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

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.

<p>A Pharmacogenomic Dissection of a Rosuvastatin-Induced Rhabdomyolysis Case Evokes the Polygenic Nature of Adverse Drug Reactions</p>

“…As hypothesized by Floy, it is possible that there are rare variants associated with SMR in non-coding regions that escape the WES analysis. 18 Taken together, our findings reveal the potential relevance of WES as a comprehensive pharmacogenomics approach to identify common and/or rare variants potentially related to SMR. We estimate that in vitro functional studies can validate the implication of rare case-specific variants such as the one reported in this study.…”

“…Even so, we must recognize that there may be unknown drug-drug interactions with statins that are potentially related to the increased risk of myopathies and that may influence the accurate identification of drug-gene interactions. 18 To date, 8 cases of rhabdomyolysis induced by rosuvastatin and ticagrelor have been reported. 6 We performed a molecular multilevel analysis according to the mechanisms involved in the potential influence of ticagrelor on the elimination/disposal of rosuvastatin: a) kidney damage caused by ticagrelor, b) Genetic polymorphisms in drug metabolizing enzymes and c) decreased biliary and renal excretion of rosuvastatin secondary to transporter competition.…”

“…Advances in large-scale DNA sequencing technology, such as WES, have allowed us to explore the contribution of rare or low-frequency variants in human phenotypes and adverse drug reactions. 18,46 For personal use only.…”

“…46 Recently, Floyd et al reported a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of statin-related myopathy (SMR),included rhabdomyolisis. 18 The analysis sample included 505 cases that received treatment with statins at the onset time of muscle injury symptoms and 2047 controls from North America and the United Kingdom. Rare variants (MAF<1%) identified by WES were collapsed into gene-burden scores and tested for association with the risk of SMR.…”

“…Similar to other reports, the study revealed the association of SNP SLCO1B1-c.521T >C with a 4-fold increased risk of severe SMR, while in mild forms of SMR this association was not evidenced. 18 Nevordola et al conducted a WES study in 88 patients with statin-associated myopathy and assessed the burden of rare variants using candidategene and exome-wide association analysis. The strategy allowed the identification of a new gene potentially related to the phenotype (CLCN1) and case-specific pathogenic variants in MYOT,CYP3A5,SH3TC2,FBXO32 and RMB20.…”