de Keyser10,
  9. Harshal A Deshmukh11,
  10. Daniel S Evans12,
  11. QiPing Feng13,
  12. Xiaohui Li14,
  13. Roelof A J Smit4,
  14. Albert V Smith15,16,
  15. Fangui Sun17,
  16. Kent D Taylor14,
  17. Alice M Arnold18,
  18. Michael R Barnes2,3,
  19. Bryan J Barratt19,
  20. John Betteridge20,
  21. S Matthijs Boekholdt21,
  22. Eric Boerwinkle22,
  23. Brendan M Buckley23,
  24. Y-D Ida Chen14,
  25. Anton J M de Craen1,,
  26. Steven R Cummings12,
  27. Joshua C Denny24,25,
  28. Marie Pierre Dubé5,
  29. Paul N Durrington26,
  30. Gudny Eiriksdottir15,
  31. Ian Ford27,
  32. Xiuqing Guo14,
  33. Tamara B Harris28,
  34. Susan R Heckbert29,30,31,
  35. Albert Hofman10,32,
  36. G Kees Hovingh33,
  37. John J P Kastelein33,
  38. Leonore J Launer28,
  39. Ching-Ti Liu17,
  40. Yongmei Liu34,
  41. Thomas Lumley7,35,
  42. Paul M McKeigue36,
  43. Patricia B Munroe2,3,
  44. Andrew Neil37,
  45. Deborah A Nickerson38,
  46. Fredrik Nyberg39,40,
  47. Eoin O'Brien41,
  48. Christopher J O'Donnell42,43,44,
  49. Wendy Post45,
  50. Neil Poulter46,
  51. Ramachandran S Vasan47,
  52. Kenneth Rice18,
  53. Stephen S Rich48,
  54. Fernando Rivadeneira49,
  55. Naveed Sattar50,
  56. Peter Sever46,
  57. Sue Shaw-Hawkins2,3,
  58. Denis C Shields41,51,
  59. P Eline Slagboom52,
  60. Nicholas L Smith29,31,53,
  61. Joshua D Smith38,
  62. Nona Sotoodehnia7,54,
  63. Alice Stanton55,56,
  64. David J Stott57,
  65. Bruno H Stricker10,49,58,
  66. Til Stürmer6,
  67. André G Uitterlinden10,32,49,
  68. Wei-Qi Wei24,
  69. Rudi G J Westendorp59,
  70. Eric A Whitsel6,60,
  71. Kerri L Wiggins7,
  72. Russell A Wilke61,62,
  73. Christie M Ballantyne63,
  74. Helen M Colhoun11,64,
  75. L Adrienne Cupples17,42,
  76. Oscar H Franco10,
  77. Vilmundur Gudnason15,16,
  78. Graham Hitman65,
  79. Colin N A Palmer11,
  80. Bruce M Psaty7,29,31,66,
  81. Paul M Ridker8,
  82. Jeanette M Stafford67,
  83. Charles M Stein25,68,
  84. Jean-Claude Tardif5,
  85. Mark J Caulfield2,3,
  86. J Wouter Jukema4,69,70,
  87. Jerome I Rotter14,
  88. Ronald M Krauss71
  1. 1Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands
  2. 2Department 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
  3. 3Barts NIHR Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, EC1M 6BQ, UK
  4. 4Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
  5. 5Montreal Heart Institute, Université de Montréal, Montreal, Canada
  6. 6Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA
  7. 7Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA
  8. 8Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
  9. 9Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA
  10. 10Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
  11. 11Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK
  12. 12California Pacific Medical Center Research Institute, San Francisco, California, USA
  13. 13Department of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee, USA
  14. 14Institute 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
  15. 15Icelandic Heart Association, Kopavogur, Iceland
  16. 16Department of Medicine, University of Iceland, Reykjavik, Iceland
  17. 17Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA
  18. 18Department of Biostatistics, University of Washington, Seattle, Washington, USA
  19. 19Personalised Healthcare and Biomarkers AstraZeneca Research and Development, Alderley Park, UK
  20. 20University College London Hospital, London, UK
  21. 21Department of Cardiology, Academic Medical Center, Amsterdam, North Holland, Netherlands
  22. 22Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA
  23. 23Department of Pharmacology and Therapeutics, University College Cork, Western Road, Cork, Ireland
  24. 24Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, USA
  25. 25Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA
