Deleterious Non-Synonymous Single Nucleotide Polymorphisms (nsSNPs) in the Human Interleukin 12B Gene: Identification and Structural Characterization

Awad A. Algarni

Abstract


Background: Interleukin -12B (IL12B) polymorphism has been identified as a factor in the development of various Immunological disorders and cancer. The objective of this study was to identify the non-synonymous SNPs (nsSNPs) with the strongest predicted negative impact on the function of the IL12B protein.

Methods: We employed a variety of computational methods, including SIFT, PolyPhen2, PROVEAN, SNAP2 to determine the functional impact of nsSNPs. Also, In order to investigate the potential association of nsSNPs in the IL12B gene with disease, a computational analysis was conducted using PhD-SNP, SNP&GO, and Pmut. Additionally, I-mutant and MuPro were employed to predict protein stability, while ConSurf was used to identify functional domains and conserved amino acid residues within the protein. Furthermore, SOPMA was used in combination with Project Hope and MutPred2 to predict the impact of mutations on both the structure and function of proteins. Finally, we used GeneMania to analyze the gene-gene interactions of the IL12B gene with other genes.

Results: Our results indicate that nine nsSNPs (G72C, G86C, C90R, C131S, Y136D, P235L, V254G, Y258H and P259S) were found to be potentially deleterious in the IL12B gene.

Conclusion: Our study emphasizes the significance of identifying functional and structural polymorphisms in the IL12B gene, as they may reveal potential therapeutic targets and provide insight into the underlying mechanisms of related diseases. Further experimental investigation is necessary to fully explore the role of these nsSNPs in disease pathogenesis.

Keywords: Interleukin 12B; deleterious nsSNPs; Polymorphisms.; Computational analysis;


Full Text:

PDF

References


Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nature Reviews Immunology, (2003); 3(2):133-146.

Moschen AR, Tilg H, Raine T. IL-12, IL-23 and IL-17 in IBD: immunobiology and therapeutic targeting. Nature Reviews Gastroenterology & Hepatology, (2019); 16(3): 185-196.

Saravia J, Chapman, NM. and Chi H.. Helper T cell differentiation. Cellular & molecular immunology, (2019); 16(7): 634-643.

Li J, Zhang C, Wang JB, Chen SS, Zhang TP, et al. Relationship between the IL12B (rs3212227) gene polymorphism and susceptibility to multiple autoimmune diseases: a meta-analysis. Modern Rheumatology, (2016); 26(5): 749-756.

Wu PB, Wu XM, Qian R, Hong C, Yitian G, et al. Association between IL12B polymorphisms and inflammatory bowel disease in Caucasian population: a meta-analysis. Cytokine, (2020); 136:155296.

Epaneshnikova VB, Smolnikova MV, Smirnova SV. Analysis of polymorphisms of genes regulating the immune response in patients with atopic asthma. Medical Genetics, (2016); 15(4):36-38.

Manolova I, Ivanova M, Vasilev G, Stoilov R, Miteva L, Stanilova S. Impact of IL12B polymorphisms on genetic susceptibility and IL-12p40 and IL-23 serum levels in rheumatoid arthritis. Immunological Investigations, (2020); 49(1-2):1-4.

Falahi S, Salari F, Rezaiemanesh A, Mortazavi SH, Koohyanizadeh F, et al. Association of interleukin-12B rs6887695 with susceptibility to allergic rhinitis. Immunologic research, (2021); 69:189-195.

Tabatabaei-Panah PS, Moravvej H, Delpasand S, Jafari M, Sepehri S, et al, Akbarzadeh R. IL12B and IL23R polymorphisms are associated with alopecia areata. Genes & Immunity, (2020); 21(3):203-210.

Zhang W, Dang S, Zhang G, He H, Wen X. Genetic polymorphisms of IL-10, IL-18 and IL12B are associated with risk of non-small cell lung cancer in a Chinese Han population. International Immunopharmacology, (2019); 77:105938.

Núñez-Marrero A, Arroyo N, Godoy L, Rahman MZ, Matta JL, Dutil J. SNPs in the interleukin-12 signaling pathway are associated with breast cancer risk in Puerto Rican women. Oncotarget, (2020); 11(37):3420

Orenay-Boyacioglu S, Kasap E, Yuceyar H, Korkmaz M. Association of interleukin 12B rs3212227 polymorphism with gastric cancer, intestinal metaplasia, and helicobacter pylori infection. Genetika, (2020); 115-126.

