Pro-inflammatory cytokine response pre-dominates immuno-genetic pathway in development of rheumatoid arthritis
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ORIGINAL ARTICLE
Pro‑inflammatory cytokine response pre‑dominates immuno‑genetic pathway in development of rheumatoid arthritis E. K. Krishna Priya1 · Lekshmy Srinivas2 · S. Rajesh3 · Kesavarao Sasikala1 · Moinak Banerjee2 Received: 20 August 2020 / Accepted: 10 October 2020 © Springer Nature B.V. 2020
Abstract Rheumatoid arthritis (RA) is a crucial inflammatory joint disease characterized by loss of self-tolerance and severe cartilage loss, autoimmune, and subchondral bone erosions. Cytokines are the key regulators of inflammatory responses. Homeostatic imbalances in pro- and anti-inflammatory cytokine activities can result in pathogenic inflammatory reactions. These imbalances could be initiated by environmental factors but the ability to define the threshold of environmental impact relies on the genetic background of the pro- and anti-inflammatory cytokines. To address this a case-control association study was carried out in 429 individuals from Malayalam speaking ethnic population from South India. Functionally relevant SNPs from IL-10, IL-6, IL-1β and IL-1RN were genotyped using PCR -RFLP and sequencing. Meta-analysis was performed for the associated variants of IL-10, IL-1β. Significant association with RA was observed with IL-1β rs1143634, rs1143627, IL-10 rs1800896, IL-6 rs1800796, rs1800797. The associated SNPs are likely to impact transcriptional activity of a gene. Meta-analysis with global populations also provide evidence that IL-10 and IL-1β could be a global marker for RA. The functional significance of associated risk variants of IL-1β and IL-6 indicate increased production of the pro-inflammatory cytokines while IL-10 risk allele suggest reduced production of anti- inflammatory cytokines. The study concludes that increased production of pro-inflammatory cytokines and reduced production of anti- inflammatory cytokines may influence the Th1/Th2 equilibrium resulting in a triggering of Th1 mediated inflammatory responses in development of RA. Keywords Rheumatoid arthritis · Cytokines · Inflammation · Meta-analysis · Genetic variants
Introduction Rheumatoid arthritis (RA) is an auto-inflammatory disease characterized by the loss of self-tolerance that leads to bone and joint damages [1] thereby affecting the physical quality of life. The prevalence rate of RA in global population is about 0.5–1% [1] and 0.75% in Indian population [2]. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11033-020-05909-2) contains supplementary material, which is available to authorized users. * Moinak Banerjee [email protected]; [email protected] 1
Human Genetics Laboratory, Department of Zoology, Bharathiar University, Coimbatore, India
2
Neurobiology and Genetics Division, Human Molecular Genetics Laboratory, Rajiv Gandhi Center for Biotechnology, Thiruvananthapuram, Kerala 695 014, India
3
Kerala Institute of Medical Science (KIMS) Hospital, Thiruvananthapuram, India
In earlier stages of life the disease impacts more often in females than in males
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