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Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing
Univ Washington, Dept Med, Seattle, WA 98195 USA.
Univ Liverpool, MRC Ctr Drug Safety Sci, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England.
Univ Washington, Dept Med, Seattle, WA 98195 USA.
Univ Dundee, Div Mol & Clin Med, Dundee, Scotland.
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2019 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 6, article id e0218115Article in journal (Refereed) Published
Abstract [en]

Aims Statin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins worldwide 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.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE , 2019. Vol. 14, no 6, article id e0218115
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Medical Genetics
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URN: urn:nbn:se:uu:diva-393839DOI: 10.1371/journal.pone.0218115ISI: 000482883600021PubMedID: 31242253OAI: oai:DiVA.org:uu-393839DiVA, id: diva2:1355312
Funder
EU, FP7, Seventh Framework Programme, 602108Swedish Research Council, Medicine 521-2011-2440Swedish Research Council, 521-2014-3370Swedish Research Council, 2017-00641Knut and Alice Wallenberg FoundationAvailable from: 2019-09-27 Created: 2019-09-27 Last updated: 2019-09-27Bibliographically approved

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