title: Systematic protein-protein interaction and pathway analyses in the idiopathic inflammatory myopathies.
abstract: The idiopathic inflammatory myopathies (IIM) are autoimmune diseases characterised by acquired proximal muscle weakness, inflammatory cell infiltrates in muscle and myositis-specific/associated autoantibodies. It is unclear which pathways are involved in IIM, and the functional relationship between autoantibody targets has not been systematically explored. Protein-protein interaction and pathway analyses were conducted to identify pathways relevant to disease, using autoantibody targets and gene products of IIM-associated single nucleotide polymorphism (SNP) loci.
  
  
  
  Protein-protein interactions were analysed using Disease Association Protein-Protein Link Evaluator (DAPPLE). Gene ontology and pathway analyses were conducted using Database for Annotation Visualisation and Integrated Discovery (DAVID) and Gene Relationships Across Implicated Loci (GRAIL). Analyses were undertaken including the targets of published autoantibodies, significant and suggestive SNPs from an IIM association study and autoantibody targets plus SNPs combined.
  
  
  
  The protein-protein interaction networks formed by autoantibody targets and associated SNPs showed significant direct and/or indirect connectivity (p < 0.05). Autoantibody targets plus associated SNPs combined resulted in more significant indirect and common interactor connectivity, suggesting autoantibody targets and proteins encoded by IIM-associated loci may be involved in common pathways. Tumour necrosis factor receptor-associated factor 6 (TRAF6) was identified as a hub protein, and UBE3B, HSPA1A, HSPA1B and PSMD3 also were identified as genes with significant connectivity. Pathway analysis identified that autoantibody targets and associated SNP regions are significantly interconnected (p < 0.01), and confirmed autoantibody target involvement in translational and post-translational processes. 'Ubiquitin' was the only keyword strongly linking significant genes across regions in all three GRAIL analyses of autoantibody targets and IIM-associated SNPs.
  
  
  
  Autoantibody targets and IIM-associated loci show significant connectivity and inter-relatedness, and identify several key genes and pathways in IIM pathogenesis, possibly mediated via the ubiquitination pathway.
authors.affiliation: Centre for Epidemiology, University of Manchester, 2.722 Stopford Building, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Joanna E
authors.initials: JE
authors.lastname: Parkes
authors.affiliation: Centre for Genetics and Genomics, Arthritis Research UK, University of Manchester, Manchester, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Rothwell
authors.affiliation: Centre for Epidemiology, University of Manchester, 2.722 Stopford Building, Oxford Road, Manchester, M13 9PT, UK.|Manchester Institute of Biotechnology, University of Manchester, Manchester, UK.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Day
authors.affiliation: Bath Institute of Rheumatic Diseases, Royal National Hospital for Rheumatic Diseases, Bath, UK.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: McHugh
authors.affiliation: Bath Institute of Rheumatic Diseases, Royal National Hospital for Rheumatic Diseases, Bath, UK.
authors.forename: Zoë E
authors.initials: ZE
authors.lastname: Betteridge
authors.affiliation: MRC/ARUK Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Cooper
authors.affiliation: Centre for Epidemiology, University of Manchester, 2.722 Stopford Building, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: William E
authors.initials: WE
authors.lastname: Ollier
authors.affiliation: National Institute of Health Research Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, University of Manchester, Manchester, UK.
authors.forename: Hector
authors.initials: H
authors.lastname: Chinoy
authors.affiliation: Centre for Epidemiology, University of Manchester, 2.722 Stopford Building, Oxford Road, Manchester, M13 9PT, UK. Janine.Lamb@manchester.ac.uk.
authors.forename: Janine A
authors.initials: JA
authors.lastname: Lamb
mesh_terms: D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D009220:Myositis / Q000235:genetics / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide; D025941:Protein Interaction Mapping; D060066:Protein Interaction Maps
chemical_list: D001323:Autoantibodies; D001324:Autoantigens
keywords: Association; Autoantibodies; Idiopathic inflammatory myopathies; Pathway analysis; Protein-protein interaction