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:

Association of the CTLA4 promoter region (−1661G allele) with type 1 diabetes in the South Moroccan population

Abstract

The contribution of the candidate gene CTLA4 to type 1 diabetes is not well established. Although several polymorphisms have been repeatedly associated to the disease, several studies have not confirmed the association. The joint analysis of three SNPs in the CTLA4 promoter region (−1722, −1661, and −319), one SNP in the first exon (+49), and one dinucleotide repeat in the 3′ untranslated region, in a case–control study in a North African population, shows a strong association of the CTLA4 region with the disease. The −1661G allele showed a significant association with an odds ratio of 2.13. Moreover, the internal structure of the dinucleotide repeat has been deeply analyzed. The present results reveal the importance of polymorphisms in the CTLA4 promoter region, their probable role in gene expression and, ultimately, their relation to the etiology of type 1 diabetes. Previous contradictory association studies might be due to the effect of linkage disequilibrium between the polymorphism analyzed and the alteration within the CTLA4 region. This alteration may be different depending on the genetic background of the population. The present work stresses the need to perform exhaustive analysis of the promoter region polymorphisms in order to detect association with the disease.

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

Access options

Buy this article

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

Similar content being viewed by others

References

  1. Todd JA, Farrall M . Panning for gold: genome-wide scanning for linkage in type 1 diabetes. Hum Mol Genet 1996; 5: 1443–1448.

    Article  CAS  Google Scholar 

  2. Pociot F, McDermott MF . Genetics of type 1 diabetes mellitus. Genes Immun 2002; 3: 235–249.

    Article  CAS  Google Scholar 

  3. Nistico L, Buzzetti R, Pritchard LE et al. The CTLA-4 gene region of chromosome 2q33 is linked to and associated with, type 1 diabetes Belgian Diabetes Registry. Hum Mol Genet 1996; 5: 1075–1080.

    Article  CAS  Google Scholar 

  4. Luo DF, Buzzetti R, Rotter JI et al. Confirmation of three susceptibility genes to insulin-dependent diabetes mellitus: IDDM4, IDDM5 and IDDM8. Hum Mol Genet 1996; 5: 693–698.

    Article  CAS  Google Scholar 

  5. Waterhouse P, Penninger JM, Timms E et al. Lymphoproliferative disorders with early lethality in mice deficient in CTLA-4. Science 1995; 270: 985–988.

    Article  CAS  Google Scholar 

  6. Gribben JG, Freeman GJ, Boussiotis VA et al. CTLA4 mediates antigen-specific apoptosis of human T cells. Proc Natl Acad Sci USA 1995; 92: 811–815.

    Article  CAS  Google Scholar 

  7. Robey E, Allison JP . T-cell activation: integration of signals from the antigen receptor and costimulatory molecules. Immunol Today 1995; 16: 306–310.

    Article  CAS  Google Scholar 

  8. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH . Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995; 3: 541–547.

    Article  CAS  Google Scholar 

  9. Harper K, Balzano C, Rouvier E, Mattei MG, Luciani MF, Golstein P . CTLA-4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal location. J Immunol 1991; 147: 1037–1044.

    CAS  PubMed  Google Scholar 

  10. Polymeropoulos MH, Xiao H, Rath DS, Merril CR . Dinucleotide repeat polymorphism at the human CTLA4 gene. Nucleic Acids Res 1991; 19: 4018.

    PubMed  PubMed Central  Google Scholar 

  11. Awata T, Kurihara S, Iitaka M et al. Association of CTLA-4 gene A-G polymorphism (IDDM12 locus) with acute-onset and insulin-depleted IDDM as well as autoimmune thyroid disease (Graves' disease and Hashimoto's thyroiditis) in the Japanese population. Diabetes 1998; 47: 128–129.

    Article  CAS  Google Scholar 

  12. Abe T, Takino H, Yamasaki H et al. CTLA4 gene polymorphism correlates with the mode of onset and presence of ICA512 Ab in Japanese type 1 diabetes. Diabetes Res Clin Pract 1999; 46: 169–175.

    Article  CAS  Google Scholar 

  13. Lee YJ, Huang FY, Lo FS et al. Association of CTLA4 gene A-G polymorphism with type 1 diabetes in Chinese children. Clin Endocrinol 2000; 52: 153–157.

    Article  CAS  Google Scholar 

  14. Lowe RM, Graham J, Sund G et al. The length of the CTLA-4 microsatellite (AT)N-repeat affects the risk for type 1 diabetes. Diabetes Incidence in Sweden Study Group. Autoimmunity 2000; 32: 173–180.

    Article  CAS  Google Scholar 

  15. Donner H, Rau H, Walfish PG et al. CTLA4 alanine-17 confers genetic susceptibility to Graves' disease and to type 1 diabetes mellitus. J Clin Endocrinol Metab 1997; 82: 143–146.

    CAS  PubMed  Google Scholar 

  16. Marron MP, Zeidler A, Raffel LJ et al. Genetic and physical mapping of a type 1 diabetes susceptibility gene (IDDM12) to a 100-kb phagemid artificial chromosome clone containing D2S72-CTLA4-D2S105 on chromosome 2q33. Diabetes 2000; 49: 492–499.

    Article  CAS  Google Scholar 

  17. Owerbach D, Naya FJ, Tsai MJ, Allander SV, Powell DR, Gabbay KH . Analysis of candidate genes for susceptibility to type I diabetes: a case–control and family–association study of genes on chromosome 2q31–35. Diabetes 1997; 46: 1069–1074.

