Transgenic mouse model reveals an unsuspected role of the acetylcholine receptor in statin-induced neuromuscular adverse drug reactions.
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.
Department of Biology, University of Puerto Rico, Río Piedras Campus, San Juan, PR, USA.
G E
GE
Grajales-Reyes
C A
CA
Báez-Pagán
H
H
Zhu
J G
JG
Grajales-Reyes
M
M
Delgado-Vélez
W F
WF
García-Beltrán
C A
CA
Luciano
O
O
Quesada
R
R
Ramírez
C M
CM
Gómez
J A
JA
Lasalde-Dominicci
D000483:Alleles; D000596:Amino Acids / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D064420:Drug-Related Side Effects and Adverse Reactions; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009135:Muscular Diseases / Q000139:chemically induced / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011978:Receptors, Nicotinic / Q000235:genetics*
D000596:Amino Acids; C555576:CHRNA1 protein, mouse; D051242:Caveolin 1; D011978:Receptors, Nicotinic; D002784:Cholesterol; C013165:statine