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An integrative Bayesian network approach to highlight key drivers in systemic lupus erythematosus
BACKGROUND: A comprehensive intuition of the systemic lupus erythematosus (SLE), as a complex and multifactorial disease, is a biological challenge. Dealing with this challenge needs employing sophisticated bioinformatics algorithms to discover the unknown aspects. This study aimed to underscore key...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310461/ https://www.ncbi.nlm.nih.gov/pubmed/32576231 http://dx.doi.org/10.1186/s13075-020-02239-3 |
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author | Maleknia, Samaneh Salehi, Zahra Rezaei Tabar, Vahid Sharifi-Zarchi, Ali Kavousi, Kaveh |
author_facet | Maleknia, Samaneh Salehi, Zahra Rezaei Tabar, Vahid Sharifi-Zarchi, Ali Kavousi, Kaveh |
author_sort | Maleknia, Samaneh |
collection | PubMed |
description | BACKGROUND: A comprehensive intuition of the systemic lupus erythematosus (SLE), as a complex and multifactorial disease, is a biological challenge. Dealing with this challenge needs employing sophisticated bioinformatics algorithms to discover the unknown aspects. This study aimed to underscore key molecular characteristics of SLE pathogenesis, which may serve as effective targets for therapeutic intervention. METHODS: In the present study, the human peripheral blood mononuclear cell (PBMC) microarray datasets (n = 6), generated by three platforms, which included SLE patients (n = 220) and healthy control samples (n = 135) were collected. Across each platform, we integrated the datasets by cross-platform normalization (CPN). Subsequently, through BNrich method, the structures of Bayesian networks (BNs) were extracted from KEGG-indexed SLE, TCR, and BCR signaling pathways; the values of the node (gene) and edge (intergenic relationships) parameters were estimated within each integrated datasets. Parameters with the FDR < 0.05 were considered significant. Finally, a mixture model was performed to decipher the signaling pathway alterations in the SLE patients compared to healthy controls. RESULTS: In the SLE signaling pathway, we identified the dysregulation of several nodes involved in the (1) clearance mechanism (SSB, MACROH2A2, TRIM21, H2AX, and C1Q gene family), (2) autoantigen presentation by MHCII (HLA gene family, CD80, IL10, TNF, and CD86), and (3) end-organ damage (FCGR1A, ELANE, and FCGR2A). As a remarkable finding, we demonstrated significant perturbation in CD80 and CD86 to CD28, CD40LG to CD40, C1QA and C1R to C2, and C1S to C4A edges. Moreover, we not only replicated previous studies regarding alterations of subnetworks involved in TCR and BCR signaling pathways (PI3K/AKT, MAPK, VAV gene family, AP-1 transcription factor) but also distinguished several significant edges between genes (PPP3 to NFATC gene families). Our findings unprecedentedly showed that different parameter values assign to the same node based on the pathway topology (the PIK3CB parameter values were 1.7 in TCR vs − 0.5 in BCR signaling pathway). CONCLUSIONS: Applying the BNrich as a hybridized network construction method, we highlight under-appreciated systemic alterations of SLE, TCR, and BCR signaling pathways in SLE. Consequently, having such a systems biology approach opens new insights into the context of multifactorial disorders. |
format | Online Article Text |
id | pubmed-7310461 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-73104612020-06-23 An integrative Bayesian network approach to highlight key drivers in systemic lupus erythematosus Maleknia, Samaneh Salehi, Zahra Rezaei Tabar, Vahid Sharifi-Zarchi, Ali Kavousi, Kaveh Arthritis Res Ther Research Article BACKGROUND: A comprehensive intuition of the systemic lupus erythematosus (SLE), as a complex and multifactorial disease, is a biological challenge. Dealing with this challenge needs employing sophisticated bioinformatics algorithms to discover the unknown aspects. This study aimed to underscore key molecular characteristics of SLE pathogenesis, which may serve as effective targets for therapeutic intervention. METHODS: In the present study, the human peripheral blood mononuclear cell (PBMC) microarray datasets (n = 6), generated by three platforms, which included SLE patients (n = 220) and healthy control samples (n = 135) were collected. Across each platform, we integrated the datasets by cross-platform normalization (CPN). Subsequently, through BNrich method, the structures of Bayesian networks (BNs) were extracted from KEGG-indexed SLE, TCR, and BCR signaling pathways; the values of the node (gene) and edge (intergenic relationships) parameters were estimated within each integrated datasets. Parameters with the FDR < 0.05 were considered significant. Finally, a mixture model was performed to decipher the signaling pathway alterations in the SLE patients compared to healthy controls. RESULTS: In the SLE signaling pathway, we identified the dysregulation of several nodes involved in the (1) clearance mechanism (SSB, MACROH2A2, TRIM21, H2AX, and C1Q gene family), (2) autoantigen presentation by MHCII (HLA gene family, CD80, IL10, TNF, and CD86), and (3) end-organ damage (FCGR1A, ELANE, and FCGR2A). As a remarkable finding, we demonstrated significant perturbation in CD80 and CD86 to CD28, CD40LG to CD40, C1QA and C1R to C2, and C1S to C4A edges. Moreover, we not only replicated previous studies regarding alterations of subnetworks involved in TCR and BCR signaling pathways (PI3K/AKT, MAPK, VAV gene family, AP-1 transcription factor) but also distinguished several significant edges between genes (PPP3 to NFATC gene families). Our findings unprecedentedly showed that different parameter values assign to the same node based on the pathway topology (the PIK3CB parameter values were 1.7 in TCR vs − 0.5 in BCR signaling pathway). CONCLUSIONS: Applying the BNrich as a hybridized network construction method, we highlight under-appreciated systemic alterations of SLE, TCR, and BCR signaling pathways in SLE. Consequently, having such a systems biology approach opens new insights into the context of multifactorial disorders. BioMed Central 2020-06-23 2020 /pmc/articles/PMC7310461/ /pubmed/32576231 http://dx.doi.org/10.1186/s13075-020-02239-3 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Article Maleknia, Samaneh Salehi, Zahra Rezaei Tabar, Vahid Sharifi-Zarchi, Ali Kavousi, Kaveh An integrative Bayesian network approach to highlight key drivers in systemic lupus erythematosus |
title | An integrative Bayesian network approach to highlight key drivers in systemic lupus erythematosus |
title_full | An integrative Bayesian network approach to highlight key drivers in systemic lupus erythematosus |
title_fullStr | An integrative Bayesian network approach to highlight key drivers in systemic lupus erythematosus |
title_full_unstemmed | An integrative Bayesian network approach to highlight key drivers in systemic lupus erythematosus |
title_short | An integrative Bayesian network approach to highlight key drivers in systemic lupus erythematosus |
title_sort | integrative bayesian network approach to highlight key drivers in systemic lupus erythematosus |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310461/ https://www.ncbi.nlm.nih.gov/pubmed/32576231 http://dx.doi.org/10.1186/s13075-020-02239-3 |
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