REGULATION OF THE CXCL10 EXPRESSION AND INVESTIGATION OF THE RELATIONSHIPS OF THE CXCL10 DNA SEQUENCE VARIATION AND DISEASE

Abstract

Chemokine proteins are significantly effective in inflammation and immunity. Chemokines are from the family of the chemokine proteins and they organise the leukocyte trafficking through the formation of chemotactic activity in the cells that express the appropriate chemokine receptors. CXCL10 is involved in the CXC chemokine family and is effective in biological events such as chemotaxis, apoptosis, cell growth, and angiostasis through the attachment to the CXCR3 receptor. CXCL10 is pleiotropic due to its effects on different disease groups such as autoimmune disorders, transplantation, infectious diseases, and cancer. The aim of this study was to assess the potential role of CXCL10 on the pathogenesis of various diseases. Material and methods: The eQTL effects of CXCL10 expression and the regulation of microRNAs (miRNAs) in terms of co-regulated gene clusters were examined. The STRING/GeneMANIA/KEGG PATHWAY/GeneCards was used for the investigation of the gene-protein and pathway interactions; for the detection of miRNA targeting CXCL102, TargetScan/ miRDB was used; for the investigation of the association of CXCL10 and miRNA region single nucleotide polymorphisms (SNP) with the diseases, GRASP and GWAS were used; GSEA/MSigDB database was used for gene enrichment analysis Results: Both the GSEA/MSigDB tool and the gene set enrichment analysis recommended the use of the enriched forms of the genes involved in breast and prostate cancers and in response to inflammation, and to interferon and regulatory T cells (FDR<1E-50). 182 genes (at a 5-fold threshold) that are structurally co-expressed with five additional CXCL genes close to CXCL10 were identified with the use of the CO-Regulation database (CORD. No enrichment was detected for the common targets of any miRNA in the co-expressed gene sets. The CXCL10 targeting miRNAs were selected, and the TargetScan program was used to identify other target genes in our study. Thus, 80 miRNAs were identified, and the same GSEA analysis was performed for each miRNA target. The association of SNPs with the diseases was investigated for the gene region of each miRNA in the GWAS databases, and an association was detected with the autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, and psoriasis, and with multiple sclerosis, Type 1 diabetes, myasthenia gravis, and allergy/asthma (P<1E-04). For SNPs in CXCL10, no GWAS associations were found; however, SNPs acting as eQTL/ meQTL in the blood for CXCL10 had GWAS associations with longevity, aging, inflammatory bowel disease (IBD), and breast cancer (P<1E-04). Although we found no strong evidence for miRNA-mediated CXCL10 expression in our study, strong genetic associations were found associated with inflammatory and immune disorders in the miRNAs neighboring variants. Conclusion: In conclusion, we suggest that there is a stronger role of CXCL10 in inflammation, autoimmunity, and possibly cancer than its role in transplantation.