Skip to main content

Advertisement

Log in

Association between IL-18 and IL-6 gene polymorphisms and the risk of T1D in Egyptian children

  • Research article
  • Published:
Journal of Diabetes & Metabolic Disorders Aims and scope Submit manuscript

Abstract

Purpose

To test the involvement between IL-18 and IL-6 genetic polymorphisms and susceptibility to Type 1 diabetes (T1D).

Methods

Single nucleotide polymorphisms (SNPs) at positions −607A/C and − 137G/C in IL-18 promoter region were examined by sequence specific primers-polymerase chain reaction (SSP-PCR) and position -174G/C in promoter region of IL-6 gene which analyzed by Mutagenically Separated PCR (MS-PCR) in 104 T1D participants and 114 controls.

Results

IL-18 -137GC and -137CC genotypes and -137C allele were significantly decreased in T1D subjects (P < 0.05), while -137GG genotype was insignificantly increased as compared to controls. A significant decrease was detected in haplotype -137C/-607C frequency in T1D participants compared with controls (OR = 0.04, P < 0.001). There was significant association between IL-18 -607 of (CC, AC and AA genotypes) in age at diagnosis, glycated hemoglobin (HbA1c) and higher body mass index (BMI) (P < 0.05).

Conclusion

This study demonstrated that IL-18 gene promoter polymorphisms might be associated with susceptibility to T1D in Egyptian children. Individuals carrying CC genotype at position −137 of IL-18 promoter may be at a low risk of T1D progression. Additionally, the susceptible combination of IL-18 and IL-6 cytokine genes associated with T1D highlight their risk toward the disease.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Wp Y, Henneberg M. Type 1 diabetes prevalence increasing globally and regionally: the role of natural selection and life expectancy at birth. BMJ Open Diabetes Res. Care. 2016;4(1):161–6.

    Google Scholar 

  2. Pociot F. Type 1 diabetes genome-wide association studies: not to be lost in translation. Clin Trans Immunol. 2017;6(12):162–8.

    Article  Google Scholar 

  3. Blanter M, Sork H, Tuomela S, et al. Genetic and environmental interaction in type 1 diabetes: a relationship between genetic risk alleles and molecular traits of enterovirus infection? Curr Diab Rep. 2019;19(82):1–14.

    Google Scholar 

  4. Alnek K, Kisand K, Heilman K, et al. Increased blood levels of growth factors, Proinflammatory cytokines, and Th17 cytokines in patients with newly diagnosed type 1 diabetes. PLoS One. 2015;10(12):0142976.

    Article  Google Scholar 

  5. Myung DS, Lee WS, Park YL, et al. Association between interleukin-18 gene polymorphism and Helicobacter pylori infection in the Korean population. Sci Rep. 2015;5:11535. https://doi.org/10.1038/srep11535.

  6. Srivastava S, Salim N, Robertson MJ. Interleukin-18: biology and role in the immunotherapy of cancer. Curr. Med. Chem. 2010;17:3353–7.

    Article  CAS  Google Scholar 

  7. Harms RZ, Yarde DN, Guinn Z, Lorenzo-Arteaga KM, Corley KP, Cabrera MS, et al. Increased expression of IL-18 in the serum and islets of type 1 diabetics. Mol. Immunol. 2015;64(2):306–12.

    Article  CAS  Google Scholar 

  8. Lewis EC, Dinarello CA. Responses of IL-18- and IL-18 receptor deficient pancreatic islets with convergence of positive and negative signals for the IL-18 receptor. Proc. Natl. Acad. Sci. U. S. A. 2006;103:16852–7.

    Article  CAS  Google Scholar 

  9. Thmpson SR, Humphries SE. Interleukin-18 genetics and inflammatory disease susceptibility. Genes Immun. 2007;8:91–9.

    Article  Google Scholar 

  10. Smith AJP, Humphries SE. Cytokine and cytokine receptor gene polymorphisms and their functionality. Cytokine Growth Factor Rev. 2009;20(1):43–59.

