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Role of IL-13 Genetic Variants in Signalling of Asthma

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Abstract

Asthma is a chronic inflammatory disease of the lower airways characterised by intermittent airway narrowing and airflow obstruction. The aim of this study was to examine the association of IL-13 Arg 130 Gln (A/G) and -1112C/T cytokine gene polymorphisms and to know the secretion of IL-13 cytokine levels and the interactions between the IL-13 130A/G and IL-13Rα1/IL-4Rα complex cytokine genes. The study population comprised of atopic and non-atopic asthma patients and healthy controls (HC) (N = 120). Single nucleotide polymorphisms (SNPs) were determined by restriction fragment length polymorphism (RFLP). IL-13 cytokine serum levels were measured by enzyme-linked immunosorbent assay (ELISA), and homology modelling of IL-13 A/G cytokine gene was performed through in silico analysis. In IL-13 130A/G cytokine gene AG, GG genotypes (p < 0.0042, OR = 2.87, CI 1.46–5.65; OR = 1.92, CI 1.06–3.48) were found to be significant in atopic asthma patients vs HC. The mean IL-13 serum cytokine levels were found to be significantly high in atopic (38.48 ± 36.54) and non-atopic (36.05 ± 34.54) asthma patients whereas total serum IgE levels were significantly high at p < 0.0001 in atopic and low in non-atopic asthma patients at p < 0.003 compared to HC. In silico analysis indicated that residue IL-13 130 with charge modifying variants was crucial in ligand-receptor interactions. IL-13 cytokine serum levels were significantly high in atopic and non-atopic asthma patients compared to HC. The GG genotype of IL-13 130A/G cytokine gene might be involved in the induced production of total IgE and IL-13 cytokine serum levels suggesting IL-13 may be important in the signalling of asthma.

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References

  1. Coffman, R.L., J. Ohara, M.W. Bond, J. Carty, A. Zlotnik, and W.E. Paul. 1986. B cell stimulatory factor-1 enhances the IgE response of lipopolysaccharide-activated B cells. Journal of Immunology 136: 4538–4541.

    CAS  Google Scholar 

  2. Del Prete, G.F., E. Maggi, and P. Parronchi. 1988. IL-4 is an essential factor for IgE synthesis induced in vitro by human T cell clones and their supernatants. Journal of Immunology 140: 4193–4198.

    Google Scholar 

  3. Bacharier, L.B., and R.S. Geha. 2000. Molecular mechanisms of IgE regulation. Journal of Allergy and Clinical Immunology 105: 547–558.

    Article  Google Scholar 

  4. Pene, J., F. Rousset, and F. Briere. 1988. IgE production by normal human lymphocytes is induced by interleukin 4 and suppressed by interferons gamma and alpha and prostaglandin E2. Proceedings of the National Academy of Sciences of the United States of America 85: 6880–6884.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Moy, F.J., E. Diblasio, J. Wilhelm, and R. Powers. 1988. Solution structure of human IL-13 and implication for receptor binding. Journal of Molecular Biology 310: 219–230.

    Article  Google Scholar 

  6. Zurawski, S.M., F. Vega, B. Juyghe, and G. Zurawski. 1993. Receptors for interleukin-13 and interleukin-4 are complex and share a novel component that functions in signal transduction. European Molecular Biology Organization 12: 2663–2670.

    CAS  Google Scholar 

  7. Wills-Karp, M. 2004. Interleukin-13 in asthma pathogenesis. Immunology Reviews 202: 175–190.

    Article  CAS  Google Scholar 

  8. Willis-Karp, M., J. Luyimbazi, X. Xu, B. Schofield, and T.Y. Neben. 1998. Interleukin-13: central mediator of allergic asthma. Science 282: 2258–2261.

    Article  Google Scholar 

  9. Webb, D.C., A.N. McKenzie, A.M. Koskinen, M. Yang, J. Mattes, and P.S. Foster. 2000. Integrated signals between IL-13, IL-4, and IL-5 regulate airways hyper reactivity. Journal of Immunology 165: 108–113.

