Date Published: June 26, 2019
Publisher: Public Library of Science
Author(s): 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. Morrison, Etienne 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 A. N. Palmer, Bruce M. Psaty, Ana Alfirevic, Katriina Aalto-Setala.
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.
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.
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.
Lipid-lowering drugs that inhibit 5-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA), known as statins, are widely used for the primary and secondary prevention of cardiovascular disease (CVD). All statins can cause muscle toxicity that ranges in severity from mild muscle pain to severe myopathy or rhabdomyolysis, which can lead to kidney failure and death . The most severe forms of statin-related muscle injury are uncommon, suggesting a genetic predisposition. For instance, severe statin-related myopathy (SRM) restricted to cases with creatine phosphokinase (CK) levels >10x the upper limit of normal (ULN) (SRM 4) requiring hospitalisation, occurs in approximately 1–10 out of every 10,000 individuals taking standard statin doses .
Across the two case-control studies, there were 505 SRM cases and 2,047 treatment-tolerant controls that passed sample-level quality control (Table 1). Most of the US-UK cases (mean CK 159x ULN) were severe (65%) and used cerivastatin or simvastatin, while most of the PREDICTION-ADR cases (mean CK 32x ULN) were moderate (61%) and used simvastatin or atorvastatin.
We recruited more than 500 patients with statin-related muscle injury from multiple sites in North America and Europe to conduct the largest whole-exome sequencing study of this adverse drug reaction to date. Using high-throughput sequencing technology, joint variant calling at two experienced analysis centres, and rigorous statistical methods, we did not identify any novel coding variants associated with SRM 3–5. We also evaluated hypotheses about the burden of rare coding variants within genes, muscle injury due to specific statin drugs, and the severity of muscle injury; the findings from these analyses were null as well.