Dissecting the Role of NF-κb Protein Family and Its Regulators in Rheumatoid Arthritis Using Weighted Gene Co-Expression Network

Jamal S M Sabir; Abdelfatteh El Omri; Babajan Banaganapalli; Majed A Al-Shaeri; Naser A Alkenani; Mumdooh J Sabir; Nahid H Hajrah; Houda Zrelli; Lukasz Ciesla; Khalidah K Nasser; Ramu Elango; Noor Ahmad Shaik; Muhummadh Khan

doi:10.3389/fgene.2019.01163

Dissecting the Role of NF-κb Protein Family and Its Regulators in Rheumatoid Arthritis Using Weighted Gene Co-Expression Network

Front Genet. 2019 Nov 20:10:1163. doi: 10.3389/fgene.2019.01163. eCollection 2019.

Authors

Jamal S M Sabir^{1

2}, Abdelfatteh El Omri^{1

2}, Babajan Banaganapalli³, Majed A Al-Shaeri¹, Naser A Alkenani⁴, Mumdooh J Sabir⁵, Nahid H Hajrah^{1

2}, Houda Zrelli^{1

2}, Lukasz Ciesla⁶, Khalidah K Nasser⁷, Ramu Elango³, Noor Ahmad Shaik³, Muhummadh Khan^{1

2}

Affiliations

¹ Center of Excellence in Bionanoscience Research, King Abdulaziz University, Jeddah, Saudi Arabia.
² Genomics and Biotechnology Section and Research Group, Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.
³ Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
⁴ Biology-Zoology Division, Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.
⁵ Department of Computer Sciences, Faculty of Computers and Information Technology, King Abdulaziz University, Jeddah, Saudi Arabia.
⁶ Department of Biological Sciences, Science and Engineering Complex, The University of Alabama, Tuscaloosa, AL, United States.
⁷ Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.

Abstract

Rheumatoid arthritis (RA) is a chronic synovial autoinflammatory disease that destructs the cartilage and bone, leading to disability. The functional regulation of major immunity-related pathways like nuclear factor kappa B (NF-κB), which is involved in the chronic inflammatory reactions underlying the development of RA, remains to be explored. Therefore, this study has adopted statistical and knowledge-based systemic investigations (like gene correlation, semantic similarity, and topological parameters based on graph theory) to study the gene expression status of NF-κB protein family (NK^PF) and its regulators in synovial tissues to trace the molecular pathways through which these regulators contribute to RA. A complex protein-protein interaction map (PPIM) of 2,742 genes and 37,032 interactions was constructed from differentially expressed genes (p ≤ 0.05). PPIM was further decomposed into a Regulator Allied Protein Interaction Network (RA^PIN) based on the interaction between genes (5 NK^PF, 31 seeds, 131 hubs, and 652 bottlenecks). Pathway network analysis has shown the RA-specific disturbances in the functional connectivity between seed genes (RIPK1, ATG7, TLR4, TNFRSF1A, KPNA1, CFLAR, SNW1, FOSB, PARVA, CX3CL1, and TRPC6) and NK^PF members (RELA, RELB, NFKB2, and REL). Interestingly, these genes are known for their involvement in inflammation and immune system (signaling by interleukins, cytokine signaling in immune system, NOD-like receptor signaling, MAPK signaling, Toll-like receptor signaling, and TNF signaling) pathways connected to RA. This study, for the first time, reports that SNW1, along with other NK regulatory genes, plays an important role in RA pathogenesis and might act as potential biomarker for RA. Additionally, these genes might play important roles in RA pathogenesis, as well as facilitate the development of effective targeted therapies. Our integrative data analysis and network-based methods could accelerate the identification of novel drug targets for RA from high-throughput genomic data.

Keywords: GEO; NF-κB; auto-inflammatory disease; gene expression; rheumatoid arthritis.