Skip to main content

Advertisement

SpringerLink
Log in

Polymorphisms in the Genes Encoding TGF-β1, TNF-α, and IL-6 Show Association with Type 1 Diabetes Mellitus in the Slovak Population

  • ORIGINAL ARTICLE
  • Published:
Archivum Immunologiae et Therapiae Experimentalis Aims and scope

Abstract

Numerous cytokines have been shown to participate in the pathogenesis of type 1 diabetes (T1D). As gene polymorphisms can influence cytokine production or function, they may potentially contribute to genetic predisposition to the disease. The aim of this study was therefore to investigate the role of 22 single nucleotide polymorphisms (SNPs) in 13 cytokine and cytokine receptor genes in genetic susceptibility to T1D. Polymerase chain reaction with sequence-specific primers was used to genotype cytokine SNPs and HLA-DRB1 alleles in 151 diabetics and 140 healthy individuals of Slovak origin. Univariate analysis showed that transforming growth factor (TGF)-β1 codon 10 TT homozygotes were significantly more susceptible to developing T1D than C allele carriers (P c = 0.0066, OR = 2.46). Furthermore, tumor necrosis factor (TNF)-α −308 A allele carriers were also significantly overrepresented among the diabetics (P c = 0.0031, OR = 2.62); however, the association of the −308 A allele with T1D might be due to its strong linkage disequilibrium with the susceptibility allele HLA-DRB1*0301. An association was also found with interleukin (IL)-6 −174 G/C and nt565 G/A SNPs; however, its significance was lost when statistical correction was applied. These data suggest that the TGF-β1 codon 10 SNP is among numerous genetic variations with small individual effects on T1D development. Moreover, a possible role of TNF-α and IL-6 SNPs cannot be ruled out, although their association with T1D was due to strong LD with the HLA class II susceptibility allele or did not withstand statistical correction, respectively.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • American Diabetes Association (2004) Diagnosis and classification of diabetes mellitus. Diabetes Care 27(suppl 1):S5–S10

    Google Scholar 

  • Barrett JC, Clayton DG, Concannon P et al (2009) Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 41:703–707

    Article  CAS  PubMed  Google Scholar 

  • Bidwell J, Keen L, Gallagher G et al (1999) Cytokine gene polymorphism in human disease: on-line databases. Genes Immun 1:3–19

    Article  CAS  PubMed  Google Scholar 

  • Bidwell J, Keen L, Gallagher G et al (2001) Cytokine gene polymorphism in human disease: on-line databases, supplement 1. Genes Immun 2:61–70

    Article  CAS  PubMed  Google Scholar 

  • Cambien F, Ricard S, Troesch A et al (1996) Polymorphisms of transforming growth factor-β1 gene in relation to myocardial infarction and blood pressure. The Etude Cas-Temoin de l’Infarctus du Myocarde (ECTIM) Study. Hypertension 28:881–887

    CAS  PubMed  Google Scholar 

  • Choi SE, Choi KM, Yoon IH et al (2004) IL-6 protects pancreatic islet beta cells from proinflammatory cytokines-induced cell death and functional impairment in vitro and in vivo. Transpl Immunol 13:43–53

    Article  CAS  PubMed  Google Scholar 

  • Cooper JD, Smyth DJ, Bailey R et al (2007) The candidate genes TAF5L, TCF7, PDCD1, IL6 and ICAM1 cannot be excluded from having effects in type 1 diabetes. BMC Med Genet 8:71

    Article  PubMed  Google Scholar 

  • Cooper JD, Smyth DJ, Smiles AM et al (2008) Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. Nat Genet 40:1399–1401

    Article  CAS  PubMed  Google Scholar 

  • Cox A, Gonzalez AM, Wilson AG et al (1994) Comparative analysis of the genetic associations of HLA-DR3 and tumour necrosis factor-alpha with human IDDM. Diabetologia 37:500–503

    Article  CAS  PubMed  Google Scholar 

  • Deja G, Jarosz-Chobot P, Polańska J et al (2006) Is the association between TNF-α-308 A allele and DMT1 independent of HLA-DRB1, DQB1 alleles? Mediators Inflamm 2006:19724

    Article  PubMed  Google Scholar 

  • Dendrou CA, Wicker LS (2008) The IL-2/CD25 pathway determines susceptibility to T1D in humans and NOD mice. J Clin Immunol 28:685–696

    Article  CAS  PubMed  Google Scholar 

  • DiCosmo BF, Picarella D, Flavell RA (1994) Local production of human IL-6 promotes insulitis but retards the onset of insulin-dependent diabetes mellitus in non-obese diabetic mice. Int Immunol 6:1829–1837

    Article  CAS  PubMed  Google Scholar 

  • Dunning AM, Ellis PD, McBride S et al (2003) A transforming growth factorbeta1 signal peptide variant increases secretion in vitro and is associated with increased incidence of invasive breast cancer. Cancer Res 63:2610–2615

