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Transgenic mouse model reveals an unsuspected role of the acetylcholine receptor in statin-induced neuromuscular adverse drug reactions

The Pharmacogenomics Journal volume 13, pages 362–368 (2013)Cite this article

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Abstract

High cholesterol levels are an established risk factor for cardiovascular disease (CVD), the world's leading cause of death. Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (statins) are prescribed to lower serum cholesterol levels and reduce the risk of CVD. Despite the success of statins, many patients abandon treatment owing to neuromuscular adverse drug reactions (ADRs). Genome-wide association studies have identified the single-nucleotide polymorphism (SNP) rs4149056 in the SLCO1B1 gene as being associated with an increased risk for statin-induced ADRs. By studying slow-channel syndrome transgenic mouse models, we determined that statins trigger ADRs in mice expressing the mutant allele of the rs137852808 SNP in the nicotinic acetylcholine receptor (nAChR) α-subunit gene CHRNA1. Mice expressing this allele show a remarkable contamination of end-plates with caveolin-1 and develop early signs of neuromuscular degeneration upon statin treatment. This study demonstrates that genes coding for nAChR subunits may contain variants associated with statin-induced ADRs.

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Acknowledgements

This work was supported in part by National Institutes of Health (NIH) grants 2R01GM56371-12 and SNRP U54NS0430311 to J.A. Lasalde-Dominicci and NIH grant R01NS033202 to C. Gómez. We acknowledge the contribution to this study by grants ISI0 RR-13705-01 and DBI-0923132 to establish and upgrade the Confocal Microscopy Facility at the University of Puerto Rico (CIF-UPR). G. Grajales-Reyes, J.G. Grajales-Reyes, and W.F. García-Beltrán were supported by the Research Initiative for Scientific Enhancement (RISE) Program Grant R25GM61151 and the Minority Access to Research Careers (MARC) Program Grant T34GM007821. M. Delgado-Vélez was supported by the Research Initiative for Scientific Enhancement (RISE) Program Grant R25GM61151 and the PR-LSAMP Program Grant HRD0601843. We thank Andrew Loza for his excellent assistance with the MATLAB heat map analysis.

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Authors and Affiliations

  1. Department of Biology, University of Puerto Rico, Río Piedras Campus, San Juan, PR, USA

    G E Grajales-Reyes, C A Báez-Pagán, J G Grajales-Reyes, M Delgado-Vélez, R Ramírez & J A Lasalde-Dominicci

  2. Myo ADR Technologies Corp., Carolina, PR, USA,

    C A Báez-Pagán, C A Luciano, O Quesada & J A Lasalde-Dominicci

  3. Neurology Department, The University of Chicago, Chicago, IL, USA

    H Zhu & C M Gómez

  4. Department of Chemistry, University of Puerto Rico, Río Piedras Campus, San Juan, PR, USA

    W F García-Beltrán & J A Lasalde-Dominicci

  5. Division of Neurology, University of Puerto Rico, School of Medicine, San Juan, PR, USA

    C A Luciano

  6. Department of Physical Sciences, University of Puerto Rico, Río Piedras Campus, San Juan, PR, USA

    O Quesada

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  1. G E Grajales-Reyes
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Correspondence to O Quesada or J A Lasalde-Dominicci.

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Competing interests

GEGR, CABP, CAL, OQ and JALD have filed a provisional patent application for materials related to this manuscript. Myo ADR Technologies, Corp. was founded by CABP, CAL, OQ and JALD to commercialize intellectual property published in this manuscript.

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Grajales-Reyes, G., Báez-Pagán, C., Zhu, H. et al. Transgenic mouse model reveals an unsuspected role of the acetylcholine receptor in statin-induced neuromuscular adverse drug reactions. Pharmacogenomics J 13, 362–368 (2013). https://doi.org/10.1038/tpj.2012.21

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Keywords

  • adverse drug reactions
  • cholesterol
  • neuromuscular junction
  • nicotinic acetylcholine receptor
  • statins

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