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Defining the contribution of the HLA region to cis DQ2-positive coeliac disease patients

Genes & Immunity volume 5, pages 215–220 (2004)Cite this article

Abstract

The major genetic susceptibility to coeliac disease is contributed by the human leukocyte antigen (HLA) region. The primary association is with the HLA-DQ2 molecule, encoded by the DQA1*05 and DQB1*02 alleles, which is expressed by over 90% of patients. The aim of our study was to perform an extensive scan of the entire HLA region to determine whether there is evidence for the presence of additional HLA susceptibility genes for coeliac disease in the Dutch population, acting independently of DQ2. In all, 16 microsatellite markers and the DQA1 and DQB1 genes were genotyped in simplex cis DQ2-positive coeliac disease families and cis DQ2-positive control families. Allele frequencies of markers on phase-known DQ2-positive haplotypes transmitted to patients were compared to a combined group of DQ2-positive nontransmitted and control haplotypes, thereby controlling for the DQ2 contribution. No significant differences at any of the marker loci were detected, suggesting that DQ2 is the major HLA risk factor for coeliac disease. Individuals homozygous for DQ2 or heterozygous for DQA1*05-DQB1*02/DQA1*0201-DQB1*02 were found to be at five-fold increased risk for development of coeliac disease (P<10−8). This risk seems to be conferred by the presence of a second DQB1*02 allele next to one DQA1*05-DQB1*02 haplotype, independently of the second DQA1 allele.

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References

  1. Csizmadia CG, Mearin ML, von Blomberg BM, Brand R, Verloove-Vanhorick SP . An iceberg of childhood coeliac disease in the Netherlands. Lancet 1999; 353: 813–814.

    Article  CAS  Google Scholar 

  2. Rostami K, Mulder CJ, Werre JM et al. High prevalence of celiac disease in apparently healthy blood donors suggests a high prevalence of undiagnosed celiac disease in the Dutch population. Scand J Gastroenterol 1999; 34: 276–279.

    Article  CAS  Google Scholar 

  3. Rostami K, Kerckhaert J, Tiemessen R, von Blomberg BM, Meijer JW, Mulder CJ . Sensitivity of antiendomysium and antigliadin antibodies in untreated celiac disease: disappointing in clinical practice. Am J Gastroenterol 1999; 94: 888–894.

    Article  CAS  Google Scholar 

  4. Marsh MN . Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’). Gastroenterology 1992; 102: 330–354.

    Article  CAS  Google Scholar 

  5. Farrell RJ, Kelly CP . Celiac sprue. N Engl J Med 2002; 346: 180–188.

    Article  CAS  Google Scholar 

  6. Sollid LM, Thorsby E . HLA susceptibility genes in celiac disease: genetic mapping and role in pathogenesis. Gastroenterology 1993; 105: 910–922.

    Article  CAS  Google Scholar 

  7. van de Wal Y, Kooy Y, van Veelen P et al. Selective deamidation by tissue transglutaminase strongly enhances gliadin-specific T cell reactivity. J Immunol 1998; 161: 1585–1588.

    CAS  PubMed  Google Scholar 

  8. Molberg O, McAdam SN, Korner R et al. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat Med 1998; 4: 713–717.

    Article  CAS  Google Scholar 

  9. Alper CA, Fleischnick E, Awdeh Z, Katz AJ, Yunis EJ . Extended major histocompatibility complex haplotypes in patients with gluten-sensitive enteropathy. J Clin Invest 1987; 79: 251–256.

    Article  CAS  Google Scholar 

  10. Candore G, Lio D, Colonna Romano G, Caruso C . Pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype: effect of multiple gene interactions. Autoimmun Rev 2002; 1: 29–35.

    Article  CAS  Google Scholar 

  11. Louka AS, Nilsson S, Olsson M et al. HLA in coeliac disease families: a novel test of risk modification by the ‘other’ haplotype when at least one DQA1*05-DQB1*02 haplotype is carried. Tissue Antigens 2002; 60: 147–154.

    Article  CAS  Google Scholar 

  12. Ploski R, Ek J, Thorsby E, Sollid LM . On the HLA-DQ(alpha 1*0501, beta 1*0201)-associated susceptibility in celiac disease: a possible gene dosage effect of DQB1*0201. Tissue Antigens 1993; 41: 173–177.

    Article  CAS  Google Scholar 

  13. Mearin ML, Biemond I, Pena AS et al. HLA-DR phenotypes in Spanish coeliac children: their contribution to the understanding of the genetics of the disease. Gut 1983; 24: 532–537.

    Article  CAS  Google Scholar 

  14. Mearin ML, Bouquet J, Mourad N et al. HLA-DR antigens and phenotypes in Dutch coeliac children and their families. Clin Genet 1985; 27: 45–50.

    Article  CAS  Google Scholar 

  15. Bolognesi E, Karell K, Percopo S et al. Additional factor in some HLA DR3/DQ2 haplotypes confers a fourfold increased genetic risk of celiac disease. Tissue Antigens 2003; 61: 308–316.

    Article  CAS  Google Scholar 

  16. Lopez-Vazquez A, Rodrigo L, Fuentes D et al. MHC class I chain related gene A (MICA) modulates the development of coeliac disease in patients with the high risk heterodimer DQA1*0501/DQB1*0201. Gut 2002; 50: 336–340.

    Article  CAS  Google Scholar 

  17. Rueda B, Pascual M, Lopez-Nevot MA et al. Association of MICA-A5.1 allele with susceptibility to celiac disease in a family study. Am J Gastroenterol 2003; 98: 359–362.