    Article  CAS  Google Scholar 

  11. Barker BR, Taxman DJ, Ting JP. Cross-regulation between the IL-1beta/IL-18 processing inflmmasome and other inflammatory cytokines. Curr. Opin. Immunol. 2011;23:591–7.

    Article  CAS  Google Scholar 

  12. Dong GP, Yu ZS, Liang L, Zou CC, Fu JF, Wang CL. IL-18 gene promoter -137C/G and -607C/a polymorphisms in Chinese Han children with type 1 diabetes mellitus. Int J Immunogenetics. 2007;34:75–9.

    Article  CAS  Google Scholar 

  13. Wen D, Liu J, Du X, et al. Association of interleukin-18 (−137G/C) polymorphism with rheumatoid arthritis and systemic lupus erythematosus: a meta-analysis. Int. Rev. Immunol. 2014;33:34–44.

    Article  CAS  Google Scholar 

  14. Yin Y-W, Sun Q-Q, Zhang B-B, Hu AM, Wang Q, Liu HL, et al. The lack of association between interleukin-6 gene −174 G/C polymorphism and the risk of type 1 diabetes mellitus: a meta-analysis of 18,152 subjects. Gene. 2013;515:461–5.

    Article  CAS  Google Scholar 

  15. Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S, et al. The effect of novel polymorphisms inthe interleukin-6 (IL-6) gene on IL-6 transcription and plasmaIL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J. Clin. Invest. 1998;102(7):1369–76.

    Article  CAS  Google Scholar 

  16. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215.

    Article  CAS  Google Scholar 

  17. Zhang PA, Wu JM, Li Y, Yang XS. Association of polymorphisms of interleukin-18 gene promoter region with chronic hepatitis B in Chinese Han population. World J. Gastroenterol. 2005;11(11):1594–8.

    Article  CAS  Google Scholar 

  18. Rust S, Funke H, Assmann G. Mutagenically separated PCR (MS-PCR): a highly specific one step procedure for easy mutation detection. Nucleic Acids Res. 1993;21:3623–9.

    Article  CAS  Google Scholar 

  19. Mojtahedi Z, Naeimi S, Farjadian S, Omrani GR, Ghaderi A. Association of IL-18 promoter polymorphisms with predisposition to type 1 diabetes. Diabet. Med. 2006;23:235–9.

    Article  CAS  Google Scholar 

  20. El-Kafoury AA, Haroun M, Embaby AM, et al. The association of polymorphic sites in some genes with type 1 diabetes mellitus in a sample of Egyptian children. Egypt J Med Hum Genet. 2014;15:265–72.

    Article  Google Scholar 

  21. Ide A, Kawasaki E, Abiru N, Sun F, Kobayashi M, Fukushima T, et al. Association between IL-18 gene promoter polymorphisms and CTLA-4 gene 49A/G polymorphism in Japanese patients with type 1 diabetes. J. Autoimmun. 2004;22(1):73–8.

    Article  CAS  Google Scholar 

  22. Kretowski A, Mironczuk K, Karpinska A, Bojaryn U, Kinalski M, Puchalski Z, et al. Interleukin-18 promoter polymorphisms in type 1 diabetes. Diabetes. 2002;51:3347–9.

    Article  CAS  Google Scholar 

  23. Lee YH, Kim JH, Song GG. Interleukin-18 promoter −607 C/a and −137 G/C polymorphisms and susceptibility to type 1 diabetes: a meta-analysis. Hum. Immunol. 2015;76:537–45.

    Article  CAS  Google Scholar 

  24. Hadžija MP, Korolija M, Jemin N, Pavković I, Pavković P, Medvidović EP, et al. Polymorphisms in the IL-18 and IL-12B genes and their association with the clinical outcome in Croatian patients with type 1 diabetes. Gene. 2013;512(2):477–81.

