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Pro-inflammatory cytokine response pre-dominates immuno-genetic pathway in development of rheumatoid arthritis

Molecular Biology Reports volume 47, pages 8669–8677 (2020)Cite this article

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.

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Acknowledgements

KP acknowledges Indian Council for Medical Research (ICMR), Government of India, for providing Senior Research Fellowship and Human Molecular Genetics Laboratory, Rajiv Gandhi Center for Biotechnology for providing a collaborative research platform and KIMS Hospital for patient’s sample collection to carry out the molecular work.

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Affiliations

  1. Human Genetics Laboratory, Department of Zoology, Bharathiar University, Coimbatore, India

    E. K. Krishna Priya & Kesavarao Sasikala

  2. Neurobiology and Genetics Division, Human Molecular Genetics Laboratory, Rajiv Gandhi Center for Biotechnology, Thiruvananthapuram, Kerala, 695 014, India

    Lekshmy Srinivas & Moinak Banerjee

  3. Kerala Institute of Medical Science (KIMS) Hospital, Thiruvananthapuram, India

    S. Rajesh

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  1. E. K. Krishna Priya
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  2. Lekshmy Srinivas
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  3. S. Rajesh
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  4. Kesavarao Sasikala
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  5. Moinak Banerjee
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Correspondence to Moinak Banerjee.

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Krishna Priya, E.K., Srinivas, L., Rajesh, S. et al. Pro-inflammatory cytokine response pre-dominates immuno-genetic pathway in development of rheumatoid arthritis. Mol Biol Rep 47, 8669–8677 (2020). https://doi.org/10.1007/s11033-020-05909-2

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  • DOI: https://doi.org/10.1007/s11033-020-05909-2

Keywords

  • Rheumatoid arthritis
  • Cytokines
  • Inflammation
  • Meta-analysis
  • Genetic variants