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Association of TNF-α and PTPN22 SNPs with the risk and clinical outcome of type 1 diabetes

  • Research Article
  • Published:
Central European Journal of Biology

Abstract

Type 1 Diabetes mellitus (T1DM) begins with aberrant inflammatory process followed by auto-destruction in genetically susceptible individuals. Therefore, we hypothesized that gain-of-function allelic variants TNF-α-238A, -308A and PTPN22 1858T could be associated not only with T1DM development but also with the clinical outcome in patients of Bosnia and Herzegovina. A total of 402 subjects were enrolled in the association study. SNPs were determined by PCR-RFLP. Data was analyzed by GraphPad Prism and Sigma Stat 3.5 software. Genotypes frequencies at TNF-α-238 and -308 loci were not statistically different between patients and controls. In contrast, distribution of genotypes at the 1858 position of PTPN22 was significantly different, due to higher frequency of gain-of-function gene variants in patients than controls. Moreover, long term glucose regulation (based on HbA1c level) was significantly worse in patients with the risk TNF-α-308A allele than in patients with non-risk (G) allele. However, patients with the risk allele of both genes (TNF-α-308A and PTPN22 1858T) had the worst glycemic control, suggesting that those two work synergistically. In conclusion, in a cohort from Bosnia and Herzegovina TNF-α-308A allele is significantly associated with the worse long-term glucose control, but PTPN22 1858T allele is significantly associated with diabetes development.

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References

  1. Hawa M.I., Beyan H., Buckley L.R., Leslie R.D., Impact of genetic and non-genetic factors in type 1 diabetes, Am. J. Med. Genet., 2002, 115, 8–17

    Article  PubMed  Google Scholar 

  2. Movahedi B., Van de Casteele M., Caluwe N., Stange G., Breckpot K., Thielemans K,. Human pancreatic duct cells can produce tumour necrosis factor-α that damages neighbouring beta cells and activates dendritic cells, Diabetologia, 2004, 47, 998–1008

    Article  PubMed  CAS  Google Scholar 

  3. Christen U., Wolfe T., Mohrle U., Hughes A.C., Rodrigo E., Green E.A., et al., A dual role for TNF-alpha in type 1 diabetes: islet-specific expression abrogates the ongoing autoimmune process when induced late but not early during pathogenesis, J. Immunol., 2001, 166, 7023–7032

    PubMed  CAS  Google Scholar 

  4. Hamaguchi K., Kimura A., Seki N., Higuchi T., Yasunaga S., Takahashi M., Analysis of tumor necrosis factor-alpha promoter polymorphism in type 1 daibetes: HLA-B and -DRB1 alleles are primarly associated with the disease in Japanese, Tissue Antigens, 2000, 55, 10–16

    Article  PubMed  CAS  Google Scholar 

  5. Anderson M.S, Bluestone J.A., The NOD mouse: a model of immune dysregulation, Annu. Rev. Immunol., 2005, 23, 447–485

    Article  PubMed  CAS  Google Scholar 

  6. Vang T., Congia M., Macis M.D., Musumeci L., Orru V., Zavattari P., Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant, Nat. Genet., 2005, 37, 1317–1319

    Article  PubMed  CAS  Google Scholar 

  7. Bottini N., Vang T., Cucca F., Mustelin T., Role of PTPN22 in type 1 diabetes and other autoimmune diseases, Semin Immunol, 2006, 18, 207–213

    Article  PubMed  CAS  Google Scholar 

  8. Miller S.A., Dykes DD, Polesky H.F., A simple salting out procedure for extracting DNA from human nucleated cells, Nucleic Acids Res., 1988, 16, 1215

    Article  PubMed  CAS  Google Scholar 

  9. Wieser F., Fabjani G., Tempfer C., Schneeberger C., Zeillinger R., Huber C.J., et al., Tumor necrosis factor -alpha promotor polymorphisms and endometriosis, J]_Soc. Gynecol. Investig., 2002, 9, 313–318

    Article  CAS  Google Scholar 

  10. Zheng W., She J.X., Genetic association between a lymphoid tyrosine phosphatase (PTPN22) and type 1 diabetes, Diabetes, 2005, 54, 906–908

    Article  PubMed  CAS  Google Scholar 

  11. Hosking L., Lumsden S., Lewis K., Yeo A., McCarthy L., Bansal A., et al., Detection of genotyping errors by Hardy-Weinberg equilibrium testing, Eur. J. Hum. Genet., 2004, 12, 395–399

    Article  PubMed  CAS  Google Scholar 

  12. Gomes I., Collins A., Lonjou C., Thomas N.S., Wilkinson J., Watson M., et al., Hardy-Weinberg quality control, Ann Hum Genet, 1999, 63, 535–538

    Article  PubMed  CAS  Google Scholar 

  13. Wilson A.G., Symons J.A., McDowell T.L., McDevitt H.O., Duff G.W., Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation, Proc. Natl. Acad. Sci. USA, 1997, 94, 3195–3199

    Article  PubMed  CAS  Google Scholar 

  14. Louis E., Franchimont D., Piron A., Gevaert Y., Schaaf-Lafontaine N., Roland S., et al., Tumour necrosis factor (TNF) gene polymorphism influences TNF-alpha production in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans, Clin. Exp. Immunol., 1998, 113, 401–406

