The association between IL18, FOXP3 and IL13 genes polymorphisms and risk of allergic rhinitis: a meta-analysis

Abstract

Objectives

Allergic rhinitis (AR) is a chronic inflammatory disease of nasal mucosa. Loss of function of Th17 cells and regulatory T (Treg) cells plays a role in the pathogenesis of AR. IL18, FOXP3, and IL13 are key genes in the development of AR. However, the genetic associations between IL18, FOXP3 and IL13 genes polymorphisms and AR risk were inconclusive yet.

Methods

A meta-analysis was performed by searching through Pubmed, EMBASE, web of science and CNKI databases. The ORs and 95%CIs were used to assess the genetic association between the allelic, dominant and recessive models of IL18, FOXP3 and IL13 genes polymorphisms and AR risk.

Results

A total of 15 articles (6 for FOXP3, 5 for IL18, and 5 for IL13) were enrolled in the present study. No association was detected between the IL18 rs187238, rs1946518, rs360721, FOXP3 rs2232365, rs3761548 and IL13 rs1800925 polymorphisms and AR risk (p > 0.05). Significant associations were observed between the allelic (p = 0.001, OR 1.32, 95% CI 1.12–1.56), dominant (p = 0.005, OR 1.43, 95% CI 1.11–1.83) and recessive models (p = 0.01, OR 1.64, 95% CI 1.13, 2.40) of IL13 rs20541 and AR risk. Subgroup analysis based on ethnicity revealed that the IL13 rs20541 was significantly associated with AR risk in Asian population (allelic model: p = 0.009, OR 1.36, 95% CI 1.13–1.63, dominant model: p = 0.005, OR 1.43, 95% CI 1.11–1.83; recessive model: p = 0.01, OR 1.64, 95% CI 1.13–2.40).

Conclusions

IL13 rs20541 may contribute to the risk of AR in Asian population. To confirm these results, larger number of case–control study with more subjects is necessary in the future.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. 1.

    Plaut M, Valentine MD. Allergic Rhinitis. N Engl J Med. 2005;353:1934–44.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Bernstein DI, Schwartz G, Bernstein JA. Allergic rhinitis: mechanisms and treatment. Immunol allergy Clin N Am. 2016;36(2):261–78.

    Article  Google Scholar 

  3. 3.

    May JR, Dolen WK. Management of allergic rhinitis: a review for the community pharmacist. Clin Ther. 2017;39(12):2410–9.

    Article  PubMed  Google Scholar 

  4. 4.

    Sinha B, Vibha X, Singla R, Chowdhury R. Allergic rhinitis: a neglected disease—a community based assessment among adults in Delhi. J Postgrad Med. 2015;61(3):169–75.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Dunlop J, Matsui E, Sharma HP. Allergic rhinitis: environmental determinants. Immunol Allergy Clin N Am. 2016;36(2):367–77.

    Article  Google Scholar 

  6. 6.

    Lee JH, Koh SH. Genetic role in allergic rhinitis. J Rhinol. 2010;17(1):7–12.

    Google Scholar 

  7. 7.

    Gu ZW, Wang YX, Cao ZW. Neutralization of interleukin-9 ameliorates symptoms of allergic rhinitis by reducing Th2, Th9, and Th17 responses and increasing the Treg response in a murine model. Oncotarget. 2017;8(9):14314–24.

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Xiao C, Li H, Li H, Cheng Z, Qin J, Zhou W, et al. The effect of specific immunotherapy on the regulation of Th1/Th2 cell ratio of the patients with allergic rhinitis in serum. J Clin Otorhinolaryngol. 2010;24(20):924–7.

    Google Scholar 

  9. 9.

    Yu SQ. Content of CD4+CD25+ regulatory T cells in peripheral blood lymphocytes in patients with allergic rhinitis. J Clin Otorhinolaryngol Head Neck Surg. 2011;25(8):354–9.

    Google Scholar 

  10. 10.

    Larsson K, Lindstedt M, Lundberg K, Dexlin L, Wingren C, Korsgren M, et al. CD4+ T cells have a key instructive role in educating dendritic cells in allergy. Int Arch Allergy Immunol. 2009;149(1):1–15.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Liu Y, Zeng M, Liu Z. Clinical relevance of Th17 response in allergic rhinitis: more evidence. Clin Exp Allergy. 2015;45(12):1875.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Ciprandi G, Filaci G, Fenoglio D. Th17 cells and allergic rhinitis: is there clinical relevance? Otolaryngol Head Neck Surg. 2010;143(4):604–5.

