Skip to main content
Top
Published in: Journal of Diabetes & Metabolic Disorders 1/2021

01-06-2021 | Polymerase Chain Reaction | Research article

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

Authors: Yasser B. M. Ali, Hend E. El-Gahel, Nehal E. Abdel-Hakem, Mahmoud E. Gadalla, Mohamed H. El-Hefnawy, Mohamed El-Shahat

Published in: Journal of Diabetes & Metabolic Disorders | Issue 1/2021

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
go back to reference 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. 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.
2.
go back to reference Pociot F. Type 1 diabetes genome-wide association studies: not to be lost in translation. Clin Trans Immunol. 2017;6(12):162–8.CrossRef Pociot F. Type 1 diabetes genome-wide association studies: not to be lost in translation. Clin Trans Immunol. 2017;6(12):162–8.CrossRef
3.
go back to reference 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. 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.
4.
go back to reference 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.CrossRef 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.CrossRef
6.
go back to reference Srivastava S, Salim N, Robertson MJ. Interleukin-18: biology and role in the immunotherapy of cancer. Curr. Med. Chem. 2010;17:3353–7.CrossRef Srivastava S, Salim N, Robertson MJ. Interleukin-18: biology and role in the immunotherapy of cancer. Curr. Med. Chem. 2010;17:3353–7.CrossRef
7.
go back to reference 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.CrossRef 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.CrossRef
8.
go back to reference 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.CrossRef 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.CrossRef
9.
go back to reference Thmpson SR, Humphries SE. Interleukin-18 genetics and inflammatory disease susceptibility. Genes Immun. 2007;8:91–9.CrossRef Thmpson SR, Humphries SE. Interleukin-18 genetics and inflammatory disease susceptibility. Genes Immun. 2007;8:91–9.CrossRef
10.
go back to reference Smith AJP, Humphries SE. Cytokine and cytokine receptor gene polymorphisms and their functionality. Cytokine Growth Factor Rev. 2009;20(1):43–59.CrossRef Smith AJP, Humphries SE. Cytokine and cytokine receptor gene polymorphisms and their functionality. Cytokine Growth Factor Rev. 2009;20(1):43–59.CrossRef
11.
go back to reference 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.CrossRef 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.CrossRef
12.
go back to reference 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.CrossRef 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.CrossRef
13.
go back to reference 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.CrossRef 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.CrossRef
14.
go back to reference 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.CrossRef 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.CrossRef
15.
go back to reference 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.CrossRef 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.CrossRef
16.
go back to reference Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215.CrossRef Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215.CrossRef
17.
go back to reference 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.CrossRef 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.CrossRef
18.
go back to reference 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.CrossRef 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.CrossRef
19.
go back to reference 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.CrossRef 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.CrossRef
20.
go back to reference 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.CrossRef 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.CrossRef
21.
go back to reference 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.CrossRef 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.CrossRef
22.
go back to reference 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.CrossRef 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.CrossRef
23.
go back to reference 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.CrossRef 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.CrossRef
24.
go back to reference 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.CrossRef 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.CrossRef
25.
go back to reference 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.CrossRef 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.CrossRef
26.
go back to reference 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.CrossRef 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.CrossRef
27.
go back to reference 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.CrossRef 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.CrossRef
28.
go back to reference 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.CrossRef 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.CrossRef
29.
go back to reference 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.CrossRef 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.CrossRef
30.
go back to reference 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.CrossRef 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.CrossRef
31.
go back to reference 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.CrossRef 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.CrossRef
32.
go back to reference 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.CrossRef 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.CrossRef
33.
go back to reference 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.CrossRef 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.CrossRef
Metadata
Title
Association between IL-18 and IL-6 gene polymorphisms and the risk of T1D in Egyptian children
Authors
Yasser B. M. Ali
Hend E. El-Gahel
Nehal E. Abdel-Hakem
Mahmoud E. Gadalla
Mohamed H. El-Hefnawy
Mohamed El-Shahat
Publication date
01-06-2021
Publisher
Springer International Publishing
Published in
Journal of Diabetes & Metabolic Disorders / Issue 1/2021
Electronic ISSN: 2251-6581
DOI
https://doi.org/10.1007/s40200-021-00763-w

Other articles of this Issue 1/2021

Journal of Diabetes & Metabolic Disorders 1/2021 Go to the issue