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

Sumbul Afroz,Sandeep Vishwakarma,Jeevan Giddaluru,Aleem Ahmed Khan,Saima Naz,Nooruddin Khan

doi:10.3389/fimmu.2017.00074

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 Cγ2) 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.

Highlights

Rheumatoid arthritis (RA) is a chronic, progressive, and inflammatory autoimmune disease, which continues to cause global disability having a worldwide prevalence of 1% [1]
To further understand the significance of these meta-genes in RA pathogenesis, we performed a GO functional and pathway enrichment analysis, which led to the identification of novel gene signatures that went unnoticed in previous RA studies
Our meta-analysis study exemplifies the involvement of few inflammatory genes (PLCG2, AIM2, and ALOX-5), which might act as novel candidates for controlling inflammation during the disease condition (Figure 2B)

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic, progressive, and inflammatory autoimmune disease, which continues to cause global disability having a worldwide prevalence of 1% [1]. Unprecedented efforts have been made to identify multitude of factors that have foremost allusions in RA pathogenesis including proinflammatory cytokines (TNF-α, IL-6, IL-17, and IL-1) [8] as the orchestrator of vital processes during RA progression involving synovitis [9], angiogenesis (production of pro- angiogenic factors VEGF) [10, 11], osteoclastogenesis (increased production of macrophage colony-stimulating factor and RANK ligand) [12], cartilage degradation (enhanced secretion of MMPs into synovial fluid at the joints) [9, 13], and acute-phase proteins production such as CRP (exacerbates RA-related tissue damage) [14]

Methods

Results

Conclusion