Incidence of statin-associated muscle symptoms in patients taking statins with RYR1 or CACNA1S variants

Abstract

Background: Statins are commonly used medications. Variants in SLCO1B1, CYP2C9, and ABCG2 are known predictors of muscle effects when taking statins. More exploratory genes include RYR1 and CACNA1S, which can also be associated with disease conditions. Methods: Patients with pathogenic/likely pathogenic variants in RYR1 or CACNA1S were identified through an elective genomic testing program. Through chart review, patients with a history of statin use were assessed for statin-associated muscle symptoms (SAMS) along with collection of demographics and other known risk factors for SAMS. Results: Of the 23 patients who had a pathogenic or likely pathogenic RYR1 or CACNA1S variant found, 12 had previous statin use; of these, SAMS were identified in four patients. Conclusion: These data contribute to previous literature suggesting patients with RYR1 variants may have an increased SAMS risk. Additional research will be helpful in further investigating this relationship and providing recommendations.

Summary points

• Statins are commonly used medications to treat high cholesterol and to prevent cardiovascular disease.

• Discontinuation of statins is often due to statin-associated muscle symptoms (SAMS).

• Gene variants known to be predictors of SAMS include variants in SLCO1B1, CYP2C9, ABCG2, CPT2, PYGM, AMPD1, PHKA1, LPIN1, CNBP, RYR1, and CACNA1S.

• Elective genetic testing often includes RYR1 and CACNA1S because of their association with malignant hyperthermia susceptibility, and therefore increasing numbers of patients are incidentally identified to have variants in these genes.

• This study examined 23 patients from a single health system who had identified pathogenic or likely pathogenic variants for RYR1 or CACNA1S, of whom 12 were current or past statin users.

• Four patients had evidence of SAMS, of whom three had documented statin intolerance noted in the electronic health record.

• RYR1 and CACNA1S should be further investigated as a potential risk factor for SAMS.

Keywords: :

• adverse drug reaction
• CACNA1S
• malignant hyperthermia
• myopathy
• RYR1
• statins

Author contributions

N Petry, A Massmann, M Bell, A Schultz, and J Van Heukelom all meet the following criteria: (a) substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND (b) drafting the work or revising it critically for important intellectual content; AND (c) final approval of the version to be published; AND (d) agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Financial disclosure

This work was funded by a generous gift from T. Denny Sanford creating the Imagenetics initiative (merging Internal Medicine and Genetics). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board (IRB) approval for all human investigations. In addition, for investigations involving human subjects, informed consent was not needed per the IRB due to the retrospective nature of the article.

Acknowledgments

The authors would like to thank S Wirz for her help with reference formatting; A Skarphol for proofreading; A Glanzer, M Knouse, P Stys, B Black and S Leier for compiling some background information; the Sanford Medical Genetics Lab, the clinical genetic counselor team who see MHS patients, and the METRICS team.