Rare variants in known and novel candidate genes predisposing to statin-associated myopathy.
Genetic variants affecting statin uptake, metabolism or predisposing to muscular diseases may confer susceptibility to statin-induced myopathy. Besides the SLCO1B1 rs4149056 genotype, common genetic variants do not seem to determine statin-associated myopathy. Here we aimed to address the potential role of rare variants.



We performed whole exome sequencing in 88 individuals suffering from statin-associated myopathy and assessed the burden of rare variants using candidate-gene and exome-wide association analysis.



In the novel candidate gene CLCN1, we identified a heterozygote truncating mutation p.R894* in four patients. In addition, we detected predictably pathogenic case-specific variants in MYOT, CYP3A5, SH3TC2, FBXO32 and RBM20.



These findings support the role of rare variants and nominate loci for follow-up studies.
Laboratory of Experimental Hepatology, Center for Experimental Medicine, Institute for Clinical & Experimental Medicine, Prague, Czech Republic.
Magdaléna
M
Neřoldová
Institute of Inherited Metabolic Diseases, First Medical Faculty, Charles University, Prague, Czech Republic.
Viktor
V
Stránecký
Institute of Inherited Metabolic Diseases, First Medical Faculty, Charles University, Prague, Czech Republic.
Kateřina
K
Hodaňová
Institute of Inherited Metabolic Diseases, First Medical Faculty, Charles University, Prague, Czech Republic.
Hana
H
Hartmannová
Institute of Inherited Metabolic Diseases, First Medical Faculty, Charles University, Prague, Czech Republic.
Lenka
L
Piherová
Institute of Inherited Metabolic Diseases, First Medical Faculty, Charles University, Prague, Czech Republic.
Anna
A
Přistoupilová
Laboratory for Atherosclerosis Research, Center for Experimental Medicine, Institute for Clinical & Experimental Medicine, Prague, Czech Republic.
Lenka
L
Mrázová
Third Medical Department, First Faculty of Medicine, Charles University & General Faculty Hospital, Prague, Czech Republic.
Michal
M
Vrablík
Preventive Cardiology Department, Institute for Clinical & Experimental Medicine, Prague, Czech Republic.
Věra
V
Adámková
Laboratory for Atherosclerosis Research, Center for Experimental Medicine, Institute for Clinical & Experimental Medicine, Prague, Czech Republic.
Jaroslav A
JA
Hubáček
Laboratory of Experimental Hepatology, Center for Experimental Medicine, Institute for Clinical & Experimental Medicine, Prague, Czech Republic.
Milan
M
Jirsa
Institute of Inherited Metabolic Diseases, First Medical Faculty, Charles University, Prague, Czech Republic.
Stanislav
S
Kmoch
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018118:Chloride Channels / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D027381:Liver-Specific Organic Anion Transporter 1 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009135:Muscular Diseases / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics*; D035583:Rare Diseases / Q000235:genetics
C086321:CLC-1 channel; D018118:Chloride Channels; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; C503999:SLCO1B1 protein, human
CLCN1; atorvastatin; gene; myopathy; rosuvastatin; simvastatin; statin