    Article  CAS  Google Scholar 

  18. McManus R, Wilson AG, Mansfield J, Weir DG, Duff GW, Kelleher D . TNF2, a polymorphism of the tumour necrosis-alpha gene promoter, is a component of the celiac disease major histocompatibility complex haplotype. Eur J Immunol 1996; 26: 2113–2118.

    Article  CAS  Google Scholar 

  19. Louka AS, Lie BA, Talseth B et al. Coeliac disease patients carry conserved HLA-DR3-DQ2 haplotypes revealed by association of TNF alleles. Immunogenetics 2003; 55: 339–343.

    Article  CAS  Google Scholar 

  20. Garrote JA, Arranz E, Telleria JJ, Castro J, Calvo C, Blanco-Quiros A . TNF alpha and LT alpha gene polymorphisms as additional markers of celiac disease susceptibility in a DQ2-positive population. Immunogenetics 2002; 54: 551–555.

    Article  CAS  Google Scholar 

  21. de la Concha EG, Fernandez-Arquero M, Vigil P et al. Celiac disease and TNF promoter polymorphisms. Hum Immunol 2000; 61: 513–517.

    Article  CAS  Google Scholar 

  22. Bolognesi E, Dalfonso S, Rolando V, Fasano ME, Pratico L, Momigliano-Richiardi P . MICA and MICB microsatellite alleles in HLA extended haplotypes. Eur J Immunogenet 2001; 28: 523–530.

    Article  CAS  Google Scholar 

  23. Grimaldi MC, Clayton J, Pontarotti P, Cambon-Thomsen A, Crouau-Roy B . New highly polymorphic microsatellite marker in linkage disequilibrium with HLA-B. Hum Immunol 1996; 51: 89–94.

    Article  CAS  Google Scholar 

  24. Polvi A, Maki M, Partanen J . Celiac patients predominantly inherit HLA-DPB1*0101 positive haplotype from HLA-DQ2 homozygous parent. Hum Immunol 1997; 53: 156–158.

    Article  CAS  Google Scholar 

  25. Lie BA, Sollid LM, Ascher H et al. A gene telomeric of the HLA class I region is involved in predisposition to both type 1 diabetes and coeliac disease. Tissue Antigens 1999; 54: 162–168.

    Article  CAS  Google Scholar 

  26. Thomson G . Mapping disease genes: family-based association studies. Am J Hum Genet 1995; 57: 487–498.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Louka AS, Moodie SJ, Karell K et al. A collaborative European search for non-DQA1*05-DQB1*02 celiac disease loci on HLA-DR3 haplotypes: analysis of transmission from homozygous parents. Hum Immunol 2003; 64: 350–358.

    Article  CAS  Google Scholar 

  28. Congia M, Frau F, Lampis R et al. A high frequency of the A30, B18, DR3, DRw52, DQw2 extended haplotype in Sardinian celiac disease patients: further evidence that disease susceptibility is conferred by DQ A1*0501, B1*0201. Tissue Antigens 1992; 39: 78–83.

    Article  CAS  Google Scholar 

  29. Vader W, Stepniak D, Kooy Y et al. The HLA-DQ2 gene dose effect in celiac disease is directly related to the magnitude and breadth of gluten-specific T cell responses. Proc Natl Acad Sci USA 2003; 100: 12390–12395.

    Article  CAS  Google Scholar 

  30. Carrington M, Miller T, White M et al. Typing of HLA-DQA1 and DQB1 using DNA single-strand conformation polymorphism. Hum Immunol 1992; 33: 208–212.

    Article  CAS  Google Scholar 

  31. Koeleman BP, Dudbridge F, Cordell HJ, Todd JA . Adaptation of the extended transmission/disequilibrium test to distinguish disease associations of multiple loci: the conditional extended transmission/disequilibrium test. Ann Hum Genet 2000; 64: 207–213.

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful to Winny van der Hoeven for her help in collecting the case families, to Jessica Bader for DQA1 and DQB1 genotyping of the case and control families and to Frank Dudbridge for his advice with regard to the analysis of the data. We thank Jackie Senior for improving the manuscript. The study was financially supported by a grant from the Dutch Digestive Diseases Foundation (WS 97-44). This paper is dedicated to the memory of Lodewijk Sandkuijl who unexpectedly died on 4 December 2002. He participated in this project from the beginning and his contribution to the design of the study and analysis of the data was of great importance to us.

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Author notes

  1. L A Sandkuijl: Dedicated to the memory of Lodewijk Sandkuijl (1953–2002).

Authors and Affiliations

  1. Department of Biomedical Genetics, Complex Genetics Group, University Medical Centre Utrecht, Utrecht, The Netherlands

    M J van Belzen, B P C Koeleman, A F J Bardoel, P L Pearson & C Wijmenga

  2. Department of Paediatric Gastroenterology, University Medical Centre Utrecht, Utrecht, The Netherlands

    M J van Belzen & R H J Houwen

  3. Laboratory for Immunogenetics, VU University Medical Centre, Amsterdam, The Netherlands

    J B A Crusius

  4. Department of Pathology, Rijnstate Hospital, Arnhem, The Netherlands

    J W R Meijer

Authors
  1. M J van Belzen
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  2. B P C Koeleman
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  3. J B A Crusius
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  4. J W R Meijer
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  7. L A Sandkuijl
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Correspondence to C Wijmenga.

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Supplementary Information accompanies the paper on Genes and Immunity's website (http://www.nature.com/ gene).

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van Belzen, M., Koeleman, B., Crusius, J. et al. Defining the contribution of the HLA region to cis DQ2-positive coeliac disease patients. Genes Immun 5, 215–220 (2004). https://doi.org/10.1038/sj.gene.6364061

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