    Article  PubMed  Google Scholar 

  13. 13.

    Lee SM, Gao BX, Dahl M, Calhoun K, Fang D. Decreased FOXP3 gene expression in the nasal secretions from patients with allergic rhinitis. Otolaryngol Head Neck Surg. 2009;140(2):197–201.

    Article  PubMed  Google Scholar 

  14. 14.

    Zhang L, Zhang Y, Desrosiers M, Wang C, Zhao Y, Han D. Genetic association study of FOXP3 polymorphisms in allergic rhinitis in a Chinese population. Human Immunol. 2009;70(11):934.

    Article  CAS  Google Scholar 

  15. 15.

    Fodor E, Garaczi E, Hilda P, et al. The rs3761548 polymorphism of FOXP3 is a protective genetic factor against allergic rhinitis in the Hungarian female population. Human Immunol. 2011;72(10):930–4.

    Article  CAS  Google Scholar 

  16. 16.

    Zhang Y, Duan S, Wei X, Zhao Y, Zhao L, Zhang L. Association between polymorphisms in FOXP3 and EBI3 genes and the risk for development of allergic rhinitis in Chinese subjects. Hum Immunol. 2012;73(9):939–45.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Miller AL. The etiologies, pathophysiology, and alternative/complementary treatment of asthma. Altern Med Rev. 2001;6(1):20–47.

    CAS  PubMed  Google Scholar 

  18. 18.

    Huebner M, Kim DY, Ewart S, Karmaus W, Sadeghnejad A, Arshad SH. Patterns of GATA3 and IL13 gene polymorphisms associated with childhood rhinitis and atopy in a birth cohort. J Allergy Clin Immunol. 2008;121(2):408–14.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Llanes E, Quiralte J, López E. Analysis of polymorphisms in olive pollen allergy: IL13, IL4RA, IL5 and ADRB2 genes. Int Arch Allergy Immunol. 2009;148(3):228–38.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Wang M, Xing ZM, Lu C, Ma YX, Yu DL, Yan Z. A common IL-13 Arg130Gln single nucleotide polymorphism among Chinese atopy patients with allergic rhinitis. Hum Genet. 2003;113(5):387–90.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Bottema RWB, Nolte IM, Howard TD. Interleukin 13 and interleukin 4 receptor-α polymorphisms in rhinitis and asthma. Int Arch Allergy Immunol. 2010;153(3):259–67.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Wong CK, Ho CY, Ko FW, Chan CH, Ho AS, Hui DS, et al. Proinflammatory cytokines (IL-17, IL-6, IL-18 and IL-12) and Th cytokines (IFN-gamma, IL-4, IL-10 and IL-13) in patients with allergic asthma. Clin Exp Immunol. 2001;125(2):177–83.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Sebelova S, Izakovicova-Holla L, Stejskalova A, Schüller M, Znojil V, Vasku A. Interleukin-18 and its three gene polymorphisms relating to allergic rhinitis. J Hum Genet. 2007;52(2):152–8.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Tungtrongchitr A, Jumpasri J, Sookrung N, Visitsunthorn N, Tantilipikorn P, Piboonpocanan O, et al. Alteration of -656(G/T) and -607(C/A) polymorphisms in interleukin-18 (IL-18) gene in house dust mite-sensitive allergic rhinitis patients in Thailand. Genet Mol Res. 2017;16:3.

    Article  CAS  Google Scholar 

  25. 25.

    Ibrahim GH, Eltabbakh MT, Gomaa AHA, Mohamed EA. Interleukin-18 gene polymorphisms in Egyptian patients with allergic diseases. Am J Rhinol Allergy. 2012;26(5):385–9.

    Article  PubMed  Google Scholar 

  26. 26.

    Holla LI, Hrdliková B, Schüller M, Buckova D, Kindlova D, Izakovic V, et al. Haplotype analysis of the interleukin-18 gene in Czech patients with allergic disorders. Human Immunol. 2010;71(6):597.

    Google Scholar 

  27. 27.

    Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Euro J Epidemiol. 2010;25(9):603–5.

    Article  Google Scholar 

  28. 28.

    Li ZL, Li YG, Lu JP, Chen SQ. Study on FOXP3 -924 polymorphisms in patients with allergic rhinitis. Anat Res. 2014;36(2):124–7.

    Google Scholar 

  29. 29.

    Hassannia H, Abediankenari S, Ghaffari J. FOXP3 and TGFβgene polymorphisms in allergic rhinitis. Iran J Immunol. 2011;8(4):218–25.

    CAS  PubMed  Google Scholar 

  30. 30.

    Song QL. Study on the relationship between FOXP3 gene polymorphism and allergic rhinitis. Int J Immunol. 2016;39(2):139–41.

    Google Scholar 

  31. 31.

    Kim JJ, Min JY, Lee JH. Polymorphisms in the IL-13 and IL-4 receptor alpha genes and allergic rhinitis. Eur Arch Otorhinolaryngol. 2007;264(4):395–9.

    Article  PubMed  Google Scholar 

  32. 32.

    Micheal S, Minhas K, Ishaque M, Ahmed F, Ahmed A. IL-4 gene polymorphisms and their association with atopic asthma and allergic rhinitis in Pakistani patients. J Investig Allergol Clin Immunol. 2013;23(2):107–11.

    CAS  PubMed  Google Scholar 

  33. 33.

    Li YG, Liu ZW, Lu JP. Investigation into the polymorphism of interleukin-13 1112 C%3eT in allergic rhinitis patients. China Trop Med. 2012;12(1):67–9.

    CAS  Google Scholar 

  34. 34.

    Lee HM, Park SA, Chung SW, Woo JS, Chae SW, Lee SH, et al. Interleukin-18/-607 gene polymorphism in allergic rhinitis. Int J Pediatr Otorhinolaryngol. 2006;70(6):1085–8.

    Article  PubMed  Google Scholar 

  35. 35.

    KleinJan A, Willart M, Van Nimwegen M, Leman K, Hoogsteden HC, Hendriks RW, et al. United airways: circulating Th2 effector cells in an allergic rhinitis model are responsible for promoting lower airways inflammation. Clin Exp Allergy. 2010;40(3):494–504.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Ciprandi G. Symptom severity and allergen-specific IgE in allergic rhinitis. Iran J Allergy Asthma Immunol. 2017;16(1):79–81.

    PubMed  Google Scholar 

  37. 37.

    Devos FC, Pollaris L, Cremer J, Seys S, Hoshino T, Ceuppens J, et al. IL-13 is a central mediator of chemical-induced airway hyperreactivity in mice. PLoS ONE. 2017;12(7):e0180690.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Barlow JL, Bellosi A, Hardman CS, Drynan LF, Wong SH, Cruickshank JP, et al. Innate IL-13-producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity. J Allergy Clin Immunol. 2011;129(1):191.e1–4–8.e1–4.

    Google Scholar 

  39. 39.

    Yosri H, Elkashef WF, Said E, Gameil NM. Crocin modulates IL-4/IL-13 signaling and ameliorates experimentally induced allergic airway asthma in a murine model. Int Immunopharmacol. 2017;50:305–12.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Guo LY, Li JH, Paul WE. Probabilistic regulation in TH2 Cells accounts for monoallelic expression of IL-4 and IL-13. Immunity. 2005;23(1):89–99.

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Defrance T. Interleukin 13 is a B cell stimulating factor. J Exp Med. 1994;179(1):135–43.

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Ngoc PL, Ngoc LP, Gold DR, Tzianabos AO, Weiss ST, Celedón JC. Cytokines, allergy, and asthma. Curr Opin Allergy Clin Immunol. 2005;5(2):161–6.

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Alasandagutti ML, Ansari MSS, Sagurthi SR, Valluri V, Gaddam S. Role of IL-13 genetic variants in signalling of asthma. Inflammation. 2017;40(2):1–12.

    Article  CAS  Google Scholar 

  44. 44.

    Gleń J, Trzeciak M, Sobjanek M, Bandurski T, Wilkowska A, Nedoszytko B, et al. Interleukin-13 promoter gene polymorphism -1112 C/T is associated with Atopic dermatitis in Polish patients. Acta Dermatovenerol Croat. 2012;20(4):231–8.

