Rooted in risk: genetic predisposition for low-density lipoprotein cholesterol level associates with diminished low-density lipoprotein cholesterol response to statin treatment

Roelof Aj Smit; Iris Postmus; Stella Trompet; Michael R Barnes; Helen Warren; Benoit J Arsenault; Daniel I Chasman; L Adrienne Cupples; Graham A Hitman; Ronald M Krauss; Xiaohui Li; Bruce M Psaty; Charles M Stein; Jerome I Rotter; J Wouter Jukema

doi:10.2217/pgs-2016-0091

Rooted in risk: genetic predisposition for low-density lipoprotein cholesterol level associates with diminished low-density lipoprotein cholesterol response to statin treatment

Pharmacogenomics. 2016 Oct;17(15):1621-1628. doi: 10.2217/pgs-2016-0091. Epub 2016 Sep 20.

Authors

Roelof Aj Smit^{1

2}, Iris Postmus², Stella Trompet^{1

2}, Michael R Barnes^{3

4}, Helen Warren^{3

4}, Benoit J Arsenault⁵, Daniel I Chasman^{6

7}, L Adrienne Cupples^{8

9}, Graham A Hitman¹⁰, Ronald M Krauss¹¹, Xiaohui Li¹², Bruce M Psaty^{13

14}, Charles M Stein^{15

16}, Jerome I Rotter¹², J Wouter Jukema^{1

17

18}

Affiliations

¹ Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
² Section of Gerontology & Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands.
³ William Harvey Research Institute, Barts & The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, UK.
⁴ NIHR Barts Cardiovascular Biomedical Research Unit, Barts & The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, UK.
⁵ Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Québec, Canada.
⁶ Division of Preventive Medicine, Brigham & Women's Hospital, Boston, MA 02215, USA.
⁷ Harvard Medical School, Harvard University, Boston, MA 02115, USA.
⁸ Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
⁹ National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA 01702-5827, USA.
¹⁰ Blizard Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
¹¹ Department of Atherosclerosis Research, Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.
¹² Institute for Translational Genomics & Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
¹³ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology & Health Services, University of Washington, Seattle, WA 98101, USA.
¹⁴ Group Health Research Institute, Group Health Cooperative, Seattle, WA 98101, USA.
¹⁵ Department of Medicine, Vanderbilt University, Nashville, TN 37232-6602, USA.
¹⁶ Department of Pharmacology, Vanderbilt University, Nashville, TN 37232-6602, USA.
¹⁷ Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
¹⁸ Interuniversity Cardiology Institute Netherlands, Utrecht, The Netherlands.

Abstract

Aims: To utilize previously reported lead SNPs for low-density lipoprotein cholesterol (LDL-c) levels to find additional loci of importance to statin response, and examine whether genetic predisposition to LDL-c levels associates with differential statin response.

Methods: We investigated effects on statin response of 59 LDL-c SNPs, by combining summary level statistics from the Global Lipids Genetics and Genomic Investigation of Statin Therapy consortia.

Results: Lead SNPs for APOE, SORT1 and NPC1L1 were associated with a decreased LDL-c response to statin treatment, as was overall genetic predisposition for increased LDL-c levels as quantified with 59 SNPs, with a 5.4% smaller statin response per standard deviation increase in genetically raised LDL-c levels.

Conclusion: Genetic predisposition for increased LDL-c level may decrease efficacy of statin therapy.

Keywords: MR–Egger; pharmacogenetics; statin therapy.

MeSH terms

Cholesterol, LDL / blood*
Genetic Predisposition to Disease*
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
Pharmacogenetics
Polymorphism, Single Nucleotide*
Triglycerides / blood

Substances

Cholesterol, LDL
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Triglycerides

Abstract

MeSH terms

Substances

Grants and funding