Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
The idiopathic inflammatory myopathies (IIM) are autoimmune diseases characterised by acquired proximal muscle weakness, inflammatory cell infiltrates in muscle and myositis-specific/associated autoantibodies (MSA/MAA). The cornerstone of IIM treatment is prompt control of inflammation with immunosuppressive therapy, before irreversible tissue damage ensues from muscle atrophy and fatty replacement of tissue. Despite treatments, many patients become progressively disabled with co-morbidities due to both the underlying disease and treatment. There is thus a clear need to identify pathways involved in IIM pathogenesis to develop future treatment approaches. We therefore conducted protein-protein interaction and pathway analyses using myositis autoantibody targets and gene products of IIM associated 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). Three analysis strategies were used, including: i) the targets of all published MSAs and the MAA anti-PMScl-75/100; ii) significant and suggestive single nucleotide polymorphisms (SNPs) from a recently reported IIM association study; iii) SNPs plus MSA/MAA targets combined.
The protein-protein interaction networks formed by MSA/MAA targets and associated SNPs showed significant direct and/or indirect connectivity. Inclusion of both MSA/MAA targets and associated SNPs resulted in more significant indirect and common interactor connectivity than the separate networks, identifying TRAF6 as a hub protein, and suggesting interaction between MSA/MAA targets and proteins encoded by IIM associated loci. Protein-protein interaction analysis of associated loci also identified UBE3B, HSPA1A, HSPA1B and PSMD3as genes with significant connectivity. DAVID pathway analyses confirmed previous knowledge of MSA target involvement in translational processes. ‘Ubiquitin’ was the sole keyword strongly linking significant genes in each region in all three GRAIL analyses of MSA/MAA targets and IIM associated SNPs.
Autoantibody targets and associated loci in IIM show significant connectivity and inter-relatedness and identify several key genes in IIM pathogenesis, possibly mediated via the ubiquitination-proteasome pathway.
To cite this abstract in AMA style:Parkes J, Rothwell S, Day P, McHugh NJ, Betteridge Z, Cooper R, Ollier WE, Chinoy H, Lamb J. Systematic Protein-Protein Interaction and Pathway Analyses in the Idiopathic Inflammatory Myopathies [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/systematic-protein-protein-interaction-and-pathway-analyses-in-the-idiopathic-inflammatory-myopathies/. Accessed July 8, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/systematic-protein-protein-interaction-and-pathway-analyses-in-the-idiopathic-inflammatory-myopathies/