    CAS  PubMed  Google Scholar 

  • Excoffier L, Laval G, Schneider S (2005) Arlequin ver. 3.0.: an integrated software package for population genetics data analysis. Evol Bioinform Online 1:47–50

    CAS  PubMed  Google Scholar 

  • Feng RN, Li Y, Sun CH (2009) TNF 308 G/A polymorphism and type 1 diabetes: a meta-analysis. Diabetes Res Clin Pract 85:e4–e7

    Article  CAS  PubMed  Google Scholar 

  • Gallo J, Mrazek F, Petrek M (2009) Variation in cytokine genes can contribute to severity of acetabular osteolysis and risk for revision in patients with ABG 1 total hip arthroplasty: a genetic association study. BMC Med Genet 10:109

    Article  PubMed  Google Scholar 

  • Hamaguchi K, Kimura A, Seki N et al (2000) Analysis of tumor necrosis factor-α promoter polymorphism in type 1 diabetes: HLA-B and -DRB1 alleles are primarily associated with the disease in Japanese. Tissue Antigens 55:10–16

    Article  CAS  PubMed  Google Scholar 

  • Haukim N, Bidwell JL, Smith AJP et al (2002) Cytokine gene polymorphisms in human disease: on-line databases, Supplement 2. Genes Immun 3:313–330

    Article  CAS  PubMed  Google Scholar 

  • Hollegaard MV, Bidwell JL (2006) Cytokine gene polymorphism in human disease: on-line databases, Supplement 3. Genes Immun 7:269–276

    Article  CAS  PubMed  Google Scholar 

  • Ichinose K, Kawasaki E, Eguchi K (2007) Recent advancement of understanding pathogenesis of type 1 diabetes mellitus and potential relevance to diabetic nephropathy. Am J Nephrol 27:554–564

    Article  CAS  PubMed  Google Scholar 

  • Ishihara K, Hirano T (2002) IL-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine Growth Factor Rev 13:357–368

    Article  CAS  PubMed  Google Scholar 

  • Jahromi MM, Millward BA, Demaine AG (2000) A polymorphism in the promoter region of the gene for interleukin-6 is associated with susceptibility to type 1 diabetes mellitus. J Interferon Cytokine Res 20:885–888

    Article  CAS  PubMed  Google Scholar 

  • Jahromi MM, Millward BA, Demaine AG (2010) Significant correlation between association of polymorphism in codon 10 of the transforming growth factor-beta1 T (29) C with type 1 diabetes and patients with nephropathy disorder. J Interferon Cytokine Res 30:59–66

    Article  CAS  PubMed  Google Scholar 

  • Javor J, Bucova M, Ferencik S et al (2007) Single nucleotide polymorphisms of cytokine genes in the healthy Slovak population. Int J Immunogenet 34:273–280

    Article  CAS  PubMed  Google Scholar 

  • Kleinrath T, Gassner C, Lackner P et al (2007) Interleukin-4 promoter polymorphisms: a genetic prognostic factor for survival in metastatic renal cell carcinoma. J Clin Oncol 25:845–851

    Article  CAS  PubMed  Google Scholar 

  • Krikovszky D, Vásárhelyi B, Tóth-Heyn P et al (2002) Association between G-308A polymorphism of the tumor necrosis factor-α gene and 24-hour ambulatory blood pressure values in type 1 diabetic adolescents. Clin Genet 62:474–477

    Article  CAS  PubMed  Google Scholar 

  • Kristiansen OP, Mandrup-Poulsen T (2005) Interleukin-6 and diabetes. The good, the bad or the indifferent? Diabetes 54(suppl 2):S114–S124

    Article  CAS  PubMed  Google Scholar 

  • Kroeger KM, Carville KS, Abraham LJ (1997) The −308 tumor necrosis factor-α promoter polymorphism affects transcription. Mol Immunol 34:391–399

    Article  CAS  PubMed  Google Scholar 

  • Kubistova Z, Mrazek F, Tudos Z et al (2006) Distribution of 22 cytokine gene polymorphisms in the healthy Czech population. Int J Immunogenet 33:261–267

    Article  CAS  PubMed  Google Scholar 

  • Mauricio D, Mandrup-Poulsen T (1998) Apoptosis and the pathogenesis of IDDM: a question of life and death. Diabetes 47:1537–1543

    Article  CAS  PubMed  Google Scholar 

  • Myśliwiec M, Myśliwska J, Zorena K et al (2008) Interleukin 6–174(G>C) gene polymorphism is related to celiac disease and autoimmune thyroiditis coincidence in diabetes type 1 children. Diabetes Res Clin Pract 82:108–112

    Article  PubMed  Google Scholar 

  • Naugler WE, Karin M (2008) The wolf in sheep’s clothing: the role of interleukin-6 in immunity, inflammation and cancer. Trends Mol Med 14:109–119

