Meta-Analysis

. 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

Iris Postmus¹, Helen R Warren^{2

3}, Stella Trompet^{1

4}, Benoit J Arsenault⁵, Christy L Avery⁶, Joshua C Bis⁷, Daniel I Chasman^{8

9}, Catherine E de Keyser¹⁰, Harshal A Deshmukh¹¹, Daniel S Evans¹², QiPing Feng¹³, Xiaohui Li¹⁴, Roelof A J Smit⁴, Albert V Smith^{15

16}, Fangui Sun¹⁷, Kent D Taylor¹⁴, Alice M Arnold¹⁸, Michael R Barnes^{2

3}, Bryan J Barratt¹⁹, John Betteridge²⁰, S Matthijs Boekholdt²¹, Eric Boerwinkle²², Brendan M Buckley²³, Y-D Ida Chen¹⁴, Anton J M de Craen¹, Steven R Cummings¹², Joshua C Denny^{24

25}, Marie Pierre Dubé⁵, Paul N Durrington²⁶, Gudny Eiriksdottir¹⁵, Ian Ford²⁷, Xiuqing Guo¹⁴, Tamara B Harris²⁸, Susan R Heckbert^{29

30

31}, Albert Hofman^{10

32}, G Kees Hovingh³³, John J P Kastelein³³, Leonore J Launer²⁸, Ching-Ti Liu¹⁷, Yongmei Liu³⁴, Thomas Lumley^{7

35}, Paul M McKeigue³⁶, Patricia B Munroe^{2

3}, Andrew Neil³⁷, Deborah A Nickerson³⁸, Fredrik Nyberg^{39

40}, Eoin O'Brien⁴¹, Christopher J O'Donnell^{42

43

44}, Wendy Post⁴⁵, Neil Poulter⁴⁶, Ramachandran S Vasan⁴⁷, Kenneth Rice¹⁸, Stephen S Rich⁴⁸, Fernando Rivadeneira⁴⁹, Naveed Sattar⁵⁰, Peter Sever⁴⁶, Sue Shaw-Hawkins^{2

3}, Denis C Shields^{41

51}, P Eline Slagboom⁵², Nicholas L Smith^{29

31

53}, Joshua D Smith³⁸, Nona Sotoodehnia^{7

54}, Alice Stanton^{55

56}, David J Stott⁵⁷, Bruno H Stricker^{10

49

58}, Til Stürmer⁶, André G Uitterlinden^{10

32

49}, Wei-Qi Wei²⁴, Rudi G J Westendorp⁵⁹, Eric A Whitsel^{6

60}, Kerri L Wiggins⁷, Russell A Wilke^{61

62}, Christie M Ballantyne⁶³, Helen M Colhoun^{11

64}, L Adrienne Cupples^{17

42}, Oscar H Franco¹⁰, Vilmundur Gudnason^{15

16}, Graham Hitman⁶⁵, Colin N A Palmer¹¹, Bruce M Psaty^{7

29

31

66}, Paul M Ridker⁸, Jeanette M Stafford⁶⁷, Charles M Stein^{25

68}, Jean-Claude Tardif⁵, Mark J Caulfield^{2

3}, J Wouter Jukema^{4

69

70}, Jerome I Rotter¹⁴, Ronald M Krauss⁷¹

Affiliations

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.

PMID: 27587472
PMCID: PMC5309131
DOI: 10.1136/jmedgenet-2016-103966

Meta-Analysis

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

Iris Postmus et al. J Med Genet. 2016 Dec.

. 2016 Dec;53(12):835-845.

doi: 10.1136/jmedgenet-2016-103966. Epub 2016 Sep 1.

Authors

Affiliations

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.

PMID: 27587472
PMCID: PMC5309131
DOI: 10.1136/jmedgenet-2016-103966

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.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

PubMed Disclaimer

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.

Figures

**Figure 1**
Results of the GWAS meta-analysis. Manhattan plot presenting the –log₁₀ P-values from the combined stage 1 and 2 meta-analysis on HDL-C response to statin treatment. The top (red) line represents the genome-wide significant P-value 5×10⁻⁸, the second (blue) line represents the P-value 1×10⁻⁴, the threshold used for selecting SNPs to take forward to the second stage. Hence the results of these SNPs come from the lager combined meta-analysis, whereas all other results are taken from the stage 1 discovery meta-analysis.

**Figure 2**
Forest plot showing the association in each study and overall association of the lead *CETP* SNP rs247616 with HDL-C response to statin treatment. Beta represents fractional HDL-C change for each copy of the minor allele.

**Figure 3**
Regional association plot of the *CETP* region that was genome-wide significant for association with HDL-C response to statin treatment, using the results of the combined meta-analysis (generated using LocusZoom [39]). The color of each SNP is based on the LD (r²) with the lead SNP rs247616 (shown in purple). The RefSeq genes in the region are shown in the lower panel.

**Figure 4**
Plot of the per-allele association of genetic variants with HDL-C levels (x-axis, per allele in SD units, as reported by Willer *et al.* [11]) against the association with HDL-C response to statin treatment (y-axis, percentage) (generated using [22]). The regression line shows the linear relationship between these two variables, with 95% confidence boundaries.

See this image and copyright information in PMC

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

Affiliations

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

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Conflict of interest statement

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