    Article  Google Scholar 

  25. Altinova AE, Engin D, Akbay E, Akturk M, Toruner F, Ersoy R, et al. Association of polymorphisms in the IL-18 and IL-12 genes with susceptibility to type 1 diabetes in Turkish patients. J. Endocrinol. Investig. 2010;33(7):451–4.

    Article  CAS  Google Scholar 

  26. Altinova AE, Yetkin I, Akbay E, Bukan N, Arslan M. Serum IL-18 levels in patients with type 1 diabetes: relations to metabolic control and microvascular complications. Cytokine. 2008;42:217–21.

    Article  CAS  Google Scholar 

  27. Kim HL, Cho SO, Kim SY, Kim SH, Chung WS, Chung SH, et al. Association ofinterleukin18 gene polymorphism with body mass index in women. Reprod. Biol. Endocrinol. 2012;10:31.

    Article  CAS  Google Scholar 

  28. Tsiavou A, Hatziagelaki E, Chaidaroglou A, et al. TNF-alpha, TGF-beta1, IL-10, IL-6, gene polymorphisms in latent autoimmune diabetes of adults (LADA) and type 2 diabetes mellitus. J. Clin. Immunol. 2004;24:591–9.

    Article  CAS  Google Scholar 

  29. Xu WD, Zhou M, Peng H, Pan HF, Ye DQ. Lack of association of IL-6 polymorphism with rheumatoid arthritis/type 1 diabetes: a meta-analysis. Joint Bone Spine. 2013;80(5):477–81.

    Article  CAS  Google Scholar 

  30. Settin A, Ismail A, El-Magd MA, et al. Gene polymorphisms of TNF-alpha-308 (G/a), IL-10(−1082) (G/a), IL-6(−174) (G/C) and IL-1Ra (VNTR) in Egyptian cases with type 1 diabetes mellitus. Autoimmun. 2009;42:50–5.

    Article  CAS  Google Scholar 

  31. Ururahy MA, De Souza KS, Oliveira YM, et al. Association of polymorphisms in IL6 gene promoter region with type 1 diabetes and increase albumin-to creatinine ratio. Diabetes Metab. Res. Rev. 2015;31(5):500–6.

    Article  CAS  Google Scholar 

  32. Pérez-Bravo F, Soto MF, López AP, et al. 174 G/C polymorphism of interleukin 6 gene in women with type 1 diabetes. Rev. Med. Chil. 2011;139:158–64.

    Article  Google Scholar 

  33. Ponnana M, Sivangala R, Joshi L, Valluri V, Gaddam S. IL-6 and IL-18 cytokine gene variants of pulmonary tuberculosis patients with co-morbid diabetes mellitus and their household contacts in Hyderabad. Gene. 2017;627:298–306.

    Article  CAS  Google Scholar 

Download references

Funding

This study was supported by Genetic Engineering and Biotechnology Research Institute, University of Sadat City, Menoufia, Egypt.

Author information

Authors and Affiliations

Authors

Contributions

Yasser, El-Gahel conceived and designed the study. El-Gahel and Abdel-Hakem participated in the experimental study and acquisition of data. El-Hefnawy and Gadalla participated in the clinical study. Yasser, El-Shahat and Abdel-Hakem analyzed and/or interpreted the data. Yasser, El-Gahel, Abdel-Hakem drafted the manuscript. Yasser and El-Shahat critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yasser B. M. Ali.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest.

Additional information

Publisher’s note

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

Supplementary Information

ESM 1

(DOCX 14 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ali, Y.B.M., El-Gahel, H.E., Abdel-Hakem, N.E. et al. Association between IL-18 and IL-6 gene polymorphisms and the risk of T1D in Egyptian children. J Diabetes Metab Disord 20, 439–446 (2021). https://doi.org/10.1007/s40200-021-00763-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40200-021-00763-w

Keywords

Navigation