Systematic protein-protein interaction and pathway analyses in the idiopathic inflammatory myopathies.
Systematic protein-protein interaction and pathway analyses in the idiopathic inflammatory myopathies.
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DOI：
10.1186/s13075-016-1061-7
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发表时间：
2016-07-07
影响因子：
4.9
通讯作者：
Myositis Genetics Consortium (MYOGEN)
中科院分区：
文献类型：
--
作者：
Parkes JE;Rothwell S;Day PJ;McHugh NJ;Betteridge ZE;Cooper RG;Ollier WE;Chinoy H;Lamb JA;Myositis Genetics Consortium (MYOGEN)
特发性炎性肌病（IIM）是以获得性近端肌无力、肌肉中的炎性细胞浸润和肌炎特异性/相关自身抗体为特征的自身免疫性疾病。目前还不清楚哪些途径参与IIM，自身抗体靶点之间的功能关系尚未系统地探讨。蛋白质-蛋白质相互作用和途径分析，以确定相关的疾病的途径，使用自身抗体的目标和基因产物的IIM相关的单核苷酸多态性（SNP）位点。使用疾病协会蛋白质-蛋白质连接评估器（DAPPLE）分析蛋白质-蛋白质相互作用。使用注释可视化和集成发现数据库（大卫）和跨关联基因座的基因关系（GRAIL）进行基因本体和途径分析。进行分析，包括已发表的自身抗体的靶标、来自IIM关联研究的显著和提示性SNP以及自身抗体靶标加SNP组合。由自身抗体靶标和相关SNP形成的蛋白质-蛋白质相互作用网络显示出显著的直接和/或间接连接性（p < 0.05）。自身抗体靶标加上相关SNP组合导致更显著的间接和共同相互作用物连接，表明自身抗体靶标和由IM相关基因座编码的蛋白质可能参与共同途径。肿瘤坏死因子受体相关因子6（TRAF 6）被鉴定为一个枢纽蛋白，UBE 3B，HSPA 1A，HSPA 1B和PSMD 3也被鉴定为具有显著连接性的基因。途径分析鉴定了自身抗体靶和相关SNP区域显著互连（p < 0.01），并证实了自身抗体靶参与翻译和翻译后过程。“泛素”是在所有三个GRAIL自身抗体靶点和IIM相关SNP分析中强烈连接跨区域重要基因的唯一关键词。自身抗体靶点和IIM相关位点显示出显著的连通性和相互关联性，并确定了IIM发病机制中的几个关键基因和途径，可能通过泛素化途径介导。本文的在线版本（doi：10.1186/s13075-016-1061-7）包含补充材料，可供授权用户使用。
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. The online version of this article (doi:10.1186/s13075-016-1061-7) contains supplementary material, which is available to authorized users.