    Article  CAS  Google Scholar 

  10. Heinzmann, A., X.Q. Mao, M. Akaiwa, R.T. Kreomer, P.S. Gao, K. Ohshima, R. Umeshita, Y. Abe, S. Braun, and T. Yamashita. 2000. Genetic variants of IL-13 signalling and human asthma and atopy. Human Molecular Genetics 9: 549–559.

    Article  CAS  PubMed  Google Scholar 

  11. Wei, N., Z. Yuansheng, C. Jiquan, and X. Qingyu. 2013. Association between Interleukin-4 Receptor a Chain (IL4RA) I50V and Q551R polymorphisms and asthma risk: an update meta-analysis. Plos One 8, e69120.

    Article  Google Scholar 

  12. Jung, Y.H., J.H. Seo, H.Y. Kim, J.W. Kwon, B.J. Kim, H.B. Kim, S.Y. Lee, and G.C. Jang. 2015. The relationship between asthma and bronchiolitis is modified by TLR4, CD14, and IL-13 polymorphisms. Pediatric Pulmonology 50: 8–16.

    Article  PubMed  Google Scholar 

  13. Homsak, M., B. Zagradišnik, N.K. Vokac, Z. Roskar, M.S. Kavalar, and A. Bruncko. 2002. IL13 polymorphism R130Q and total serum IgE levels in children with asthma. European Respiratory Journal 20: 524–528.

    Article  Google Scholar 

  14. Lin, C., J. Jia, F.M. Chun, L. Su-Yun, W. You-Ping, and G. Xiao-Min. 2012. IL-13 polymorphisms contribute to the risk of asthma: a meta-analysis. Clinical Biochemistry 45: 285–288.

    Article  Google Scholar 

  15. Sara Hosseini, F., A. Jalil Tavakkol, R. Houshang, H. Reza Farid, and Khaje D. Mohammad. 2007. Association between the polymorphisms of IL-4 gene promoter (-590C>T), IL-13 coding region (R130Q) and IL-16 gene promoter (-295T>C) and allergic asthma. Iranian Journal of Allergy, Asthma and Immunology 6: 9–14.

    Google Scholar 

  16. He, J.Q., M. Chan-Yeung, A.B. Becker, H. Dimich-Ward, A.C. Ferguson, J. Manfreda, W.T.A. Watson, and A.J. Sandford. 2003. Genetic variants of the IL13 and IL4 genes and atopic diseases in at-risk children genes and immunity. Nature 4: 385–389.

    CAS  Google Scholar 

  17. Zeinab El-Sayed, A., S. Shereen ElSayed, B. Shereen El-Sayed, and G. Sherif Eladawy. 2010. IL-13 R130Q single nucleotide polymorphism in asthmatic Egyptian children. The Egyptian Society of Pediatric Allergy and Immunology 8: 9–18.

    Google Scholar 

  18. Timothy Howard, D., A. Paul Whittaker, L. Ari Zaiman, H. Gerard Koppelman, X. Jianfeng, T. Marcus Hanley, and A. Deborah Meyers. 2001. Identification and association of polymorphisms in the interleukin-13 gene with asthma and atopy in a Dutch population. American Journal of Respiratory Cell and Molecular Biology 25: 377–384.

    Article  Google Scholar 

  19. Renske Bottema, W.B., M. Ilja Nolte, D. Timothy, F. Howard, H. Gerard, E.J. Koppelman Anthony, and D. Dubois Gea de Meer. 2010. Interleukin 13 and interleukin 4 receptor-polymorphisms in rhinitis and asthma. International Archives of Allergy and Immunology 153: 259–267.

    Article  PubMed  Google Scholar 

  20. Mohamed, N., T.H. Medha, D. Iman, E. Sabah, and A. Nashwa. 2014. Association of interleukin 13 +2044G/A polymorphism with bronchial asthma development, severity and immunoglobulin E levels in an Egyptian population. Clinical Medicine and Diagnostics 4: 71–77.

