Abstract
BackgroundInterleukin-10 (IL-10) is an anti-inflammatory cytokine that affects different immune cells. It is also associated with the stimulation of the T and B cells for the production of antibodies. Several genetic polymorphisms in the IL-10 gene have been reported to cause or aggravate certain diseases like inflammatory bowel disease, rheumatoid arthritis, systemic sclerosis, asthma, etc. However, the disease susceptibility and abnormal function of the mutated IL-10 variants remain obscure.ResultsIn this study, we used seven bioinformatics tools (SIFT, PROVEAN, PMut, PANTHER, PolyPhen-2, PHD-SNP, and SNPs&GO) to predict the disease susceptible non-synonymous SNPs (nsSNPs) of IL-10. Nine nsSNPs of IL-10 were predicted to be potentially deleterious: R42G, R45Q, F48L, E72G, M95T, A98D, R125S, Y155C, and I168T. Except two, all of the putative deleterious mutations are found in the highly conserved region of IL-10 protein structure, thus affecting the protein's stability. The 3-D structure of mutant proteins was modeled by project HOPE, and the protein–protein interactions were assessed with STRING. The predicted nsSNPs: R42Q, R45Q, F48L, E72G, and I168T are situated in the binding site region of the IL-10R1 receptor. Disruption of binding affinity with its receptor leads to deregulation of the JAK-STAT pathway and results in enhanced inflammation that imbalance in cellular signaling. Finally, Kaplan–Meier Plotter analysis displayed that deregulation of IL-10 expression affects gastric and ovarian cancer patients' survival rate. Thus, IL-10 could be useful as a potential prognostic marker gene for some cancers.ConclusionThis study has determined the deleterious nsSNPs of IL-10 that might contribute to the malfunction of IL-10 protein and ultimately lead to the IL-10 associated diseases.
Highlights
Interleukin-10 (IL-10) is an anti-inflammatory cytokine that affects different immune cells
The tools like Protein analysis through evolutionary relationship (PANTHER), SNPs&GO, PHD- SNP, and PMut were used for the prediction of whether a single nucleotide polymorphism is likely to be involved in the insurgence of diseases using functional annotation of protein [35, 38,39,40]
Results Non-synonymous SNP (nsSNP) retrieved from dbSNP database In the dbSNP database showed the human IL-10 gene consists a total of 1800 SNPs, of which 91 were nsSNPs/missense leading to amino acid substitution (5%), 1336 were intronic SNPs (74%), 48 were synonymous SNPs (3%), and the rests were of other types (Fig. 1)
Summary
Interleukin-10 (IL-10) is an anti-inflammatory cytokine that affects different immune cells. Das et al Egyptian Journal of Medical Human Genetics (2022) 23:10 with the most diverse immune cells’ effects [6] It is produced by activated immune cells, monocytes /macrophages and T cell subsets, including Tr1, Treg, and Th1 cells. Some of the SNPs of IL-10 have already been characterized and found to significantly influence the immune response toward pathogenic challenges and disease outcome [25]. These polymorphisms cause functional changes of the IL-10 protein that are associated with various inflammatory and autoimmune diseases, such as inflammatory bowel disease: Crohn’s disease and ulcerative colitis, chronic hepatitis B and C, allergy and autoimmunity [25,26,27]. High-risk deleterious SNPs were further analyzed computationally to predict their structural and functional impact on IL-10 protein, which provides new insights for further genetic association studies
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