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J Med Genet. 2016 Dec;53(12):835-845. doi: 10.1136/jmedgenet-2016-103966. Epub 2016 Sep 1.

Meta-analysis of genome-wide association studies of HDL cholesterol response to statins.

Author information

1
Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
2
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.
3
Barts NIHR Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, EC1M 6BQ, UK.
4
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
5
Montreal Heart Institute, Université de Montréal, Montreal, Canada.
6
Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.
7
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.
8
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
9
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
10
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
11
Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
12
California Pacific Medical Center Research Institute, San Francisco, California, USA.
13
Department of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee, USA.
14
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.
15
Icelandic Heart Association, Kopavogur, Iceland.
16
Department of Medicine, University of Iceland, Reykjavik, Iceland.
17
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
18
Department of Biostatistics, University of Washington, Seattle, Washington, USA.
19
Personalised Healthcare and Biomarkers AstraZeneca Research and Development, Alderley Park, UK.
20
University College London Hospital, London, UK.
21
Department of Cardiology, Academic Medical Center, Amsterdam, North Holland, Netherlands.
22
Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA.
23
Department of Pharmacology and Therapeutics, University College Cork, Western Road, Cork, Ireland.
24
Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, USA.
25
Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
26
Cardiovascular Research Group, School of Biosciences, University of Manchester, Manchester, UK.
27
Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK.
28
Laboratory of Epidemiology, Demography, Biometry, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
29
Department of Epidemiology, University of Washington, Seattle, Washington, USA.
30
Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA.
31
Group Health Research Institute, Group Health Cooperative, Seattle, Washington, USA.
32
The Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands.
33
Department of Vascular Medicine, Academic Medical Center, Amsterdam, North Holland, Netherlands.
34
Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
35
Department of Statistic, University of Auckland, Auckland, New Zealand.
36
Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
37
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.
38
Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
39
Medical Evidence and Observational Research, AstraZeneca Gothenburg, Mölndal, Sweden.
40
Unit of Occupational and Environmental Medicine, University of Gothenburg, Gothenburg, Sweden.
41
The Conway Institute, University College Dublin, Dublin 4, Ireland.
42
Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, USA.
43
Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
44
NHLBI Division of Intramural Research, Bethesda, Maryland, USA.
45
Department of Cardiology, Johns Hopkins University, Baltimore, Maryland, USA.
46
International Centre for Circulatory Health, Imperial College London, London, UK.
47
Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston University School of Medicine, and the Framingham Heart Study, Framingham, Massachusetts, USA.
48
Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
49
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
50
Institute of Cardiovascular and Medical Science, University of Glasgow, Glasgow, Scotland.
51
School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland.
52
Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
53
Department of Veterans Affairs Office of Research and Development, Seattle Epidemiologic Research and Information Center, Seattle, Washington, USA.
54
Division of Cardiology, Harborview Medical Center, University of Washington, Seattle, Washington, USA.
55
Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
56
Beaumont Hospital, Dublin, Ireland.
57
Faculty of Medicine, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
58
Inspectorate of Health Care, the Hague, the Netherlands.
59
Department of Public Health, Center for Healthy Ageing, University of Copenhagen, Copenhagen, Denmark.
60
Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
61
Department of Internal Medicine, Sanford Healthcare, Sioux Falls, South Dakota, USA.
62
Department of Medicine, University of South Dakota, Sioux Falls, South Dakota, USA.
63
Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
64
Department of Public Health, University of Dundee, Dundee, UK.
65
Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
66
Department of Health Services, University of Washington, Seattle, Washington, USA.
67
Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
68
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA.
69
Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands.
70
Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
71
Department of Atherosclerosis Research, Children's Hospital Oakland Research Institute, Oakland, California, USA.

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.

KEYWORDS:

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

PMID:
27587472
PMCID:
PMC5309131
DOI:
10.1136/jmedgenet-2016-103966
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Competing financial 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. The remaining authors declare no competing financial interests.

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