title: Genetic factors affecting statin concentrations and subsequent myopathy: a HuGENet systematic review.
abstract: Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, have proven efficacy in both lowering low-density-lipoprotein levels and preventing major coronary events, making them one of the most commonly prescribed drugs in the United States. Statins exhibit a class-wide side effect of muscle toxicity and weakness, which has led regulators to impose both dosage limitations and a recall. This review focuses on the best-characterized genetic factors associated with increased statin muscle concentrations, including the genes encoding cytochrome P450 enzymes (CYP2D6, CYP3A4, and CYP3A5), a mitochondrial enzyme (GATM), an influx transporter (SLCO1B1), and efflux transporters (ABCB1 and ABCG2). A systematic literature review was conducted to identify relevant research evaluating the significance of genetic variants predictive of altered statin concentrations and subsequent statin-related myopathy. Studies eligible for inclusion must have incorporated genotype information and must have associated it with some measure of myopathy, either creatine kinase levels or self-reported muscle aches and pains. After an initial review, focus was placed on seven genes that were adequately characterized to provide a substantive review: CYP2D6, CYP3A4, CYP3A5, GATM, SLCO1B1, ABCB1, and ABCG2. All statins were included in this review. Among the genetic factors evaluated, statin-related myopathy appears to be most strongly associated with variants in SLCO1B1.
authors.affiliation: Pharmaceutical Outcomes Research and Policy Program, School of Pharmacy, University of Washington, Seattle, Washington, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Canestaro
authors.affiliation: Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Austin
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington, USA.
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Thummel
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000579:Amidinotransferases / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D014644:Genetic Variation; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D027381:Liver-Specific Organic Anion Transporter 1; D009135:Muscular Diseases / Q000139:chemically induced* / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics; D027361:Organic Anion Transporters / Q000235:genetics*; D019821:Simvastatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D003577:Cytochrome P-450 Enzyme System; D019821:Simvastatin; D000579:Amidinotransferases; C020681:glycine amidinotransferase