A genetic risk score is associated with statin-induced low-density lipoprotein cholesterol lowering

Maarten Leusink; Anke H Maitland-van der Zee; Bo Ding; Fotios Drenos; Erik Pa van Iperen; Helen R Warren; Mark J Caulfield; L Adrienne Cupples; Mary Cushman; Aroon D Hingorani; Ron C Hoogeveen; G Kees Hovingh; Meena Kumari; Leslie A Lange; Patricia B Munroe; Fredrik Nyberg; Pamela J Schreiner; Suthesh Sivapalaratnam; Paul Iw de Bakker; Anthonius de Boer; Brendan J Keating; Folkert W Asselbergs; N Charlotte Onland-Moret

doi:10.2217/pgs.16.8

A genetic risk score is associated with statin-induced low-density lipoprotein cholesterol lowering

Pharmacogenomics. 2016 Apr;17(6):583-91. doi: 10.2217/pgs.16.8. Epub 2016 Apr 5.

Authors

Maarten Leusink^{1

2}, Anke H Maitland-van der Zee¹, Bo Ding³, Fotios Drenos^{4

5}, Erik Pa van Iperen^{6

7}, Helen R Warren^{8

9}, Mark J Caulfield^{8

9}, L Adrienne Cupples^{10

11}, Mary Cushman¹², Aroon D Hingorani¹³, Ron C Hoogeveen¹⁴, G Kees Hovingh¹⁵, Meena Kumari¹³, Leslie A Lange¹⁶, Patricia B Munroe^{8

9}, Fredrik Nyberg^{3

17}, Pamela J Schreiner¹⁸, Suthesh Sivapalaratnam¹⁵, Paul Iw de Bakker^{2

19}, Anthonius de Boer¹, Brendan J Keating²⁰, Folkert W Asselbergs^{6

21

22}, N Charlotte Onland-Moret²

Affiliations

¹ Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
² Julius Center for Health Sciences & Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
³ Medical Evidence & Observational Research Center, Global Medical Affairs, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
⁴ Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK.
⁵ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
⁶ Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands.
⁷ Department of Clinical Epidemiology, Biostatistics & Bioinformatics, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.
⁸ Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
⁹ NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, UK.
¹⁰ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
¹¹ The National Heart, Lung, & Blood Institute Framingham Heart Study, Framingham, MA, USA.
¹² Departments of Medicine & Pathology, University of Vermont, Burlington, VT, USA.
¹³ Department of Epidemiology & Public Health, UCL Institute of Epidemiology & Health Care, University College London, London, UK.
¹⁴ Division of Atherosclerosis & Vascular Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
¹⁵ Department of Vascular Medicine, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.
¹⁶ Department of Genetics, University of North Carolina School of Medicine at Chapel Hill, Chapel Hill, NC, USA.
¹⁷ Occupational & Environmental Medicine, Department of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹⁸ School of Public Health, University of Minnesota, Minneapolis, MN, USA.
¹⁹ Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
²⁰ Division of Transplantation, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
²¹ Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
²² Faculty of Population Health Sciences, Institute of Cardiovascular Science, University College London, London, UK.

Abstract

Aim: To find new genetic loci associated with statin response, and to investigate the association of a genetic risk score (GRS) with this outcome.

Patients & methods: In a discovery meta-analysis (five studies, 1991 individuals), we investigated the effects of approximately 50000 single nucleotide polymorphisms on statin response, following up associations with p < 1 × 10(-4) (three independent studies, 5314 individuals). We further assessed the effect of a GRS based on SNPs in ABCG2, LPA and APOE.

Results: No new SNPs were found associated with statin response. The GRS was associated with reduced statin response: 0.0394 mmol/l per allele (95% CI: 0.0171-0.0617, p = 5.37 × 10(-4)).

Conclusion: The GRS was associated with statin response, but the small effect size (˜2% of the average low-density lipoprotein cholesterol reduction) limits applicability.

Keywords: pharmacogenetics cholesterol; risk score; statin therapy.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily G, Member 2 / genetics
Adult
Aged
Apolipoproteins E / genetics
Cholesterol, LDL / blood*
Cholesterol, LDL / genetics*
Female
Genome-Wide Association Study / methods
Genotype
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors / adverse effects*
Male
Middle Aged
Polymorphism, Single Nucleotide / genetics
Risk Factors

Substances

ATP Binding Cassette Transporter, Subfamily G, Member 2
Apolipoproteins E
Cholesterol, LDL
Hydroxymethylglutaryl-CoA Reductase Inhibitors

Abstract

Publication types

MeSH terms

Substances

Grants and funding