    Article  CAS  Google Scholar 

  18. Badenhoop K, Donner H, Pani M, Rau H, Siegmund T, Braun J . Genetic susceptibility to type 1 diabetes: clinical and molecular heterogeneity of IDDM1 and IDDM12 in a German population. Exp Clin Endocrinol Diabetes 1999; 107 (Suppl 3): S89–S92.

    CAS  PubMed  Google Scholar 

  19. Marron MP, Raffel LJ, Garchon HJ et al. Insulin-dependent diabetes mellitus (IDDM) is associated with CTLA4 polymorphisms in multiple ethnic groups. Hum Mol Genet 1997; 6: 1275–1282.

    Article  CAS  Google Scholar 

  20. Larsen ZM, Kristiansen OP, Mato E et al. IDDM12 (CTLA4) on 2q33 and IDDM13 on 2q34 in genetic susceptibility to type 1 diabetes (insulin-dependent). Autoimmunity 1999; 31: 35–42.

    Article  CAS  Google Scholar 

  21. Osei-Hyiaman D, Hou L, Zhiyin R et al. Association of a novel point mutation (C159G) of the CTLA4 gene with type 1 diabetes in West Africans but not in Chinese. Diabetes 2001; 50: 2169–2171.

    Article  CAS  Google Scholar 

  22. Johnson GC, Esposito L, Barratt BJ et al. Haplotype tagging for the identification of common disease genes. Nat Genet 2001; 29: 233–237.

    Article  CAS  Google Scholar 

  23. Chistiakov DA, Savost'anov KV, Nosikov VV . CTLA4 gene polymorphisms are associated with, and linked to, insulin-dependent diabetes mellitus in a Russian population. BMC Genet 2001; 2: 6.

    Article  CAS  Google Scholar 

  24. Shaw G, Kamen R . A conserved AU sequence from the 3′ untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell 1986; 46: 659–667.

    Article  CAS  Google Scholar 

  25. Ligers A, Teleshova N, Masterman T, Huang WX, Hillert J . CTLA-4 gene expression is influenced by promoter and exon 1 polymorphisms. Genes Immun 2001; 2: 145–152.

    Article  CAS  Google Scholar 

  26. Harbo HF, Celius EG, Vartdal F, Spurkland A . CTLA4 promoter and exon 1 dimorphisms in multiple sclerosis. Tissue Antigens 1999; 53: 106–110.

    Article  CAS  Google Scholar 

  27. Heward JM, Allahabadia A, Carr-Smith J et al. No evidence for allelic association of a human CTLA-4 promoter polymorphism with autoimmune thyroid disease in either population-based case–control or family-based studies. Clin Endocrinol 1998; 49: 331–334.

    Article  CAS  Google Scholar 

  28. Cooper DN, Nussbaum RL, Krawczak M . Proposed guidelines for papers describing DNA polymorphism–disease associations. Hum Genet 2002; 110: 207–208.

    Article  CAS  Google Scholar 

  29. Bosch E, Calafell F, Pérez-Lezaun A et al. Genetic structure of north-west Africa revealed by STR analysis. Eur J Hum Genet 2000; 8: 360–366.

    Article  CAS  Google Scholar 

  30. Bosch E, Calafell F, Comas D, Oefner PJ, Underhill PA, Bertranpetit J . High-resolution analysis of human Y-chromosome variation shows a sharp discontinuity and limited gene flow between northwestern Africa and the Iberian Peninsula. Am J Hum Genet 2001; 68:1019–1029.

    Article  CAS  Google Scholar 

  31. Brakez Z, Bosch E, Izaabel H et al. Human mitochondrial DNA sequence variation in the Moroccan population of the Souss area. Ann Hum Biol 2001; 28: 295–307.

    Article  CAS  Google Scholar 

  32. Izaabel H, Garchon HJ, Caillat-Zucman S et al. HLA class II DNA polymorphism in Moroccan population from Souss, Agadir area. Tissue Antigens 1998; 51: 106–110.

    Article  CAS  Google Scholar 

  33. Izaabel H, Garchon HJ, Beaurain G et al. Distribution of HLA class II alleles and haplotypes in insulin-dependent Moroccan diabetics. Hum Immunol 1996; 49: 137–143.

    Article  CAS  Google Scholar 

  34. Schneider S, Roessli D, Excoffier L . Arlequin 2.000: a software for population genetics data analysis. Genetics and Biometry Laboratory, University of Geneva, Geneva, Switzerland, 2000.

Download references

Acknowledgements

We thank Mònica Vallés for technical assistance. The present work was supported by the Cooperative Actions between Spain and Morocco (8P/00), Recherches menées dans le cadre du programme Thématique d'Appui á la Recherche Scientifique (PROTAS II, P12/03), Dirección General de Investigación Científica y Técnica, Spain (PB98-1064; BOS2001-0794), and Direcció General de Recerca, Generalitat de Catalunya (2001SGR00285).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to D Comas.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bouqbis, L., Izaabel, H., Akhayat, O. et al. Association of the CTLA4 promoter region (−1661G allele) with type 1 diabetes in the South Moroccan population. Genes Immun 4, 132–137 (2003). https://doi.org/10.1038/sj.gene.6363933

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6363933

Keywords

This article is cited by

Search

Quick links