Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Full Paper
  • Published:

Testing the possible negative association of type 1 diabetes and atopic disease by analysis of the interleukin 4 receptor gene

Genes & Immunity volume 4, pages 469–475 (2003)Cite this article

Abstract

Variations in the interleukin 4 receptor A (IL4RA) gene have been reported to be associated with atopy, asthma, and allergy, which may occur less frequently in subjects with type 1 diabetes (T1D). Since atopy shows a humoral immune reactivity pattern, and T1D results from a cellular (T lymphocyte) response, we hypothesised that alleles predisposing to atopy could be protective for T1D and transmitted less often than the expected 50% from heterozygous parents to offspring with T1D. We genotyped seven exonic single nucleotide polymorphisms (SNPs) and the –3223 C>T SNP in the putative promoter region of IL4RA in up to 3475 T1D families, including 1244 Finnish T1D families. Only the −3223 C>T SNP showed evidence of negative association (P=0.014). There was some evidence for an interaction between −3233 C>T and the T1D locus IDDM2 in the insulin gene region (P=0.001 in the combined and P=0.02 in the Finnish data set). We, therefore, cannot rule out a genetic effect of IL4RA in T1D, but it is not a major one.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. The EURODIAB Substudy 2 Study Group. Decreased prevalence of atopic diseases in children with diabetes. J Pediatr 2000; 137: 470–474.

  2. Olesen AB, Juul S, Birkebæk N. Thestrup-Pedersen K . Association between atopic dermatitis and insulin-dependent diabetes mellitus: a case–control study. Lancet 2001; 357: 1749–1752.

    Article  CAS  Google Scholar 

  3. Douek IS, Leech NJ, Bingley PJ, Gale EAM . Eczema and Type 1 diabetes. Diabet Med 2002; 19: 172–175.

    Article  Google Scholar 

  4. Douek IS, Leech NJ, Gillmor HA, Bingley PJ, Gale EAM . Children with type-1 diabetes and their unaffected siblings have fewer symptoms of asthma. Lancet 1999; 353: 1850.

    Article  CAS  Google Scholar 

  5. Kero J, Gissler M, Hemminki E, Isolauri E . Could TH1 and TH2 diseases coexist? Evaluation of asthma incidence in children with coeliac disease, type 1 diabetes, or rheumatoid arthritis: a register study. J Allergy Clin Immunol 2001; 108: 781–783.

    Article  CAS  Google Scholar 

  6. Stene LC, Nafstad P . Relation between occurrence of type 1 diabetes and asthma. Lancet 2001; 357: 607–608.

    Article  CAS  Google Scholar 

  7. Todd JA . A protective role of the environment in the development of type 1 diabetes? Diabet Med 1991; 10: 906–910.

    Article  Google Scholar 

  8. Strachan DP . Hay fever, hygiene, and household size. BMJ 1989; 299: 1259–1260.

    Article  CAS  Google Scholar 

  9. Todd JA, Wicker LS . Genetic protection from the inflammatory disease type 1 diabetes in humans and animal models. Immunity 2001; 15: 387–395.

    Article  CAS  Google Scholar 

  10. Imagawa A, Hanfusa T, Tamura S et al. Pancreatic biopsy as a procedure for detecting in situ autoimmune phenomena in type 1 diabetes. Diabetes 2001; 50: 1269–1273.

    Article  CAS  Google Scholar 

  11. Pipeleers D, Ling Z . Pancreatic beta cells in insulin-dependent diabetes. Diabetes Metab Rev 1992; 3: 209–227.

    Article  Google Scholar 

  12. Cameron MJ, Arreaza GA, Zucker P et al. IL-4 Prevents insulitis and insulin-dependent diabetes mellitus in nonobese diabetic mice by potentiation of regulatory T helper-2 cell function. J Immunol 1997; 159: 4686–4692.

    CAS  PubMed  Google Scholar 

  13. Radu DL, Noben-Trauth N, Hu-Li J, Paul WE, Bona CA . A targeted mutation in the IL-4Rα gene protects mice against autoimmune diabetes. Proc Natl Acad Sci USA 2000; 97: 12700–12704.

