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

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

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.

Publication types

  • Meta-Analysis
  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Genome-Wide Association Study
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / adverse effects*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
  • Muscle, Skeletal* / metabolism
  • Muscle, Skeletal* / pathology
  • Rhabdomyolysis* / chemically induced
  • Rhabdomyolysis* / genetics
  • Rhabdomyolysis* / metabolism
  • Rhabdomyolysis* / pathology
  • Whole Genome Sequencing*

Substances

  • Hydroxymethylglutaryl-CoA Reductase Inhibitors

Grant support