title: A statin-dependent QTL for GATM expression is associated with statin-induced myopathy.
abstract: Statins are prescribed widely to lower plasma low-density lipoprotein (LDL) concentrations and cardiovascular disease risk and have been shown to have beneficial effects in a broad range of patients. However, statins are associated with an increased risk, albeit small, of clinical myopathy and type 2 diabetes. Despite evidence for substantial genetic influence on LDL concentrations, pharmacogenomic trials have failed to identify genetic variations with large effects on either statin efficacy or toxicity, and have produced little information regarding mechanisms that modulate statin response. Here we identify a downstream target of statin treatment by screening for the effects of in vitro statin exposure on genetic associations with gene expression levels in lymphoblastoid cell lines derived from 480 participants of a clinical trial of simvastatin treatment. This analysis identified six expression quantitative trait loci (eQTLs) that interacted with simvastatin exposure, including rs9806699, a cis-eQTL for the gene glycine amidinotransferase (GATM) that encodes the rate-limiting enzyme in creatine synthesis. We found this locus to be associated with incidence of statin-induced myotoxicity in two separate populations (meta-analysis odds ratio = 0.60). Furthermore, we found that GATM knockdown in hepatocyte-derived cell lines attenuated transcriptional response to sterol depletion, demonstrating that GATM may act as a functional link between statin-mediated lowering of cholesterol and susceptibility to statin-induced myopathy.
authors.affiliation: Sage Bionetworks, 1100 Fairview Avenue North, Seattle, Washington 98109, USA. lara.mangravite@sagebase.org
authors.forename: Lara M
authors.initials: LM
authors.lastname: Mangravite
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Engelhardt
authors.forename: Marisa W
authors.initials: MW
authors.lastname: Medina
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Smith
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Brown
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Chasman
authors.forename: Brigham H
authors.initials: BH
authors.lastname: Mecham
authors.forename: Bryan
authors.initials: B
authors.lastname: Howie
authors.forename: Heejung
authors.initials: H
authors.lastname: Shim
authors.forename: Devesh
authors.initials: D
authors.lastname: Naidoo
authors.forename: QiPing
authors.initials: Q
authors.lastname: Feng
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Rieder
authors.forename: Yii-Der I
authors.initials: YD
authors.lastname: Chen
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Paul M
authors.initials: PM
authors.lastname: Ridker
authors.forename: Jemma C
authors.initials: JC
authors.lastname: Hopewell
authors.forename: Sarah
authors.initials: S
authors.lastname: Parish
authors.forename: Jane
authors.initials: J
authors.lastname: Armitage
authors.forename: Rory
authors.initials: R
authors.lastname: Collins
authors.forename: Russell A
authors.initials: RA
authors.lastname: Wilke
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.forename: Matthew
authors.initials: M
authors.lastname: Stephens
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Krauss
mesh_terms: D000579:Amidinotransferases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000172:deficiency / Q000378:metabolism / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009135:Muscular Diseases / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D019821:Simvastatin / Q000009:adverse effects* / Q000494:pharmacology; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D051779:Sterol Regulatory Element Binding Proteins; D002784:Cholesterol; D019821:Simvastatin; D000579:Amidinotransferases; C020681:glycine amidinotransferase