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PLoS One. 2019 Jun 26;14(6):e0218115. doi: 10.1371/journal.pone.0218115. eCollection 2019.

Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing.

Author information

1
Department of Medicine, University of Washington, Seattle, Washington, United States of America.
2
MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
3
Division of Molecular and Clinical Medicine, University of Dundee, Dundee, United Kingdom.
4
Functional and Comparative Genomics, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
5
School of Population Health and Environmental Sciences, London, United Kingdom.
6
Human Genetics Center, University of Texas Health Science Center, Houston, United States of America.
7
Medical School, University of Liverpool, Liverpool, United Kingdom.
8
Department of Medical Sciences, Clinical Pharmacology and Science for Life Laboratory, Uppsala University, Uppsala University Hospital, Uppsala, Sweden.
9
Medical Products Agency, Uppsala, Sweden.
10
Swedish Twin Registry, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
11
Clinical Lipidology and Rare Lipid Disorders Unit, Department of Medicine, Université de Montréal Community Gene Medicine Center, Lipid Clinic Chicoutimi Hospital and ECOGENE-21 Clinical and Translational Research Center, Chicoutimi, Quebec, Canada.
12
Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
13
Usher Institute of Population Health Sciences and Informatics, University of Edinburgh Medical School, Edinburgh, Scotland, United Kingdom.
14
Department of Epidemiology, Erasmus Medical Centre, Rotterdam, the Netherlands.
15
Paul Sabatier University - Toulouse III, UPS Toulouse, Laboratoire de Pharmacologie Medicale et Clinique, Toulouse, France.
16
Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.
17
Clinical Practice Research Datalink (CPRD) Medicines and Healthcare Products Regulatory Agency, London, United Kingdom.
18
Rheumatology Department, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Salford, United Kingdom.
19
Human Genome Sequencing Center, Baylor College of Medicine, Houston, United States of America.
20
Centre Hospitalier Universitaire de Toulouse, CHU Toulouse, Centre de Pharmacovigilance, Toulouse, France.
21
Departments of Pathology & Laboratory Medicine and Biochemistry, Larner College of Medicine, University of Vermont, Burlington, Vermont, United States of America.
22
U.O. Farmacologia, Policlinico "Gb Rossi", Verona, Italy.
23
Division of Informatics, Imaging & Data Sciences, University of Manchester, Manchester, United Kingdom.
24
Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
25
Respiratory Medicine/Pediatric Respiratory Medicine, AMC, Amsterdam, the Netherlands.
26
Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom.

Abstract

AIMS:

Statin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of SRM.

METHODS AND RESULTS:

SRM 3-5 cases (N = 505) and statin treatment-tolerant controls (N = 2047) were recruited from multiple sites in North America and Europe. SRM 3-5 was defined as symptoms consistent with muscle injury and an elevated creatine phosphokinase level >4 times upper limit of normal without another likely cause of muscle injury. Whole-exome sequencing and variant calling was coordinated from two analysis centres, and results of single-variant and gene-based burden tests were meta-analysed. No genome-wide significant associations were identified. Given the large number of cases, we had 80% power to identify a variant with minor allele frequency of 0.01 that increases the risk of SRM 6-fold at genome-wide significance.

CONCLUSIONS:

In this large whole-exome sequencing study of severe statin-related muscle injury conducted to date, we did not find evidence that rare coding variants are responsible for this adverse drug reaction. Larger sample sizes would be required to identify rare variants with small effects, but it is unclear whether such findings would be clinically actionable.

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