RGD Reference Report - Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy. - Rat Genome Database

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Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy.

Authors: Mammen, AL  Chung, T  Christopher-Stine, L  Rosen, P  Rosen, A  Doering, KR  Casciola-Rosen, LA 
Citation: Mammen AL, etal., Arthritis Rheum. 2011 Mar;63(3):713-21. doi: 10.1002/art.30156.
RGD ID: 5508448
Pubmed: PMID:21360500   (View Abstract at PubMed)
PMCID: PMC3335400   (View Article at PubMed Central)
DOI: DOI:10.1002/art.30156   (Journal Full-text)

OBJECTIVE: In addition to inducing a self-limited myopathy, statin use is associated with an immune-mediated necrotizing myopathy (IMNM), with autoantibodies that recognize approximately 200-kd and approximately 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 approximately 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 approximately 200-kd/ approximately 100-kd autoantigens in cultured cells. HMGCR was identified as the approximately 100-kd autoantigen. Competition experiments demonstrated no distinct autoantibodies recognizing the approximately 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. CONCLUSION: 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
muscular disease  IDA 5508448 RGD 
muscular disease  ISOHMGCR (Homo sapiens)5508448; 5508448 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Hmgcr  (3-hydroxy-3-methylglutaryl-CoA reductase)

Genes (Mus musculus)
Hmgcr  (3-hydroxy-3-methylglutaryl-Coenzyme A reductase)

Genes (Homo sapiens)
HMGCR  (3-hydroxy-3-methylglutaryl-CoA reductase)


Additional Information