Emadi E, Akhoundi F, Kalantar SM, Emadi-Baygi M. Predicting the most deleterious missense nsSNPs of the protein isoforms of the human HLA-G gene and in silico evaluation of their structural and functional consequences. BMC genetics, (2020); 21(1):1-27

Molineros JE, Looger LL, Kim K, Okada Y, Terao C, et al. Amino acid signatures of HLA Class-I and II molecules are strongly associated with SLE susceptibility and autoantibody production in Eastern Asians. PLoS genetics, (2019); 15(4):e1008092

Ahmad HI, Ijaz N, Afzal G, Asif AR, Rahman A, et al. Computational Insights into the Structural and Functional Impacts of nsSNPs of bone morphogenetic proteins. BioMed Research International, (2022); 2022

Allemailem KS, Almatroudi A, Alrumaihi F, Almansour NM, Aldakheel FM, et al. Single nucleotide polymorphisms (SNPs) in prostate cancer: its implications in diagnostics and therapeutics. American Journal of Translational Research, (2021); 13(4):3868.

Vaser R, Adusumalli S, Leng SN, Sikic M, Ng PC. SIFT missense predictions for genomes. Nature protocols, (2016); 11(1):1-9

Choi Y, Sims GE, Murphy S, Miller JR, Chan AP. Predicting the functional effect of amino acid substitutions and indels. PLoS ONE, (2012); 7:e46688.

Poon KS. In silico analysis of BRCA1 and BRCA2 missense variants and the relevance in molecular genetic testing. Scientific Reports, (2021); 11(1):1-8.

Dalmer TR, Clugston RD. Gene ontology enrichment analysis of congenital diaphragmatic hernia-associated genes. Pediatric research, (2019); 85(1):13-19.

López-Ferrando V, Gazzo A, De La Cruz X, Orozco M, Gelpí JL. PMut: a web-based tool for the annotation of pathological variants on proteins, 2017 update. Nucleic acids research, (2017); 45(W1):W222-W228.

Capriotti E, Fariselli P. PhD-SNPg: a webserver and lightweight tool for scoring single nucleotide variants. Nucleic acids research, (2017); 45(W1):W247-52.

Manfredi M, Savojardo C, Martelli PL, Casadio R. E-SNPs&GO: embedding of protein sequence and function improves the annotation of human pathogenic variants. Bioinformatics, (2022); 38(23):5168-5174.

Capriotti E, Fariselli P, Casadio R. I-Mutant2. 0: predicting stability changes upon mutation from the protein sequence or structure. Nucleic acids research, (2005); 33:W306-W310.

Cheng J, Randall A, Baldi P. Prediction of protein stability changes for single-site mutations using support vector machines. Proteins: Structure, Function, and Bioinformatics, (2006); 62(4):1125-1132.

Ashkenazy H, Erez E, Martz E, Pupko T, Ben-Tal N. ConSurf 2010: calculating evolutionary conservation in sequence and structure of proteins and nucleic acids. Nucleic acids research, (2010); 38:W529-W533.

Deléage G. ALIGNSEC: viewing protein secondary structure predictions within large multiple sequence alignments. Bioinformatics, (2017); 33(24):3991–3992

Venselaar H, Te Beek TA, Kuipers RK, Hekkelman ML, Vriend G. Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. BMC bioinformatics, (2010); 11(1):1-10

Li B, Krishnan VG, Mort ME, Xin F, Kamati KK, Cooper DN, et al. Automated inference of molecular mechanisms of disease from amino acid substitutions. Bioinformatics, (2009); 25(21):2744-2750.

Warde-Farley D, Donaldson SL, Comes O, Zuberi K, Badrawi R, et al. The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function. Nucleic acids research, (2010); 38:W214-W220.

Pathak RK, Lim B, Park Y, Kim JM. Unraveling structural and conformational dynamics of DGAT1 missense nsSNPs in dairy cattle. Scientific reports, (2022); 12(1):4873.

Chai CY, Maran S, Thew HY, Tan YC, Rahman NM, Cheng WH, et al. Predicting Deleterious Non-Synonymous Single Nucleotide Polymorphisms (nsSNPs) of HRAS Gene and In Silico Evaluation of Their Structural and Functional Consequences towards Diagnosis and Prognosis of Cancer. Biology, (2022); 11(11):1604.

Zhang M, Huang C, Wang Z, Lv H, Li X. In silico analysis of non-synonymous single nucleotide polymorphisms (nsSNPs) in the human GJA3 gene associated with congenital cataract. BMC molecular and cell biology, (2020); 21(1):1-3.

Tastan O, Klein-Seetharaman J, Meirovitch H. The effect of loops on the structural organization of a-helical membrane proteins. Biophysical journal, (2009); 96(6):2299-2312.


Refbacks

  • There are currently no refbacks.