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

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-1 beta and IL-1RN were genotyped using PCR -RFLP and sequencing. Meta-analysis was performed for the associated variants of IL-10, IL-1 beta. Significant association with RA was observed with IL-1 beta 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-1 beta could be a global marker for RA. The functional significance of associated risk variants of IL-1 beta 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.