title: Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy.
abstract: OBJECTIVE
  In addition to inducing a self-limited myopathy, statin use is associated with an immune-mediated necrotizing myopathy (IMNM), with autoantibodies that recognize ∼200-kd and ∼100-kd autoantigens. The purpose of this study was to identify these molecules to help clarify the disease mechanism and facilitate diagnosis.
  
  
  METHODS
  The effect of statin treatment on autoantigen expression was addressed by immunoprecipitation using sera from patients. The identity of the ∼100-kd autoantigen was confirmed by immunoprecipitation of in vitro-translated 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) protein. HMGCR expression in muscle was analyzed by immunofluorescence. A cohort of myopathy patients was screened for anti-HMGCR autoantibodies by enzyme-linked immunosorbent assay and genotyped for the rs4149056 C allele, a predictor of self-limited statin myopathy.
  
  
  RESULTS
  Statin exposure induced expression of the ∼200-kd/∼100-kd autoantigens in cultured cells. HMGCR was identified as the ∼100-kd autoantigen. Competition experiments demonstrated no distinct autoantibodies recognizing the ∼200-kd protein. In muscle biopsy tissues from anti-HMGCR-positive patients, HMGCR expression was up-regulated in cells expressing neural cell adhesion molecule, a marker of muscle regeneration. Anti-HMGCR autoantibodies were found in 45 of 750 patients presenting to the Johns Hopkins Myositis Center (6%). Among patients ages 50 years and older, 92.3% had taken statins. The prevalence of the rs4149056 C allele was not increased in patients with anti-HMGCR.
  
  
  CONCLUSIONS
  Statins up-regulate the expression of HMGCR, the major target of autoantibodies in statin-associated IMNM. Regenerating muscle cells express high levels of HMGCR, which may sustain the immune response even after statins are discontinued. These studies demonstrate a mechanistic link between an environmental trigger and the development of sustained autoimmunity. Detection of anti-HMGCR autoantibodies may facilitate diagnosis and direct therapy.
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. amammen@jhmi.edu
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Mammen
authors.forename: Tae
authors.initials: T
authors.lastname: Chung
authors.forename: Lisa
authors.initials: L
authors.lastname: Christopher-Stine
authors.forename: Paul
authors.initials: P
authors.lastname: Rosen
authors.forename: Antony
authors.initials: A
authors.lastname: Rosen
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Doering
authors.forename: Livia A
authors.initials: LA
authors.lastname: Casciola-Rosen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000139:chemically induced* / Q000453:epidemiology / Q000276:immunology; D002675:Child, Preschool; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006367:HeLa Cells; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000737:chemistry / Q000276:immunology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000276:immunology / Q000473:pathology; D009220:Myositis / Q000139:chemically induced* / Q000453:epidemiology / Q000276:immunology; D009336:Necrosis; D017434:Protein Structure, Tertiary; D012038:Regeneration / Q000276:immunology; D016036:Seroepidemiologic Studies; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C553220:HMGCR protein, human; D006903:Hydroxymethylglutaryl CoA Reductases