    Article  CAS  Google Scholar 

  14. Serreze DV, Chapman HD, Post CM, Johnson EA, Suarez-Pinzon WL, Rabinovitch A . Th1 to Th2 cytokine shifts in nonobese diabetic mice: sometimes and outcome, rather than the cause, of diabetes resistance elicited by immunostimulation. J Immunol 2001; 166: 1352–1359.

    Article  CAS  Google Scholar 

  15. Immervoll T, Loesgen S, Dutsch G et al. Fine mapping and single nucleotide polymorphism association results of candidate genes for asthma and related phenotypes. Hum Mut 2001; 18: 327–336.

    Article  CAS  Google Scholar 

  16. Noguchi E, Nukaga-Nishio Y, Jian Z et al. Haplotypes of the 5′ region of the IL-4 gene and SNPs in the intergene sequence between the IL-4 and IL-13 genes are associated with atopic asthma. Hum Immunol 2001; 62: 1251–1257.

    Article  CAS  Google Scholar 

  17. Mitsuyasu H, Yanagihara Y, Mao X-Q et al. Ile50Val variant of IL4Rα upregulates IgE synthesis and associates with atopic asthma. Nat Genet 1998; 19: 119–120.

    Article  CAS  Google Scholar 

  18. Ober C, Leavitt SA, Tsalenko A et al. Variation in the interleukin 4-receptor α gene confers susceptibility to asthma and atopy in ethnically diverse populations. Am J Hum Genet 2000; 66: 517–526.

    Article  CAS  Google Scholar 

  19. Hershey GK, Friedrich MF, Esswein LA, Thomas ML, Chatila TA . The association of atopy with a gain-of-function mutation in the α subunit of the interleukin-4 receptor. N Engl J Med 1997; 337: 1720–1725.

    Article  CAS  Google Scholar 

  20. Hackstein H, Hecker M, Kruse S et al. A novel polymorphism in the 5' promoter region of the human interleukin-4 receptor α-chain gene is associated with decreased soluble interleukin-4 receptor protein levels. Immunogenetics 2001; 53: 264–269.

    Article  CAS  Google Scholar 

  21. Schauer U, Schmitt M, Muller S et al. Soluble interleukin-4 receptor in atopic children. Int Arch Allergy Immunol 1995; 108: 175–182.

    Article  CAS  Google Scholar 

  22. Borish L, Nelson H, Corren J et al. Phase I/II study of recombinant interleukin-4 receptor (IL-4R) in adult patients with moderate asthma. J Allergy Clin Immunol 2000; 105: A828.

    Google Scholar 

  23. Cox NJ, Wapelhorst B, Morrison VA et al. Seven regions of the genome show evidence of linkage to type 1 diabetes in a consensus analysis of 767 multiplex families. Am J Hum Genet 2001; 69: 820–830.

    Article  CAS  Google Scholar 

  24. European Consortium for IDDM Genome Studies. A genomewide scan for type 1 diabetes susceptibility in Scandinavian families: identification of new loci with evidence of interactions. Am J Hum Genet 2001; 69: 1301–1313.

  25. Reimsnider SK, Eckenrode SE, Marron MP, Muri A, She J-X . IL4 and IL4Rα genes are not linked or associated with type 1 diabetes. Pediatr Res 2000; 47: 246–249.

    Article  CAS  Google Scholar 

  26. Cookson WOCM, Young RP, Sandford AJ et al. Maternal inheritance of atopic IgE responsiveness on chromosome 11q. Lancet 1992; 340: 381–384.

    Article  CAS  Google Scholar 

  27. Daniels SE, Bhattacharrya S, James A et al. A genome-wide search for quantitative trait loci underlying asthma. Nature 1996; 383: 247–250.

    Article  CAS  Google Scholar 

  28. Moffatt MF, Sharp PA, Faux JA, Young RP, Cookson WOCM, Hopkin JM . Factors confounding genetic linkage between atopy and chromosome 11q. Clin Exp Allergy 1992; 22: 1046–1051.

    Article  CAS  Google Scholar 

  29. Deichmann K, Bardutzky J, Forster J, Heinzmann A, Kuehr J . Common polymorphisms in the coding part of the IL4-receptor gene. Biochem Biophys Res Commun 1997; 231: 696–697.