    Article  Google Scholar 

  21. Micheal, S., K. Minhas, M. Ishaque, F. Ahmed, and A. Ahmed. 2013. IL-4 gene polymorphisms and their association with atopic asthma and allergic rhinitis in Pakistani patients. Journal of Investigational Allergology and Clinical Immunology 23: 107–111.

    CAS  PubMed  Google Scholar 

  22. Postma, S. 2010. Interleukin 13 and interleukin 4 receptor-polymorphisms in rhinitis and asthma. International Archives of Allergy and Immunology 153: 259–267.

    Article  PubMed  Google Scholar 

  23. Meyers, D.A., D.S. Postma, C.I.M. Panhuysen, J. Xu, P.J. Amelung, R.C. Levit, and E.R. Bleecker. 1994. Evidence for a locus regulating total serum IgE levels mapping to chromosome 5. Genomics 23: 464–470.

    Article  CAS  PubMed  Google Scholar 

  24. Marsh, D.G., J.D. Neely, D.R. Breazeale, B. Ghosh, L.R. Friedhoff, E. Ehrlich-Kautzy, and C. Schou. 1994. Linkage analysis of IL-4 and other chromosome 5q31.1 markers and total serum IgE concentrations. Science 264: 1152–1156.

    Article  CAS  PubMed  Google Scholar 

  25. Ober, C., S.A. Leavitt, A. Tsalenko, T.D. Howard, D.M. Hoki, and R. Daniel. 2000. Variation in the interleukin 4-receptor alpha gene confers susceptibility to asthma and atopy in ethnically diverse populations. American Journal of Human Genetics 66: 517–526.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ober, C., N. Cox, M. Abney, A. DiRienzo, E.S. Lander, B. Changyaleket, and H. Gidley. 1998. Genome- wide search for asthma susceptibility loci in a founder population. Human Molecular Genetics 7: 1393–1398.

    Article  CAS  PubMed  Google Scholar 

  27. Lonjou, C., K. Barnes, H. Chen, W.O. Cookson, K.A. Deichmann, I.P. Hall, and J.W. Holloway. 2000. A first trial of retrospective collaboration for positional cloning in complex inheritance: assay of the cytokine region on chromosome 5 by the consortium on asthma genetics. Proceedings of the National Academy of Sciences of the United States of America 97: 10942–10947.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. van der Pouw Kraan, T.C.T.M., A. van Veen, L.C.M. Boeji, S.A.P. van Tuyl, E.R. de Groot, and S.O. Stapel. 1999. An IL-13 promoter polymorphism associated with increased risk of allergic asthma. Genes and Immunity 1: 61–65.

    Article  PubMed  Google Scholar 

  29. Krzysztof, K., B. Pawel, P. Agnieszka, C. Lech, and Bodzenta L. Anna. 2015. Association between IL-13 -1112 C>T promoter polymorphism and patterns of allergen-induced asthmatic response in house dust mite allergic patients. Journal of Allergy and Clinical Immunology 135: e27–e34.

    Google Scholar 

  30. Graves, P.E., M. Kabesch, M. Halonen, C.J. Holberg, M. Baldini, C. Fritzsch, S.K. Weiland, and R.P. Erickson. 2000. A cluster of seven tightly linked polymorphisms in the IL-13 gene is associated with total serum IgE levels in three populations of white children. Journal of Allergy and Clinical Immunology 105: 506–513.

    Article  CAS  PubMed  Google Scholar 

  31. Holford-Strevens, V., P. Warren, C. Wong, and J. Manfreda. 1984. Serum total immunoglobulin E levels in Canadian adults. Journal of Allergy and Clinical Immunology 73: 516–522.

    Article  CAS  PubMed  Google Scholar 

  32. Criqui, M.H., J. Seibles, and R.N. Hamburger. 1990. Epidemiology of immunoglobulin E levels in a defined population. Annals of Allergy 64: 308–313.

