RYR1 and CACNA1S genetic variants identified with statin-associated muscle symptoms

Abstract

To examine the genetic differences between subjects with statin-associated muscle symptoms and statin-tolerant controls. Materials & methods: Next-generation sequencing was used to characterize the exomes of 76 subjects with severe statin-associated muscle symptoms and 50 statin-tolerant controls. Results: 12 probably pathogenic variants were found within the RYR1 and CACNA1S genes in 16% of cases with severe statin-induced myopathy representing a fourfold increase over variants found in statintolerant controls. Subjects with probably pathogenic RYR1 or CACNA1S variants had plasma CK 5X to more than 400X the upper limit of normal in addition to having muscle symptoms. Conclusions: Genetic variants within the RYR1 and CACNA1S genes are likely to be a major contributor to the susceptibility to statin-associated muscle symptoms.

Statin-Related Myotoxicity: A Comprehensive Review of Pharmacokinetic, Pharmacogenomic and Muscle Components

“…CACNA1S encodes the alpha-1 subunit of the L-type calcium channel (the dihydropyridine receptor) which associates with RYR1 in skeletal muscle, and CACNA1S mutations are associated with malignant hyperthermia and hypokalaemic periodic paralysis. Importantly, disease-causing mutations or variants in RYR1 and CACNA1S have been found to be more frequent in statin myopathy patients than controls [135,136]. Furthermore, muscle biopsies from patients with SRM express significantly higher RYR3 mRNA and have more severe structural damage, including intracellular T-tubular vacuolisation, than both statin-naïve and statin tolerant controls [238].…”

“…It is thought that these conditions increase susceptibility to SRM through reducing the ability of skeletal muscle to compensate to statin-induced myotoxic effects. Metabolic myopathies with an identified genetic mutation that has subsequently been found in patients presenting with SRM include: adenosine monophosphate deaminase (AMPD1) deficiency (formerly myoadenylate deaminase deficiency) [129], carnitine palmitoyltransferase 2 (CPT2) deficiency [129], glycogen storage diseases II (Pompe disease; GAA deficiency) [133], V (McArdle disease, PYGM deficiency) [129] and IX (muscle phosphorylase b kinase (PHKA1) deficiency) [131], malignant hyperthermia (RYR1, CACNA1S) [135,136], recurrent childhood myoglobinuria (LPIN1 mutation) [134], and type I (DMPK) [130] and II (CNBP) [132] myotonic dystrophy. In addition, immune-mediated rippling muscle disease presenting after statin exposure has been reported [206], and mitochondrial myopathies presenting as rhabdomyolsis have been unmasked following statin treatment, although mitochondrial genetic mutations were not identified in these cases [130,207].…”

A Mechanism for Statin-Induced Susceptibility to Myopathy

“…The likely scenario is that the statin-induced RyR1 destabilization has to be combined with other factor(s) for myopathic symptoms to occur. The concept that individuals might be genetically predisposed to myopathy as a result of altered statin metabolism and/or muscle susceptibility is gaining acceptance 75, 76, 77. There is strong support for dysregulation of Ca 2+ handling contributing to muscle susceptibility.…”

“…For example, disease-causing mutations or rare variants in RyR1 have been found in those who experienced statin-associated muscle symptoms (78). Nearly one-fifth of a cohort of subjects who had severe statin myositis had rare variants within genes for RyR1 and the pore-forming subunit of the L-type Ca 2+ channel (76). Gene expression analysis of muscle from patients with a history of statin myalgia who were re-challenged with statins revealed a number of pathways and networks linked with RyR regulatory proteins, including calmodulin and autocrine motility factor (which plays a role in endoplasmic reticulum (ER)/SR-mitochondrial communication) (79), and regulatory Ca 2+ -binding proteins (calpain, calcineurin) (75).…”

Statin-Induced Myopathy: Translational Studies from Preclinical to Clinical Evidence

“…Indeed, acute applications of simvastatin on skeletal muscle fibers from human biopsies triggered an increase of intracellular Ca 2+ that mostly originates from sarcoplasmic reticulum (SR) [ 63 , 64 , 65 , 66 , 67 ]. Genetic variants within the ryanodine ( RyR ) and dihydropiridine ( DHP ) receptor genes are associated to the vulnerability to statin-associated muscle symptoms [ 68 ].…”