Abstract
Abundant evidence suggests that cytokines involve in the pathogenesis of latent autoimmune diabetes of adults (LADA). This is a slowly progressive form of type 1 diabetes, which is initially diagnosed as type 2 diabetes. In this study, healthy individuals LADA and type 2 diabetic patients were genotyped for IL-6-174G/C, TNF-α-308A/G, TGF-β1-codon10T/C, TGF-β1-codon25G/C, IL-10-1082A/G, IL-10-819T/C, IL-10-592A/C gene polymorphisms, by sequence-specific-primer polymerase chain reaction methodology. A significant difference in the frequencies of −1082A/G IL-10 alleles was observed, with the −1082*A allele (known to be associated with low IL-10 production), predominating in LADA diabetics than type 2 diabetics (p=0.036). No significant differences of genotypes, phenotypes, or haplotype frequencies in the remaining cytokine polymorphisms were observed. Analysis of allele combinations revealed a significant involvement of the low and high in vitro production IL-10 alleles in the development of LADA and type 2 diabetes, respectively. These results suggest that the G/A mutation at position −1082 of IL-10 promoter gene region might be one of the factors participating to the pathogenesis of LADA diabetes and that identification of cytokine gene polymorphisms might contribute to the characterization of the different types of diabetes mellitus.
Similar content being viewed by others
References
Zimmet PZ: The pathogenesis and prevention of diabetes in adults: Genes, autoimmunity, and demography. Diabetes Care18:1050–1064, 1995
Zimmet P, Turner R, McCarty D, Rowley M, Mackay I: Crucial points at diagnosis: Type 2 diabetes or slow type 1 diabetes. Diabetes Care22:59–64, 1999
Pozzili P, Di Mario R: Autoimmune diabetes not requiring insulin at diagnosis (Latent Autoimmune Diabetes of the Adult). Diabetes Care24:1460–1467, 2001
Rabinovitch A, Suarez-Pinzon WL: Cytokines and their roles in pancreatic islet β-cell destruction and insulin-dependent diabetes mellitus. Biochem Pharmacol55:1139–1149, 1998
Hutchinson JV, Pravica V, Sinnot PJ: Genetic regulation of cytokine synthesis: Consequences for acute and chronic organ allograft rejection. Graft1:15–21, 1998
Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV: An investigation of polymorphism in the interleukin-10 gene. Eur J Immunogenet24:1–8, 1997
Wilson AG, Symon JA, McDowell T, McDevitt HO, Duff GW: Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci USA94:3195–3199, 1997
Hutchinson IV, Turner DM, Sankaran D, Awad MR, Sinnott PJ: Influence of cytokine genotypes in allograft rejection. Transplant Proc30:862–863, 1998
Awad MR, El-Gamel A, Hasleton P, Turner DM, Sinnott PJ, Hutchinson IV: Genotypic variation in the transforming growth factor-beta1 gene: Association with transforming growth factor-beta1 production, fibrotic lung disease, and graft fibrosis after lung transplantation. Transplantation66:1014–1020, 1998
Real JMF, Vendrell J, Richart C, Gutierrez C, Wifredo R: Platelet account and interleukin-6 gene polymorphism in healthy subjects. BMC Med Genet2:6–11, 2001
Bidwell J, Keen L, Gallacher G, Kimberly R, Huizinga T, McDermott MF, Oksenberg J, McNicholl J, Pociot F, Hardt C, D’Alfonso S: Cytokine gene polymorphism in human disease: On-line databases. Genes Immun1:3–19, 1999
Zimmet PZ, Tumoi T, Mackay IR, Rowley MJ, Knowles W, Cohen M: Latent autoimmune diabetes mellitus in adults (LADA): The role of antibodies to glutamic acid decarboxylase in diagnosis and prediction of insulin dependency. Diabetic Med11:299–303, 1994
Hatziagelaki E, Jaeger C, Maeser R, Bretzel G: GAD 65 antibody but not ICA positivity in adult-onset diabetic patients is associated with early progression to clinical insulin dependency. Acta Diabetol33:291–294, 1996
Lim S, Crawley E, Woo P, Barnes PJ: Haplotype associated with low IL-10 production in patients with severe asthma (Letter). Lancet 352:113, 1998
Helminen M, Lahdeenpohja N, Hurme M: Polymorphism of the interleukin-10 gene is associated with susceptibility to Epstein--Barr virus infection. J Infect Dis180:496–499, 1999
Sankaran D, Asderakis A, Ashraf S, Roberts IS, Short CD, Dyer PA, Sinnott PJ, Hutchinson IV: Cytokine gene polymorphisms predict acute graft rejection following renal transplantation. Kidney Int56:281–288, 1999
Mosman TR: Properties and functions of interleukin-10. Adv Immunol56:1–10, 1994
Lalani I, Bhol K, Ahmed AR: Interleukin-10: Biology, role in inflammation and autoimmunity. Ann Allergy Asthma Immunol79:469–480, 1997
Pauza ME, Neal H, Hagenbaugh A, Cheroutre H, Lo D: T-cell production of an inducible interleukin-10 transgene provides limited protection from autoimmune diabetes. Diabetes48:1948–1953, 1999
Pennline KJ, Roquegaffney E, Monahan M: Recombinant human IL-10 prevents the onset of diabetes in the non-obese diabetic mice. Clin Immunol Immunopathol71:169–175, 1994
Zheng XX, Steel AW, Hancock WW, Stevens AC, Nickerson PW, Roy-Chaudhury P, Tian Y, Itakura M: A noncytolytic IL-10/Fc fusion protein prevents diabetes, blocks autoimmunity, and promotes suppressor phenomenon in NOD mice. J Immunol158:4507–4513, 1997
Moritani M, Yosimoto K, Li S, Kondo M, Iwahana H, Yamaoka T, Sano T, Nakano N, Kikutani H, Itakura M: Prevention of adoptively transferred diabetes in non-obese diabetic mice with IL-10-transduced islet-specific Th1 lymphocytes. A gene therapy model for autoimmune diabetes. J Clin Invest98:1815–1819, 1996
Ide A, Kawashaki E, Abiru N, Sun F, Takahashi R, Kuwahara H, Fujita N, Kita A, Oshima K, Sakamaki H, Uotani S, Yamasaki H, Yamaguchi Y, Eguchi K: Genetic association between interleukin-10 gene promoter region polymorphisms and type 1 diabetes age- at-onset. Hum Immunol63:430–437, 2002
Tegoshi H, Hasegawa G, Obayashi H, Nakano K, Kitagawa Y, Fukui M, Matsuo S, Deguchi M, Ohta M, Nishimura M, Nakamura N, Yoshigawa T: Polymorphism of interferon-γ gene CA-repeat and interleukin-10 promoter region (−592A/C) in Japanese type I diabetes. Hum Immunol63:121–128, 2002
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
TSIAVOU, A., HATZIAGELAKI, E., CHAIDAROGLOU, A. et al. TNF-α, TGF-β1, IL-10, IL-6, Gene Polymorphisms in Latent Autoimmune Diabetes of Adults (LADA) and Type 2 Diabetes Mellitus. J Clin Immunol 24, 591–599 (2004). https://doi.org/10.1007/s10875-004-6239-0
Issue Date:
DOI: https://doi.org/10.1007/s10875-004-6239-0