  26. 26Cardiovascular Research Group, School of Biosciences, University of Manchester, Manchester, UK
  27. 27Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK
  28. 28Laboratory of Epidemiology, Demography, Biometry, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA
  29. 29Department of Epidemiology, University of Washington, Seattle, Washington, USA
  30. 30Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA
  31. 31 Group Health Research Institute, Group Health Cooperative, Seattle, Washington, USA
  32. 32The Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands
  33. 33Department of Vascular Medicine, Academic Medical Center, Amsterdam, North Holland, Netherlands
  34. 34Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
  35. 35Department of Statistic, University of Auckland, Auckland, New Zealand
  36. 36Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK
  37. 37Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK
  38. 38Department of Genome Sciences, University of Washington, Seattle, Washington, USA
  39. 39Medical Evidence and Observational Research, AstraZeneca Gothenburg, Mölndal, Sweden
  40. 40Unit of Occupational and Environmental Medicine, University of Gothenburg, Gothenburg, Sweden
  41. 41The Conway Institute, University College Dublin, Dublin 4, Ireland
  42. 42Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, USA
  43. 43Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
  44. 44NHLBI Division of Intramural Research, Bethesda, Maryland, USA
  45. 45Department of Cardiology, Johns Hopkins University, Baltimore, Maryland, USA
  46. 46International Centre for Circulatory Health, Imperial College London, London, UK
  47. 47Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston University School of Medicine, and the Framingham Heart Study, Framingham, Massachusetts, USA
  48. 48Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA
  49. 49Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
  50. 50Institute of Cardiovascular and Medical Science, University of Glasgow, Glasgow, Scotland
  51. 51School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland
  52. 52Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
  53. 53Department of Veterans Affairs Office of Research and Development, Seattle Epidemiologic Research and Information Center, Seattle, Washington, USA
  54. 54Division of Cardiology, Harborview Medical Center, University of Washington, Seattle, Washington, USA
  55. 55Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland
  56. 56Beaumont Hospital, Dublin, Ireland
  57. 57Faculty of Medicine, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
  58. 58Inspectorate of Health Care, the Hague, the Netherlands
  59. 59Department of Public Health, Center for Healthy Ageing, University of Copenhagen, Copenhagen, Denmark
  60. 60Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
  61. 61Department of Internal Medicine, Sanford Healthcare, Sioux Falls, South Dakota, USA
  62. 62Department of Medicine, University of South Dakota, Sioux Falls, South Dakota, USA
  63. 63Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
  64. 64Department of Public Health, University of Dundee, Dundee, UK
  65. 65Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
  66. 66Department of Health Services, University of Washington, Seattle, Washington, USA
  67. 67Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
  68. 68Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA
  69. 69Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands
  70. 70Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands
  71. 71Department of Atherosclerosis Research, Children's Hospital Oakland Research Institute, Oakland, California, USA
  1. Correspondence to Ronald M Krauss, Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609, USA; rkrauss{at}chori.org

