title: Large copy-number variations in patients with statin-associated myopathy affecting statin myopathy-related loci.
abstract: Some patients are susceptible to statin-associated myopathy (SAM) either because of genetic variations affecting statin uptake and metabolism, or because they predispose their carriers to muscular diseases. Among the frequent variants examined using the genome-wide association study approach, SLCO1B1 c.521T>C represents the only validated predictor of SAM in patients treated with high-dose simvastatin. Our aim was to ascertain the overall contribution of large copy-number variations (CNVs) to SAM diagnosed in 86 patients. CNVs were detected by whole genome genotyping using Illumina HumanOmni2.5 Exome BeadChips. Exome sequence data were used for validation of CNVs in SAM-related loci. In addition, we performed a specific search for CNVs in the SLCO1B region detected recently in Rotor syndrome subjects. Rare deletions possibly contributing to genetic predisposition to SAM were found in two patients: one removed EYS associated previously with SAM, the other was present in LARGE associated with congenital muscular dystrophy. Another two patients carried deletions in CYP2C19, which may predispose to clopidogrel-statin interactions. We found no common large CNVs potentially associated with SAM and no CNVs in the SLCO1B locus. Our findings suggest that large CNVs do not play a substantial role in the etiology of SAM.
authors.affiliation: Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University, Prague, Czech Republic; Institute for Clinical and Experimental Medicine, Prague, Czech Republic. miji@ikem.cz.
authors.forename: V
authors.initials: V
authors.lastname: Stránecký
authors.forename: M
authors.initials: M
authors.lastname: Neřoldová
authors.forename: K
authors.initials: K
authors.lastname: Hodaňová
authors.forename: H
authors.initials: H
authors.lastname: Hartmannová
authors.forename: L
authors.initials: L
authors.lastname: Piherová
authors.forename: P
authors.initials: P
authors.lastname: Zemánková
authors.forename: A
authors.initials: A
authors.lastname: Přistoupilová
authors.forename: M
authors.initials: M
authors.lastname: Vrablík
authors.forename: V
authors.initials: V
authors.lastname: Adámková
authors.forename: S
authors.initials: S
authors.lastname: Kmoch
authors.forename: M
authors.initials: M
authors.lastname: Jirsa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D003402:Creatine Kinase / Q000097:blood; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D056426:Genetic Loci; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D006933:Hyperbilirubinemia, Hereditary / Q000235:genetics; D027381:Liver-Specific Organic Anion Transporter 1 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009135:Muscular Diseases / Q000139:chemically induced* / Q000235:genetics*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; C503999:SLCO1B1 protein, human; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D003402:Creatine Kinase