    CAS  PubMed  Google Scholar 

  33. Burrows, B., F.D. Martinez, and M. Halonen. 1989. Association of asthma with serum IgE levels and skin-test reactivity to allergens. New England Journal of Medicine 320: 271–277.

    Article  CAS  PubMed  Google Scholar 

  34. Wittig, H.J., J. Belloit, I. De Fillippi, and G. Royal. 1980. Age-related serum immunoglobulin E levels in healthy subjects and in patients with allergic disease. Journal of Allergy and Clinical Immunology 66: 305–313.

    Article  CAS  PubMed  Google Scholar 

  35. Sears, M.R., C.M. Chow, and D.J. Morseth. 1980. Serum total IgE in normal subjects and the influence of a family history of allergy. Clinical Allergy 10: 423–431.

    Article  CAS  PubMed  Google Scholar 

  36. Grundbacher, F.J., and F.S. Massie. 1985. Levels of immunoglobulin G, M, A, and E at various ages in allergic and nonallergic black and white individuals. Journal of Allergy and Clinical Immunology 75: 651–658.

    Article  CAS  PubMed  Google Scholar 

  37. Joseph, J., S. Benedict, S. Al-sowaidi, M. Joseph, and T. Zoubeidi. 2006. Serum interleukin-13 levels are elevated in mild and moderate persistent asthma. The Internet Journal of Asthma, Allergy and Immunology 4: 1–7.

    Google Scholar 

  38. Gerrard, J.W., C.G. Ko, R. Dalgleish, and K.T. Tan. 1977. Immunoglobulin levels in white and metis communities in Saskatchewan. Clinical and Experimental Immunology 29: 447–456.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Kalyoncu, A.F., and G. Stalenheim. 1992. Serum IgE levels and allergic spectra in immigrants to Sweden. Allergy 47: 277–280.

    Article  CAS  PubMed  Google Scholar 

  40. Liang, L., A.G. Saffron Willis-Owen, L. Catherine, C.C. Kenny Wong, A. Gwyneth Davies, J. Thomas Hudson, and B. Aristea. 2015. An epigenome-wide association study of total serum immunoglobulin E concentration. Nature 520: 670–674.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ghadah Saleh Al-Quraishi, M. 2013. Serum levels of total IgE, IL-12, IL-13 and IL-18 in children patients with asthma. Iraqi Journal of Pharmaceutical Sciences 22: 110–114.

    Google Scholar 

  42. Elias, J.A., L. Cohn, and G.L. Chupp. 2004. Asthma: mechanisms of disease persistence and progression. Annual Review of Immunology 22: 789–815.

    Article  PubMed  Google Scholar 

  43. Grunig, G., M. Warnock, and A.E. Waki. 1998. Requirement for IL-13 independently of IL-4 in experimental asthma. Science 282: 2261–2263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gabrielsson, S.S., and S.A. Paulie. 1998. Increased frequencies of allergen-induced interleukin-13 producing cells in atopic individuals during the pollen season. Scandinavian Journal of Immunology 48: 429–435.

    Article  CAS  PubMed  Google Scholar 

  45. Wosinska-becler, K., H. Plewako, and L. Hakanssou. 2004. Cytokine production in peripheral blood cells during and outside the pollen season in brich-allergic patients and non-allergic controls. Clinical and Experimental Allergy 34: 123–130.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the staff of allergy clinic for the assistance in sample collection. We also thank for the financial support provided by the Bhagwan Mahavir Medical and Research Centre, Hyderabad.

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Correspondence to Sumanlatha Gaddam.

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We thank the Bhagwan Mahavir Medical and Research Centre, Hyderabad, for the financial support provided to carry out this research work.

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Alasandagutti, M.L., Ansari, M.S.S., Sagurthi, S.R. et al. Role of IL-13 Genetic Variants in Signalling of Asthma. Inflammation 40, 566–577 (2017). https://doi.org/10.1007/s10753-016-0503-3

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