    Article  CAS  Google Scholar 

  30. Cordell H, Clayton D . A unified stepwise regression procedure for evaluating the relative effects of polymorphisms within a gene using case/control or family data: application to HLA in type 1 diabetes. Am J Hum Genet 2002; 70: 124–141.

    Article  CAS  Google Scholar 

  31. Mirel DB, Valdes AM, Lazzeroni LC, Reynolds RL, Erlich HA, Noble JA . Association of IL4R haplotypes with type 1 diabetes. Diabetes 2002; 51: 3336–3341.

    Article  CAS  Google Scholar 

  32. Graham J, Hagopian WA, Kockum I et al, for the Swedish Childhood Diabetes Study Group, and Blohmé, G for the Diabetes Incidence in Sweden Study Group. Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes. Diabetes 2002; 251: 1346–1355.

    Article  Google Scholar 

  33. Pugliese A, Zeller M, Fernandez Jr A et al. The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat Genet 1997; 15: 293–297.

    Article  CAS  Google Scholar 

  34. Risch N, Merikangas K . The future of genetic studies of complex human diseases. Science 273: 1516–1517.

    Article  CAS  Google Scholar 

  35. Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN . Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 2003; 33: 177–182.

    Article  CAS  Google Scholar 

  36. Dahlman I, Eaves IA, Kosoy R et al. Parameters for reliable results in genetic association studies in common disease. Nat Genet 2002; 30: 149–150.

    Article  CAS  Google Scholar 

  37. Weinberg CR . Methods for detection of parent-of-origin effects in genetic studies of case-parents triads. Am J Hum Genet 1999; 65: 229–235.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was funded by the Wellcome Trust and the Juvenile Diabetes Research Foundation International. LMM is the recipient of a Wellcome Trust Prize Studentship. JT and ET-W were funded by the NIH, the Novo Nordisk Foundation, the Academy of Finland, and the Juvenile Diabetes Research Foundation. DEU was supported by the Novo Nordisk Foundation. We thank Gillian Coleman, Sarah Field, Tasneem Hassanali, Jayne Hutchings, Ruth Lewis, John Lumby, Meera Sebastian, Vin Everett and Geoff Dolman for advice and help.

Author information

Authors and Affiliations

  1. JDRF/WT Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK

    L M Maier, R C J Twells, J M M Howson, A C Lam, D G Clayton, D J Smyth, L J Smink, N M Walker, O S Burren, S Nutland, H Rance & J A Todd

  2. Department of Medical Genetics, Queen's University, Belfast, Northern Ireland, UK

    D Savage

  3. Department of Child Health, Queen's University, Belfast, Northern Ireland, UK

    D Carson

  4. Department of Epidemiology and Public Health, Queen's University, Belfast, Northern Ireland, UK

    C C Patterson

  5. Diabetes and Genetic Epidemiology Unit, National Public Health Institute, Helsinki, Finland

    E Tuomilehto-Wolf & J Tuomilehto

  6. Clinic of Diabetes, Nutrition and Metabolic Diseases ‘N Paulescu’, Bucharest, Romania

    C Guja & C Ionescu-Tirgoviste

  7. Institute of Immunology, Rikshospitalet University Hospital, Oslo, Norway

    D E Undlien

  8. Division of Epidemiology, Laboratory of Molecular Epidemiology, Norwegian Institute of Public Health, Oslo, Norway

    K S Rønningen

  9. Instituto di Clinica e Biologia dell’Eta’ Evolutiva, University of Cagliari, Italy

    F Cucca

Authors
  1. L M Maier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R C J Twells
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J M M Howson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A C Lam
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D G Clayton
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D J Smyth
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D Savage
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D Carson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C C Patterson
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. L J Smink
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. N M Walker
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. O S Burren
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. S Nutland
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. H Rance
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. E Tuomilehto-Wolf
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. J Tuomilehto
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. C Guja
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. C Ionescu-Tirgoviste
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. D E Undlien
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. K S Rønningen
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. F Cucca
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. J A Todd
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J A Todd.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Maier, L., Twells, R., Howson, J. et al. Testing the possible negative association of type 1 diabetes and atopic disease by analysis of the interleukin 4 receptor gene. Genes Immun 4, 469–475 (2003). https://doi.org/10.1038/sj.gene.6364007

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6364007

Keywords

This article is cited by

Search

Advanced search

Quick links