Dataset Information

A Comprehensive Gene Expression Meta-analysis Identifies Novel Immune Signatures in Rheumatoid Arthritis Patients.

ABSTRACT: Rheumatoid arthritis (RA), a symmetric polyarticular arthritis, has long been feared as one of the most disabling forms of arthritis. Identification of gene signatures associated with RA onset and progression would lead toward development of novel diagnostics and therapeutic interventions. This study was undertaken to identify unique gene signatures of RA patients through large-scale meta-profiling of a diverse collection of gene expression data sets. We carried out a meta-analysis of 8 publicly available RA patients' (107 RA patients and 76 healthy controls) gene expression data sets and further validated a few meta-signatures in RA patients through quantitative real-time PCR (RT-qPCR). We identified a robust meta-profile comprising 33 differentially expressed genes, which were consistently and significantly expressed across all the data sets. Our meta-analysis unearthed upregulation of a few novel gene signatures including PLCG2, HLA-DOB, HLA-F, EIF4E2, and CYFIP2, which were validated in peripheral blood mononuclear cell samples of RA patients. Further, functional and pathway enrichment analysis reveals perturbation of several meta-genes involved in signaling pathways pertaining to inflammation, antigen presentation, hypoxia, and apoptosis during RA. Additionally, PLCG2 (phospholipase C?2) popped out as a novel meta-gene involved in most of the pathways relevant to RA including inflammasome activation, platelet aggregation, and activation, thereby suggesting PLCG2 as a potential therapeutic target for controlling excessive inflammation during RA. In conclusion, these findings highlight the utility of meta-analysis approach in identifying novel gene signatures that might provide mechanistic insights into disease onset, progression and possibly lead toward the development of better diagnostic and therapeutic interventions against RA.

SUBMITTER: Afroz S

PROVIDER: S-EPMC5288395 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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A Comprehensive Gene Expression Meta-analysis Identifies Novel Immune Signatures in Rheumatoid Arthritis Patients.

Afroz Sumbul S Giddaluru Jeevan J Vishwakarma Sandeep S Naz Saima S Khan Aleem Ahmed AA Khan Nooruddin N

Frontiers in immunology 20170202

Rheumatoid arthritis (RA), a symmetric polyarticular arthritis, has long been feared as one of the most disabling forms of arthritis. Identification of gene signatures associated with RA onset and progression would lead toward development of novel diagnostics and therapeutic interventions. This study was undertaken to identify unique gene signatures of RA patients through large-scale meta-profiling of a diverse collection of gene expression data sets. We carried out a meta-analysis of 8 publicly ...[more]

PMID: 28210261

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Project description:The rate of cesarean delivery (CD) in China has risen sharply and the high rate was reported to be associated with increased risk of disease in the offspring. However, there is little research on the molecular mechanism of critical pathways and gene signatures involved in the neonatal immunity of cesarean-born infants. This study was undertaken to identify unique gene signatures which was involved in the neonatal immunity of cesarean-born infants through large-scale RNA-sequencing. Genes differentially expressed in cesarean-born infants were identified and further validated through quantitative real-time PCR (RT-qPCR). Moreover, we employed weighted gene co-expression network analysis (WGCNA) to identify highly connected genes that were correlated with neonatal inflammation. In total, 73 differentially expressed genes (DEGs) were identified between cesarean-born infants and normal vagina childbirth. The results obtained by secondary validation indicated that GATM, MIF, IFI27, IL1B, CA1, and EPHB1 were significantly upregulated in phenotype CD, while CYP2A6 and DLK1 were significantly down regulated. Further, functional and pathway enrichment analysis reveals perturbation of several DEGs involved in signaling pathways pertaining to immunoregulation, inflammation, apoptosis, and nervous development. Additionally, HLA-DOB popped out as a core gene in the process of inflammation, which might indicate the risk of cesarean-born infants for inflammatory disease. Notably, our study for the first time has documented gene signatures PIK3CA, PTPRC, SOS1, IL6ST, and MALT1, which were found to be involved in neonatal inflammation. Taken together, the full expression repertoire including the differentially expressed gene sets and core differentially co-expressed genes should provide an excellent resource for identifying potential biomarkers of cesarean-born infants with inflammation, and formulating new hypotheses for physiological functions and the discovery of novel therapeutic targets for inflammatory disease.

Project description:Introduction: Overactivation of the type I interferon (IFN) signature has been observed in several systemic autoimmune conditions, such as Systemic Lupus Erythematosus (SLE) or Rheumatoid Arthritis (RA). Impaired control of Interferon-Responding Genes (IRGs) expression by their regulatory mechanisms, including Interferon Regulatory Factors (IRFs), may underlie these findings and it may explain the heterogeneity observed among these conditions. In the present study we aimed to evaluate the associations between IRF4 gene expression and those of IRGs in SLE and RA patients to gain insight about its links with the IFN signature as well as to explore the potential clinical relevance of these associations. Methods: The gene expression of IRF4 and IRGs (IFI44, IFI44L, IFI6, and MX1) in peripheral blood was analyzed in 75 SLE patients, 98 RA patients, and 28 healthy controls. A group of 13 biological-naïve RA patients was prospectively followed upon TNF?-blockade. The associations among IRF4 and IRGs were evaluated by principal component analyses (PCA), correlations and network analyses. Publicly available datasets were used for replication. Results: A broad activation of IRGs was observed in autoimmune patients, although certain heterogeneity can be distinguished, whereas IRF4 was only upregulated in RA. The differential expression of IRF4 in RA was then confirmed in publicly available gene expression datasets. PCA revealed different associations among IRF4 and IRGs in each condition, which was later confirmed by correlation and network analyses. Cluster analysis identified 3 gene expression signatures on the basis of IRF4 and IRGs expression which were differentially used by SLE and RA patients. Cluster III was associated with markers of disease severity in SLE patients. Cluster II, hallmarked by IRF4 upregulation, was linked to clinical stage and mild disease course in RA. TNF?-blockade led to changes in the association between IRF4 and IRGs, whereas increasing IRF4 expression was associated with a good clinical outcome in RA. Conclusions: The differential expression of IRF4 and IRGs observed in SLE and RA can delineate gene expression signatures associated with clinical features and treatment outcomes. These results support a clinically-relevant phenomenon of shaping of the IFN signature by IRF4 in autoimmune patients.

Dataset Information

A Comprehensive Gene Expression Meta-analysis Identifies Novel Immune Signatures in Rheumatoid Arthritis Patients.

Publications

A Comprehensive Gene Expression Meta-analysis Identifies Novel Immune Signatures in Rheumatoid Arthritis Patients.

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