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Conserved extended haplotypes discriminate HLA-DR3-homozygous Basque patients with type 1 diabetes mellitus and celiac disease

Genes & Immunity volume 7, pages 550–554 (2006)Cite this article

Abstract

The major susceptibility locus for type 1 diabetes mellitus (T1D) maps to the human lymphocyte antigen (HLA) class II region in the major histocompatibility complex on chromosome 6p21. In southern European populations, like the Basques, the greatest risk to T1D is associated with DR3 homo- and heterozygosity and is comparable to that of DR3/DR4, the highest risk genotype in northern European populations. Celiac disease (CD) is another DR3-associated autoimmune disorder showing certain overlap with T1D that has been explained by the involvement of common genetic determinants, a situation more frequent in DR3-rich populations, like the Basques. As both T1D- and CD-associated HLA alleles are part of conserved extended haplotypes (CEH), we compared DR3-homozygous T1D and CD patients to determine whether CEHs were equally distributed between both disorders or there was a differential contribution of different haplotypes. We observed a very pronounced distribution bias (P<10−5) of the two major DR3 CEHs, with DR3-B18 predominating in T1D and DR3-B8 in CD. Additionally, high-density single nucleotide polymorphism (SNP) analysis of the complete CEH [A*30-B*18-MICA*4-F1C30-DRB1*0301-DQB1*0201-DPB1*0202] revealed extraordinary conservation throughout the 4.9 Mbp analyzed supporting the existence of additional diabetogenic variants (other than HLA-DRB1*0301-DQB1*0201), conserved within the DR3-B18 CEH (but not in other DR3 haplotypes) that could explain its enhanced diabetogenicity.

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Acknowledgements

We thank George Eisenbarth and Henry Erlich for their constructive discussions over the years. This work was funded by Grants RGDM-G03/212 and RCMN-C03/08 from the Instituto de Salud Carlos III of the Spanish Ministry of Health and HL-29583 from the National Heart, Lung, and Blood Institute, NIH, USA (ZLA and CAA). JRB, BC and GPN are FIS researchers supported by the Spanish Ministry of Health Fellowships no. 99/3076, 03/0062 and 03/0064, respectively. AMP is supported by a predoctoral fellowship from the University of the Basque Country.

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Author notes

  1. J R Bilbao and B Calvo: These authors have equally contributed to this work.

Authors and Affiliations

  1. Endocrinology and Diabetes Research Group, Hospital de Cruces, Bizkaia, Barakaldo, Spain

    J R Bilbao, B Calvo, A Martin-Pagola, G Perez de Nanclares, I Rica, J C Vitoria, S Gaztambide & L Castaño

  2. Department of Nursing, University of the Basque Country, Bilbao, Spain

    J R Bilbao

  3. CIC Biogune Research Center, Derio, Bizkaia, Spain

    A M Aransay

  4. Barbara Davis Center for Childhood Diabetes, Aurora, CO, USA

    T A Aly & P R Fain

  5. Department of Pediatrics, University of the Basque Country, Bilbao, Spain

    J C Vitoria & L Castaño

  6. Department of Medicine, University of the Basque Country, Bilbao, Spain

    S Gaztambide

  7. The Children's Hospital Oakland Research Institute, Oakland, CA, USA

    J Noble

  8. The CBR Institute for Biomedical Research, Boston, MA, USA

    Z L Awdeh & C A Alper

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  1. J R Bilbao
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  2. B Calvo
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  4. A Martin-Pagola
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  8. J C Vitoria
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  11. P R Fain
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  12. Z L Awdeh
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  13. C A Alper
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  14. L Castaño
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Corresponding author

Correspondence to L Castaño.

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Bilbao, J., Calvo, B., Aransay, A. et al. Conserved extended haplotypes discriminate HLA-DR3-homozygous Basque patients with type 1 diabetes mellitus and celiac disease. Genes Immun 7, 550–554 (2006). https://doi.org/10.1038/sj.gene.6364328

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  • DOI: https://doi.org/10.1038/sj.gene.6364328

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