RORC Genetic Polymorphism of Rheumatoid Arthritis

Genetic Predisposition to Disease

Rheumatoid arthritis, Genetic polymorphism, RORc2 protein, T helper 17

Three candidate single nucleotide polymorphisms in the RORC2 gene, rs9826 A/G, rs3790515 C/T and rs3828057 C/T were examined together with estimation of nuclear hormone retinoic acid receptor-related orphan receptor variant 2 serum levels to determine their possible association with susceptibility to and clinical phenotype of rheumatoid arthritis in Egyptian population.

Rheumatoid arthritis is a chronic systemic inflammatory arthritis that affects about one percent of the population. It results from a complex interaction between genes and environment (eg, external trigger as cigarette smoking, infection, or trauma) leading to a breakdown of immune tolerance, synovial inflammation and hypertrophy and chronic joint inflammation in a characteristic symmetric pattern. The role of T helper 17 cells and T helper 17 cells -associated cytokines in the pathogenesis of rheumatoid arthritis is now widely recognized. T helper 17 cells are the dominant effector T cell involved in the induction of autoimmune chronic diseases by production of several proinflamatory cytokines especially interleukin -17. T helper 17 cells present in the joint may create a positive feedback loop leading to the continuous activation of T cells, which is a critical event in the generation of autoimmunity. Nuclear hormone retinoic acid receptor-related orphan receptor variant 2, encoded by RORC2 gene located on chromosome 1q21-q23 is a master transcriptional factor that can drive T helper 17 cells differentiation. It is now well established that for T helper 17 cells differentiation, it is critical to have transforming growth factor β1 in the presence of interleukin-1, interleukin -6, or interleukin -21 to decrease suppressive FoxP3 and upregulate RORC2 gene encoded unique lineage-specific transcription factor, nuclear hormone retinoic acid receptor-related orphan receptor variant 2. Knockdown of transcription factor nuclear hormone retinoic acid receptor-related orphan receptor variant 2 cause high forkhead transcriptional repressor levels and reduces expression of pro-inflammatory cytokines such as interleukin-1, interleukin -6, interleukin -17 and transforming growth factor β1 suggesting that the role of nuclear hormone retinoic acid receptor-related orphan receptor variant 2 in T helper 17 cells differentiation involves not only in induction of T helper 17 cells characteristics genes, but also suppression of Treg cells specific programs that play an important role in immunological tolerance. Single nucleotide polymorphisms underlie differences in our susceptibility to disease, the severity of illness and the way our body responds to pathogens, chemicals, drugs, vaccines and other agents. For example, a single base mutation in the apolipoprotein E gene is associated with a higher risk for Alzheimer's disease. RORC2 gene may represent a candidate gene for autoimmune diseases. However, not too much is known about the function of RORC2 genetic polymorphisms in autoimmune diseases, including rheumatoid arthritis. The RORC2 gene polymorphisms have been analyzed in a Behcet's disease, secondary lymphedema and type 2 diabetes mellitus and rheumatoid arthritis in a study on Polish population. This is why analysis of polymorphisms within the RORC2 gene together with estimation of nuclear hormone retinoic acid receptor-related orphan receptor variant 2 serum levels may help to uncover their correlations with some clinical and laboratory findings in rheumatoid arthritis.

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