    Article  PubMed  CAS  Google Scholar 

  15. Kaluza W., Reuss E., Grossmann S., Hug R., Schopf R.E., Galle P.R., et al., Different transcriptional activity and in vitro TNF-alpha production in psoriasis patients carrying the TNF-alpha 238A promoter polymorphism, J. Invest. Dermatol., 2000, 114, 1180–1183

    Article  PubMed  CAS  Google Scholar 

  16. Das S.N., Baniasadi V., Kapuria V., Association of -308 TNF-alpha promoter polymorphism with type 1 diabetes in North Indians, Int. J. Immunogenet., 2006, 33, 411–416

    Article  PubMed  CAS  Google Scholar 

  17. Korolija M., Hadzija M., Pape Medvidovic E., Pavkovic P., Kapitanovic S., Pavlic Renar I., et al., Genetic evaluation of the TNF-α-238G/A and -308 G/A promoter polymorphisms in Craotian patients with type 1 diabetes, Hum. Immunl., 2010, 71, 1228–1232

    Article  CAS  Google Scholar 

  18. Pérez C., González F.E, Pavez V., Araya A.V., Aguirre A., Cruzat A., et al., The -308 polymorphism in the promoter region of the tumor necrosis factor-alpha (TNF-alpha) gene and ex vivo lipopolysaccharideinduced TNF-alpha expression in patients with aggressive periodontitis and/or type 1 diabetes mellitus, Eur. Cytokine Netw., 2004, 15, 364–370

    PubMed  Google Scholar 

  19. Korolija M, Renar I.P., Hadzija M., Medvidovic E.P., Pavkovic P., Jokic M., et al., Association of PTPN22 C1858T and CTLA-4 A49G polymorphisms with Type 1 Diabetes in Croatians, Diabetes Res. Clin. Pract., 2009, 86, e54–e57

    Article  PubMed  CAS  Google Scholar 

  20. Peng H., Zhou M., Xu W.D., Xu K., Zhai Y., Li R., et al., Association of PTPN22 C1858T polymorphism and type 1 diabetes: A meta analysis, Immunol. Invest., 2012, 41, 484–496

    Article  PubMed  CAS  Google Scholar 

  21. Nielsen C., Hansen D., Husby S., Lillevang S.T., Sex-specific association of the human PTPN22 1858T allele with type 1 diabetes, Int. J. Immunogenet., 2007, 34, 469–473

    Article  PubMed  CAS  Google Scholar 

  22. Zhernakova A., Eerligh P., Wijmenga C., Barrera P., Roep B.O., Koeleman B.P.C., Differential association of the PTPN22 coding variant with autoimmune diseases in a Dutch population, Genes Immun., 2005, 6, 459–461

    Article  PubMed  CAS  Google Scholar 

  23. Fedetz M., Matesanz F., Caro-Maldonado A., Smirnov I.I., Chvorostinka V.N., Moiseenko T.A., et al., The 1858 PTPN22 gene variant contributes to a genetic risk of type 1 diabetes in a Ukrainian population, Tissue Antigens, 2006, 67, 430–433

    Article  PubMed  CAS  Google Scholar 

  24. Kahles H., Ramos-Lopez E., Lange B., Zwermann O., Reincke M., Sex-specific association of PTPN22 1858T with type 1 diabetes but not woth Hashimoto’sthyroiditis or Addison’s disease in the German population, Eur. J. Endocrinol., 2005, 153, 895–899

    Article  PubMed  CAS  Google Scholar 

  25. Elahi M.M., Asotra K., Matata B.M., Mastana S.S., Tumor necrosis factor alpha-308 gene locus promoter polymorphism: An analysis of association with health and disease, BBA-Mol. Basis Dis., 2009, 1792, 163–172

    Article  CAS  Google Scholar 

  26. Wilson A.G., di Giovine F.S., Blakemore A.I., Duff G.W., Single base polymorphism in the human tumour necrosis factor alpha gene detectable by NcoI restriction of PCR product, Hum. Mol. Genet., 1992, 1, 353

    Article  PubMed  CAS  Google Scholar 

  27. Laki J., Kiszel P., Blasko B., Kovaca B.B., Korner A., Madacsy L., et al., The HLA 8.1 ancestral haplotype is strongly linked to the C allele of −429T>C promoter polymorphism of receptor of the advanced glycation endproduct (RAGE) gene. Haplotype-independent association of the −429C allele with high hemoglobin(A1C) levels in diabetic patients, Mol. Immunol., 2006, 44, 648–655

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Molecular Medicine, Laboratory for Molecular Endocrinology and Transplantation, Ruđer Bosković Institute, 10 000, Zagreb, Croatia

    Marijana Popović Hadžija, Marina Korolija, Gabrijela Vukadinović & Mirko Hadžija

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  1. Marijana Popović Hadžija
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  2. Marina Korolija
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  3. Gabrijela Vukadinović
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  4. Mirko Hadžija
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Correspondence to Marijana Popović Hadžija.

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Hadžija, M.P., Korolija, M., Vukadinović, G. et al. Association of TNF-α and PTPN22 SNPs with the risk and clinical outcome of type 1 diabetes. cent.eur.j.biol. 8, 513–519 (2013). https://doi.org/10.2478/s11535-013-0166-5

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  • DOI: https://doi.org/10.2478/s11535-013-0166-5

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