Abstract

Background 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.

Methods and results 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<1×10−4 from 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.

Conclusions 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.

  • pharmacogenetics
  • HDL-cholesterol
  • Statins
  • Genome-wide association study

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Footnotes

  • IP, HRW, ST, JWJ, JIR and RMK contributed equally.

  • †Passed away 17 January 2016.

  • Contributors Writing and analysis group: IP, HRW, ST, BJA, DIC, HAD, XL, RAJS, GKH, PBM, MJC, HMC, LAC, GH, CNAP, BMP, CMS, JWJ, JIR, RMK. IP and ST performed quality control on the individual study summary results. IP and ST performed meta-analysis. IP, HRW and RAJS performed additional analyses. All analysis and writing group authors extensively discussed the analysis, results, interpretation and presentation of results. All authors contributed to the research and reviewed the manuscript. Study concept and design of contributing studies: (PROSPER) JWJ, DJS, BMB, IF, NS, RGJW; (ASCOT) MJC, PS, NP, AS, DCS, EO; (CARDS) HAD, HMC, PMM, JB, PND, AN, GH; (PARC) XL, YDIC, JIR, RMK; (TNT) JJPK; (AGES) LJL, TBH, VG; (ARIC) CLA, EAW, TS, EB, CMB; (BioVU) QPF, WQW, CMS, RAW, JCD; (CHS, HVH) NS, KR, TL, BMP; (FHS) LAC, RSV; (HABC) SRC, YL; (MESA) XG, SRH, WP, JIR, SSR; (Rotterdam Study) CEK, BHS, AGU, AH, FR; (JUPITER) DIC, BJB, FN, PMR; (GoDARTS) CNAP, HMC. Phenotype data acquisition of contributing studies: (PROSPER) JWJ, DJS, BMB, IF, AJMC, NS, RGJW; (ASCOT) MJC, PBM, PS, NP, AS, DCS, EO, SSH; (CARDS) HAD, HMC, PMM, JB, PND, AD, GH; (PARC) XL, YDIC, JIR, RMK; (TNT) JJPK; (AGES) GE; (ARIC) CMB; (BioVU) WQW, CMS; (CHS, HVH) KLW, JCB, AMA, NLS, BMP; (FHS) LAC, CJO, RSV; (GoDARTS) CNAP, HMC; (HABC) SRC; (MESA) SRH, JIR; (Rotterdam Study) CEK, BHS, AH, OHF; (JUPITER) DIC, PMR. Genotype data acquisition of contributing studies: (PROSPER) ST, JWJ, AJMC, PES; (ASCOT) MJC, HRW, PBM, PS, AS, SSH; (CARDS) HAD, HMC, PMM, PND, AN, GH; (PARC) YDIC, JIR, DAN, JDS; (TNT) BJA, MPD, SMB, GKH, JCT; (AGES) AVS; (ARIC) EB; (BioVU) QPF, JCD, CTL; (CHS, HVH) JCB; (FHS) CJO; (GoDARTS) CNAP, HMC; (HABC) YL; (MESA) KDT, JIR; (Rotterdam Study) AGU, FR; (JUPITER) DIC, BJB, FN, PMR. Primary analysis from contributing studies: (PROSPER) IP, ST, AJMC, RAJS, PES; (ASCOT) HRW, MRB; (CARDS) HAD, HMC, PMM; (PARC) XL, YDIC, JIR; (TNT) BJA, MPD, SMB, GKH, JCT; (AGES) AVS; (ARIC) CLA, EAW, TS; (BioVU) QPF, WQW, CTL; (CHS, HVH) KLW, KR, TL; (FHS) LAC, FS; (GoDARTS) CNAP, HMC; (HABC) DSE, JMS; (MESA) KDT, XG, JIR; (Rotterdam Study) CEK, BHS; (JUPITER) DIC.

  • Competing interests BMP serves on the Data and Safety Monitoring Board of a clinical trial funded by the device manufacturer (Zoll LifeCor) and serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. NP and AS received funding from Pfizer for the extended follow-up of the ASCOT UK participants. DIC and PMR received research support for independent genetic analysis in JUPITER from AstraZeneca. FN and BJB have employment, stock and stock options in AstraZeneca, a for-profit company engaged in the discovery, development, manufacture and marketing of proprietary therapeutics such as rosuvastatin, but do not consider that this creates any conflict of interest with the subject-matter of this publication. RMK serves on the Merck Global Atherosclerosis Advisory Board.

  • Patient consent Obtained.

  • Ethics approval All studies were performed with the approval of the Local Medical Ethics Committees.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Summary data are available upon request by the corresponding author.

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