    PubMed  Google Scholar 

  45. 45.

    Hummelshoj T, Bodtger U, Datta P, Malling HJ, Oturai A, Poulsen LK, et al. Association between an interleukin-13 promoter polymorphism and atopy. Int J Immunogenet. 2003;30(5):355–9.

    CAS  Article  Google Scholar 

  46. 46.

    Ying XJ, Zhao SW, Wang GL, Tzianabos AO, Weiss ST, Celedón JC. Association of interleukin-13 SNP rs20541 with allergic rhinitis risk: a meta-analysis. Gene. 2013;521(2):222–6.

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Ziegler SF. FOXP3: of mice and men. Annu Rev Immunol. 2006;24(1):209–26.

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Wang K, Zhu TJ, Wang HJ, Yang JX, Du SS, Dong GY, et al. Adoptive transfers of CD4+ CD25+ Tregs raise FOXP3 expression and alleviate mouse enteritis. Biomed Res Int. 2018;2018(2):1–9.

    Google Scholar 

  49. 49.

    Solomou EE, Rezvani K, Mielke S, Malide D, Visconte V, Keyvanfer K, et al. FOXP3-positive regulatory T-cells in acquired aplastic anemia. Blood. 2006;108(11):2248.

    Article  Google Scholar 

  50. 50.

    Cui G, Zhang Y, Gong Z, Zhang JZ, Zang YQ. Induction of CD4+CD25+FOXP3+ regulatory T cell response by glatiramer acetate in type 1 diabetes. Cell Res. 2009;19(5):574–83.

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Choi JM, Shin JH, Sohn MH. Cell-permeable FOXP3 protein alleviates autoimmune disease associated with inflammatory bowel disease and allergic airway inflammation. Proc Natl Acad Sci USA. 2010;107(50):21943–21943.

    CAS  Google Scholar 

  52. 52.

    Lee JH, Yu HH, Wang LC, Yang YH, Lin YT, Chiang BL. The levels of CD4+CD25+ regulatory T cells in paediatric patients with allergic rhinitis and bronchial asthma. Clin Exp Immunol. 2007;148(1):53–63.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Ban Y, Tozaki T, Tobe T, Ban Y, Jacobson EM, Concepcion ES, et al. The regulatory T cell gene FOXP3 and genetic susceptibility to thyroid autoimmunity: an association analysis in Caucasian and Japanese cohorts. J Autoimmun. 2007;28(4):201–7.

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

The present study was funded by the National Natural Science Foundation of China (Grant nos. 81873780, 61702054); Hunan Natural Science Foundation Youth Program (2019JJ50697, 2018JJ3568); The Changsha Outstanding Innovative Young People Training Scheme (kq1905047, kq1905045); The Foundation of the Education Department of Hunan Province (16A027, 19A058); The Foundation of Health and Family Planning Commission of Hunan Province (20201918); The Application Characteristic Discipline of Hunan Province; The Hunan Key Laboratory Cultivation Base of the Research and Development of Novel Pharmaceutical Preparations (No. 2016TP1029); The clinical research center of neurodegenerative diseases in Hunan province (2018SK4002); The Hunan Provincial Innovation Platform and Talents Program (No. 2018RS3105); The Hunan provincial science and technology department and Hunan provincial health and family planning commission (Grant No.[2018]85); The Natural science foundation of Hunan province (Grant No.[2017]1); The Key project of Hunan provincial commission of health and family planning (Grant No.[2017]144); The Hunan province science and technology major project (Grant No.[2016]158); Hunan Provincial Science and Technology Department Clinical Medical Technology Innovation Guide Project(2018SK51711).

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Yonghong Tang or Jianming Li.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Responsible Editor: John Di Battista.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOC 63 kb)

Supplementary file2 (DOC 23 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tang, L., Chen, Y., Xiang, Q. et al. The association between IL18, FOXP3 and IL13 genes polymorphisms and risk of allergic rhinitis: a meta-analysis. Inflamm. Res. (2020). https://doi.org/10.1007/s00011-020-01368-4

Download citation

Keywords

  • IL18
  • FOXP3
  • IL13
  • Polymorphism
  • Allergic rhinitis
  • Meta-analysis