Systematic protein-protein interaction and pathway analyses in the idiopathic inflammatory myopathies

The Myositis Genetics Consortium (MYOGEN)

doi:10.1186/s13075-016-1061-7

Systematic protein-protein interaction and pathway analyses in the idiopathic inflammatory myopathies

The Myositis Genetics Consortium (MYOGEN)

Pediatrics

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Original language	English (US)
Article number	156
Journal	Arthritis Research and Therapy
Volume	18
Issue number	1
DOIs	https://doi.org/10.1186/s13075-016-1061-7
State	Published - Jul 7 2016

Funding

This study was supported in part by: Myositis UK; Arthritis Research UK (18474); Association Francaise Contre Les Myopathies (AFM);The European Union Sixth Framework Programme (project AutoCure; LSH-018661); European Science Foundation (ESF) in the framework of the Research Networking Programme European Myositis Network (EUMYONET); The Swedish Research Council and the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet; the intramural research programme of the National Institute of Environmental Health Sciences (NIEHS); the National Institutes of Health (NIH); European Community’s FP6, AutoCure LSHB CT-2006-018661; The Cure JM Foundation; the European Science Foundation; the Wellcome Trust; the Henry Smith Charity UK; Action Medical UK; and the Swedish Research Council. The Czech cohort was supported by Project for Conceptual Development of Research Organization 00023728 from the Ministry of Health in the Czech Republic. JP is supported by a University of Manchester alumni “Research Impact” PhD studentship and President’s Doctoral Scholar Award. This report includes independent research supported by the National Institute for Health Research. The views expressed in this publication are those of the author(s) and not necessarily those of the National Health Service (NHS), the National Institute for Health Research or the Department of Health. The funding bodies had no role in the design of the study or collection, analysis, or interpretation of data or in writing the manuscript.

Keywords

Association
Autoantibodies
Idiopathic inflammatory myopathies
Pathway analysis
Protein-protein interaction

ASJC Scopus subject areas

Rheumatology
Immunology and Allergy
Immunology

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10.1186/s13075-016-1061-7

Cite this

@article{13309622c71644b18defaf474c5d0681,

title = "Systematic protein-protein interaction and pathway analyses in the idiopathic inflammatory myopathies",

abstract = "Background: 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. Methods: 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. Results: 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. Conclusions: 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.",

keywords = "Association, Autoantibodies, Idiopathic inflammatory myopathies, Pathway analysis, Protein-protein interaction",

author = "{The Myositis Genetics Consortium (MYOGEN)} and Parkes, {Joanna E.} and Simon Rothwell and Day, {Philip J.} and McHugh, {Neil J.} and Betteridge, {Zo{\"e} E.} and Cooper, {Robert G.} and Ollier, {William E.} and Hector Chinoy and Lamb, {Janine A.} and Lundberg, {Ingrid E.} and Miller, {Frederick W.} and Gregersen, {Peter K.} and Jiri Vencovsky and Katalin Danko and Vidya Limaye and Albert Selva-O'Callaghan and Machado, {Pedro M.} and Hanna, {Michael G.} and Pachman, {Lauren M.} and Reed, {Ann M.} and Rider, {Lisa G.} and Hazel Platt and {\O}yvind Molberg and Olivier Benveniste and Pernille Mathiesen and Timothy Radstake and Andrea Doria and Bleecker, {Jan De} and Paepe, {Boel De} and Britta Maurer and Leonid Padyukov and O'Hanlon, {Terrance P.} and Annette Lee and Amos, {Christopher I.} and Christian Gieger and Thomas Meitinger and Juliane Winkelmann and Wedderburn, {Lucy R.} and Christopher Denton and Herman Mann and David Hilton-Jones and Patrick Kiely and Plotz, {Paul H.} and Mark Gourley and Kelly Rouster-Stevens and Huber, {Adam M.} and Galina Marder and Mazen Dimachkie",

note = "Publisher Copyright: {\textcopyright} 2016 The Author(s).",

year = "2016",

month = jul,

day = "7",

doi = "10.1186/s13075-016-1061-7",

language = "English (US)",

volume = "18",

journal = "Arthritis Research and Therapy",

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TY - JOUR

T1 - Systematic protein-protein interaction and pathway analyses in the idiopathic inflammatory myopathies

AU - The Myositis Genetics Consortium (MYOGEN)

AU - Parkes, Joanna E.

AU - Rothwell, Simon

AU - Day, Philip J.

AU - McHugh, Neil J.

AU - Betteridge, Zoë E.

AU - Cooper, Robert G.

AU - Ollier, William E.

AU - Chinoy, Hector

AU - Lamb, Janine A.

AU - Lundberg, Ingrid E.

AU - Miller, Frederick W.

AU - Gregersen, Peter K.

AU - Vencovsky, Jiri

AU - Danko, Katalin

AU - Limaye, Vidya

AU - Selva-O'Callaghan, Albert

AU - Machado, Pedro M.

AU - Hanna, Michael G.

AU - Pachman, Lauren M.

AU - Reed, Ann M.

AU - Rider, Lisa G.

AU - Platt, Hazel

AU - Molberg, Øyvind

AU - Benveniste, Olivier

AU - Mathiesen, Pernille

AU - Radstake, Timothy

AU - Doria, Andrea

AU - Bleecker, Jan De

AU - Paepe, Boel De

AU - Maurer, Britta

AU - Padyukov, Leonid

AU - O'Hanlon, Terrance P.

AU - Lee, Annette

AU - Amos, Christopher I.

AU - Gieger, Christian

AU - Meitinger, Thomas

AU - Winkelmann, Juliane

AU - Wedderburn, Lucy R.

AU - Denton, Christopher

AU - Mann, Herman

AU - Hilton-Jones, David

AU - Kiely, Patrick

AU - Plotz, Paul H.

AU - Gourley, Mark

AU - Rouster-Stevens, Kelly

AU - Huber, Adam M.

AU - Marder, Galina

AU - Dimachkie, Mazen

PY - 2016/7/7

Y1 - 2016/7/7

N2 - Background: 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. Methods: 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. Results: 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. Conclusions: 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.

AB - Background: 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. Methods: 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. Results: 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. Conclusions: 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.

KW - Association

KW - Autoantibodies

KW - Idiopathic inflammatory myopathies

KW - Pathway analysis

KW - Protein-protein interaction

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SN - 1478-6354

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Systematic protein-protein interaction and pathway analyses in the idiopathic inflammatory myopathies

Abstract

Funding

Keywords

ASJC Scopus subject areas

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