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Nat Commun. 2014 Oct 28;5:5068. doi: 10.1038/ncomms6068.

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

Author information

1
1] Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands [2] The Netherlands Consortium for Healthy Ageing, Leiden 2300 RC, The Netherlands.
2
1] Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands [2] Department of Cardiology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
3
Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK.
4
1] Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M6BQ, UK [2] NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London EC1M 6BQ, UK.
5
Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502, USA.
6
1] NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London EC1M 6BQ, UK [2] Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M6BQ, UK.
7
1] Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215-1204, USA [2] Harvard Medical School, Boston, Massachusetts 02215, USA.
8
Montreal Heart Institute, Universite de Montreal, Montreal H1T 1C8, Quebec, Canada.
9
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, 98101 Seattle, Washington, USA.
10
Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
11
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02215, USA.
12
Department of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee 37240, USA.
13
California Pacific Medical Center Research Institute, San Francisco, California 94107, USA.
14
1] Icelandic Heart Association, IS-201 Kopavogur, Iceland [2] University of Iceland, IS-101 Reykjavik, Iceland.
15
1] Department of Epidemiology, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands [2] Health Care Inspectorate, 2595 AN The Hague, The Netherlands.
16
Framingham Heart Study (FHS) of the National Heart, Lung and Blood Institute, Cardiovascular Epidemiology and Human Genomics, Framingham, Massachusetts 01702, USA.
17
Faculty of Medicine, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G31 2ER, UK.
18
Department of Pharmacology and Therapeutics, University College Cork, Cork 30, Ireland.
19
Robertson Center for Biostatistics, University of Glasgow, Glasgow G12 8QQ, UK.
20
1] Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands [2] The Netherlands Consortium for Healthy Ageing, Leiden 2300 RC, The Netherlands [3] Leyden Academy of Vitality and Ageing, 2333 AA Leiden, The Netherlands.
21
1] The Netherlands Consortium for Healthy Ageing, Leiden 2300 RC, The Netherlands [2] Department of Molecular Epidemiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
22
Faculty of Medicine, BHF Glasgow Cardiovascular Research Centre, Glasgow G12 8QQ, UK.
23
International Centre for Circulatory Health, Imperial College, London SW7 2AZ, UK.
24
1] Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland [2] Beaumont Hospital, Dublin 9, Ireland.
25
1] The Conway Institute, University College Dublin, Dublin 4, Ireland [2] School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
26
The Conway Institute, University College Dublin, Dublin 4, Ireland.
27
Department of Genome Sciences, University of Washington, Seattle, Washington 98101, USA.
28
Department of Cardiology, Academic Medical Center, 1100 DD Amsterdam, The Netherlands.
29
Department of Vascular Medicine, Academic Medical Center, 1100 DD Amsterdam, The Netherlands.
30
University of Edinburgh, Edinburgh EH9 3JR, UK.
31
University of Oxford, Oxford OX1 2JD, UK.
32
Cardiovascular Research Group, School of Biosciences, University of Manchester, Manchester M13 9NT, UK.
33
1] Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, UK [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK [3] Oxford NIHR Biomedical Research Centre, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, UK.
34
Department of Clinical Sciences/Diabetes &Endocrinology, Lund University, Malmo 205 02, Sweden.
35
Department of Biostatistics, University of Washington, 98115 Seattle, Washington, USA.
36
1] Department of Epidemiology, University of Washington, Seattle, Washington 98195, USA [2] Group Health Research Institute, Group Health Cooperative, Seattle, Washington 98101, USA [3] Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, Washington 98101, USA.
37
1] Cardiovascular Health Research Unit, Department of Medicine, University of Washington, 98101 Seattle, Washington, USA [2] Department of Statistic, University of Auckland, Auckland 1142, New Zealand.
38
1] Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina 27599, USA [2] Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
39
Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
40
1] NHLBI Framingham Heart Study, Framingham, Massachusetts 01701, USA [2] Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [3] National Heart, Lung and Blood Institute, Bethesda, Maryland 20892, USA.
41
Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston University School of Medicine, and the Framingham Heart Study, Framingham, Massachusetts 01701, USA.
42
Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee 37240, USA.
43
Department of Internal Medicine, Center for IMAGENETICS, Sanford Healthcare, Fargo, North Dakota, 58104 USA.
44
1] Department of Epidemiology, University of Washington, Seattle, Washington 98195, USA [2] Group Health Research Institute, Group Health Cooperative, Seattle, Washington 98101, USA [3] Cardiovascular Health Research Unit, University of Washington, Seattle, Washington 98101, USA.
45
Department of Cardiology, Johns Hopkins University, Baltimore, Maryland 21218, USA.
46
1] Cardiovascular Health Research Unit, Department of Medicine, University of Washington, 98101 Seattle, Washington, USA [2] Division of Cardiology, Harborview Medical Center, University of Washington, Seattle 98101, Washington, USA.
47
Division of Public Health Sciences, Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA.
48
Division of Public Health Sciences, Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA.
49
Department of Internal Medicine, Section on Cardiology, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA.
50
Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA.
51
Icelandic Heart Association, IS-201 Kopavogur, Iceland.
52
Laboratory of Epidemiology, Demography, Biometry, National Institute on Aging, National Institutes of Health, 7201 Wisconsin Avenue, Bethesda, Maryland 20892, USA.
53
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215-1204, USA.
54
Personalised Healthcare and Biomarkers, AstraZeneca, Alderley Park SK10 4TG, UK.
55
1] AstraZeneca Research and Development, 481 83 Mölndal, Sweden [2] Unit of Occupational and Environmental Medicine, University of Gothenburg, 405 30 Gothenburg, Sweden.
56
1] Department of Epidemiology, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands [2] Health Care Inspectorate, 2595 AN The Hague, The Netherlands [3] Department of Internal Medicine, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands.
57
1] The Netherlands Consortium for Healthy Ageing, Leiden 2300 RC, The Netherlands [2] Department of Epidemiology, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands [3] Department of Internal Medicine, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands.
58
1] The Netherlands Consortium for Healthy Ageing, Leiden 2300 RC, The Netherlands [2] Department of Epidemiology, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands.
59
Department of Internal Medicine, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands.
60
Department of Epidemiology, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands.
61
1] Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee 37240, USA [2] Department of Medicine, Vanderbilt University, Vanderbilt, Tennessee 37240, USA.
62
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
63
1] Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02215, USA [2] NHLBI Framingham Heart Study, Framingham, Massachusetts 01701, USA.
64
1] Cardiovascular Health Research Unit, Department of Medicine, University of Washington, 98101 Seattle, Washington, USA [2] Department of Epidemiology, University of Washington, Seattle, Washington 98195, USA [3] Group Health Research Institute, Group Health Cooperative, Seattle, Washington 98101, USA [4] Department of Health Services, University of Washington, Seattle, Washington 98101, USA.
65
1] Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK [2] Department of Public Health, University of Dundee, Dundee DD1 9SY, UK.
66
Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
67
Children's Hospital Oakland Research Institute, Oakland, California 94609, USA.
68
1] Department of Cardiology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands [2] Durrer Center for Cardiogenetic Research, 1105 AZ Amsterdam, The Netherlands [3] Interuniversity Cardiology Institute of the Netherlands, 3511 GC Utrecht, The Netherlands.

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.

PMID:
25350695
PMCID:
PMC4220464
DOI:
10.1038/ncomms6068
[Indexed for MEDLINE]
Free PMC Article

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