    Article  CAS  PubMed  Google Scholar 

  • Noble JA, Valdes AM, Lane JA et al (2006) Linkage disequilibrium with predisposing DR3 haplotypes accounts for apparent effects of tumor necrosis factor and lymphotoxin-α polymorphisms on type 1 diabetes susceptibility. Hum Immunol 67:999–1004

    Article  CAS  PubMed  Google Scholar 

  • Pociot F, Wilson AG, Nerup J et al (1993) No independent association between a tumor necrosis factor-α promotor region polymorphism and insulin-dependent diabetes mellitus. Eur J Immunol 23:3050–3053

    Article  CAS  PubMed  Google Scholar 

  • Rabinovitch A (1998) An update on cytokines in the pathogenesis of insulin-dependent diabetes mellitus. Diabetes Metab Rev 14:129–151

    Article  CAS  PubMed  Google Scholar 

  • Richer MJ, Straka N, Fang D et al (2008) Regulatory T-cells protect from type 1 diabetes after induction by coxsackievirus infection in the context of transforming growth factor-beta. Diabetes 57:1302–1311

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Smyth DJ, Cooper JD, Bailey R et al (2006) A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nat Genet 38:617–619

    Article  CAS  PubMed  Google Scholar 

  • Todd JA, Walker NM, Cooper JD et al (2007) Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet 39:857–864

    Article  CAS  PubMed  Google Scholar 

  • Törn C, Hillman M, Sanjeevi CB et al (2006) Polymorphisms of TNF microsatellite marker a and HLA-DR-DQ in diabetes mellitus––a study in 609 Swedish subjects. Hum Immunol 67:527–534

    Article  PubMed  Google Scholar 

  • Uitenbroek DG (1997) SISA-Binomial. http://www.quantitativeskills.com/sisa/distributions/binomial.htm

  • Wang J, Wicker LS, Santamaria P (2009) IL-2 and its high-affinity receptor: genetic control of immunoregulation and autoimmunity. Semin Immunol 21:363–371

    Article  CAS  PubMed  Google Scholar 

  • Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661–678

    Article  Google Scholar 

  • Wilson AG, Symons JA, McDowell TL et al (1997) Effects of a polymorphism in the human tumor necrosis factor α promoter on transcriptional activation. Proc Natl Acad Sci USA 94:3195–3199

    Article  CAS  PubMed  Google Scholar 

  • Yamada Y, Miyauchi A, Goto J et al (1998) Association of a polymorphism of a transforming growth factor-β1 gene with genetic susceptibility to osteoporosis in postmenopausal Japanese women. J Bone Miner Res 13:1569–1576

    Article  CAS  PubMed  Google Scholar 

  • Yokota M, Ichihara S, Lin TL et al (2000) Association of a T29 → C polymorphism of the transforming growth factor-β1 gene with genetic susceptibility to myocardial infarction in Japanese. Circulation 101:2783–2787

    CAS  PubMed  Google Scholar 

  • Yoon JW, Jun HS (2005) Autoimmune destruction of pancreatic beta cells. Am J Ther 12:580–591

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the Research Program of the Ministry of Education of the Slovak Republic KEGA 3/7140/07, Comenius University Grant UK/25/2006, and a Short-Term Fellowship of European Federation of Immunological Societies.

Author information

Authors and Affiliations

  1. Department of Immunology, Faculty of Medicine, Comenius University, Odborarske nam. 14, 813 72, Bratislava 1, Slovakia

    Juraj Javor, Maria Bucova, Martina Stuchlikova & Milan Buc

  2. Institute for Transfusion Medicine, University Hospital of Essen, Essen, Germany

    Stanislav Ferencik

  3. Institute of Immunology, University Hospital of Essen, Essen, Germany

    Hans Grosse-Wilde

  4. Department of Diabetology, National Institute of Endocrinology and Diabetology, Lubochna, Slovakia

    Emil Martinka

  5. 1st Department of Pediatrics, Faculty of Medicine, Comenius University, Bratislava, Slovakia

    Lubomir Barak

  6. 2nd Department of Internal Medicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia

    Lujza Strbova

Authors
  1. Juraj Javor
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stanislav Ferencik
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria Bucova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Martina Stuchlikova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Emil Martinka
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lubomir Barak
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lujza Strbova
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hans Grosse-Wilde
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Milan Buc
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Juraj Javor.

About this article

Cite this article

Javor, J., Ferencik, S., Bucova, M. et al. Polymorphisms in the Genes Encoding TGF-β1, TNF-α, and IL-6 Show Association with Type 1 Diabetes Mellitus in the Slovak Population. Arch. Immunol. Ther. Exp. 58, 385–393 (2010). https://doi.org/10.1007/s00005-010-0092-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00005-010-0092-z

Keywords

Search

Navigation