title: Transcriptome-level microarray expression profiling implicates IGF-1 and Wnt signalling dysregulation in the pathogenesis of thyroid-associated orbitopathy.
abstract: OBJECTIVE
  The pathogenesis of thyroid-associated orbitopathy (TAO) remains unclear. The aim of this study is to elucidate the gene expression profile of orbital fat from patients with active, but untreated, TAO.
  
  
  METHODS
  A case-control gene expression study was conducted using test samples of orbital fat from TAO patients and control orbital fat specimens; apart from drugs to control thyrotoxicosis, the TAO patients had received no treatment for orbital disease. cDNA expression analysis was performed using the Affymetrix GeneChip Human Genome U133 Plus 2.0 platform and validated using quantitative PCR.
  
  
  RESULTS
  The highest-ranked differentially expressed genes were dominated by IGF-1 signalling genes. These include IGF-1, IGF-1 receptor binding/signalling genes, such as SOCS3 and IRS2, and downstream signalling and transcriptional regulators, such as SGK (PDK/Akt signalling) and c-JUN. Our microarray data also demonstrate dysregulation of wingless-type MMTV (Wnt) signalling gene expression, including Wnt5a, sFRPs and DKK.
  
  
  CONCLUSIONS
  Altered Wnt signalling confirms previous array findings. Further investigation of the role of Wnt signalling in TAO pathogenesis is warranted. These data also provide the first evidence of dysregulation of IGF-1 pathway genes in TAO tissue, further strengthening the evidence for the role of IGF-1 signalling in the pathogenesis and potential treatment of TAO.
authors.affiliation: NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital, London, UK. d.ezra@ucl.ac.uk
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Ezra
authors.forename: Jonathan
authors.initials: J
authors.lastname: Krell
authors.forename: Geoffrey E
authors.initials: GE
authors.lastname: Rose
authors.forename: Maryse
authors.initials: M
authors.lastname: Bailly
authors.forename: Justin
authors.initials: J
authors.lastname: Stebbing
authors.forename: Leandro
authors.initials: L
authors.lastname: Castellano
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D015536:Down-Regulation / Q000502:physiology; D020869:Gene Expression Profiling; D049970:Graves Ophthalmopathy / Q000209:etiology* / Q000503:physiopathology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D009915:Orbit / Q000378:metabolism / Q000473:pathology; D009916:Orbital Diseases / Q000209:etiology / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D051153:Wnt Proteins; D007334:Insulin-Like Growth Factor I