Abstract
Single-nucleotide polymorphisms (SNPs) are reported to be associated with many diseases, including autoimmune diseases. In rheumatoid arthritis (RA), about 152 SNPs are reported to account for ~15% of its heritability. These SNPs may result in the alteration of gene expression and may also affect the stability of mRNA, resulting in diseased protein. Therefore, in order to predict the underlying mechanism of these SNPs and identify novel therapeutic sites for the treatment of RA, several bioinformatics tools were used. The damaging effect of 23 non-synonymous SNPs on proteins using different tools suggested four SNPs, including rs2476601 in PTPN22, rs5029941 and rs2230926 in TNFAIP3, and rs34536443 in TYK2, to be the most damaging. In total, 42 of 76 RA-associated intronic SNPs were predicted to create or abolish potential splice sites. Moreover, the analysis of 11 RA-associated UTR SNPs indicated that only one SNP, rs1128334, located in 3'UTR of ETS1, caused functional pattern changes in BRD-BOX. For the identification of novel therapeutics sites to treat RA, extensive gene-gene interaction network interactive pathways were established, with the identification of 13 potential target sites for the development of RA drugs, including three novel target genes. The anticipated effect of these findings on RA pathogenesis may be further validated in both in vivo and in vitro studies.
Highlights
Rheumatoid arthritis (RA) is a systemic autoimmune disease with approximately 1%prevalence worldwide, and its presence carries the risk of irreparable functional disability of inflamed joints due to articular damage [1]
We found 152 SNPs in the literature which were reported to be associated with rheumatoid arthritis (RA) (Table S1)
Our study suggested that the creation of BRD-BOX by rs1128334 (ETS1) would be protective against disease
Summary
Rheumatoid arthritis (RA) is a systemic autoimmune disease with approximately 1%prevalence worldwide, and its presence carries the risk of irreparable functional disability of inflamed joints due to articular damage [1]. Rheumatoid joints exhibit an inflammatory environment that favors the activation of T cells, B cells, macrophages, osteoclasts, and synovial fibroblasts [1]. These cells maintain crosstalk through the production of cytokines, which upon activation induce the secretion of enzymes and other products that contribute to the destruction of cartilage and bone tissues [2]. Several genes have been associated with RA susceptibility [7,8,9,10,11]. Genetic association studies based on different populations have identified more than 100 genomic loci [10,11,12] which account for approximately 15% of the variance [12,13]. The actual underlying genetic mechanism concerning SNPs has not been determined
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