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

PREDICTION-ADR Consortium, EUDRAGENE, James S. Floyd, Katarzyna M. Bloch, Jennifer A. Brody, Cyrielle Maroteau, Moneeza K. Siddiqui, Richard Gregory, Daniel F. Carr, Mariam Molokhia, Xiaoming Liu, Joshua C. Bis, Ammar Ahmed, Xuan Liu, Pär Hallberg, Qun-ying Yue, Patrik K. E. Magnusson, Diane Brisson, Kerri L. Wiggins, Alanna C. MorrisonEtienne Khoury, Paul McKeigue, Bruno H. Stricker, Maryse Lapeyre-Mestre, Susan R. Heckbert, Arlene M. Gallagher, Hector Chinoy, Richard A. Gibbs, Emmanuelle Bondon-Guitton, Russell Tracy, Eric Boerwinkle, Daniel Gaudet, Anita Conforti, Tjeerd Van Staa, Colleen M. Sitlani, Kenneth M. Rice, Anke-hilse Maitland-van der Zee, Mia Wadelius, Andrew P. Morris, Munir Pirmohamed, Colin N. A. Palmer, Bruce M. Psaty, Ana Alfirevic (Lead / Corresponding author)

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17 Citations (Scopus)
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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.
Original languageEnglish
Article numbere0218115
Pages (from-to)1-13
Number of pages13
JournalPLoS ONE
Issue number6
Publication statusPublished - 26 Jun 2019

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology
  • General Agricultural and Biological Sciences


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