DefinePK

Abstract

Rheumatoid arthritis (RA) is a chronic, systematic, and progressive inflammatory disorder, causing severe damage to joints and hence increase mortality. The Chemokine (C-C motif) ligand 21 (CCL21), a member cytokines family, is involved in immuno-inflammatory and regulatory processes. Therefore, identifying the important SNPs (single nucleotide polymorphisms) in the CCL21 gene is of key importance to evaluate their structural and functional significance and to discover novel therapeutic targets for immune-related diseases, including RA. In this study, we used in silico approaches for identifying the most damaging non-synonymous SNPs (nsSNPs), playing a significant structural and functional role in CCL21 protein. The primary tools used for this study included PROVEAN, SNPs&GO, SIFT and PolyPhen2. Other tools, its stability, Structure and functional effect as well as the conservation profile, were verified using I-Mutant, MutPred, and ConSurf. The site of post-translational modification also predicted. The 3-D modeling of proteins was carried out using I-TASSER which were then visualized in Chimera v1.11. Furthermore, the gene-gene interactions were predicted using STRING and gene MANIA. It was observed that the nsSNPs D30Y (rs753133670), I62N (rs1170851787), R75C (rs759733358), R75S (rs776954599) and A83V (rs776954599) were the most damaging nsSNPs in the CCL21 gene. These nsSNPs might have a significant role in CCL2 protein’s malfunctioning and possibly causing different autoimmune diseases including RA. Our study concluded that, to study the correlation of the CCL21 gene with certain autoimmune disorders, i.e. Crohn’s Disease (CD), RA and other immune-associated diseases, these SNPs could be the most important ones. In addition, these SNPs need to be studied in animal models and cell cultures in association with certain diseases, to identify if they could be of use for the gene therapy and pharmacogenomics.