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Exploring the diabetogenicity of the HLA-B18-DR3 CEH: independent association with T1D genetic risk close to HLA-DOA

Genes & Immunity volume 10, pages 596–600 (2009)Cite this article

Abstract

The objective of this study was to identify additional diabetes susceptibility markers in the MHC that could be responsible for the differential diabetogenicity of different HLA-DR3 CEHs. High-resolution SNP genotyping of the MHC was carried out in 15 type 1 diabetes (T1D) patients and 39 non-diabetic controls, homozygous for DR3-DQ2 and with one copy of the A*30-B*18-MICA*4-F1C30-DRB1*0301-DQB1*0201-DPB1*0202 HLA haplotype. Significantly associated SNPs were replicated in an independent sample of 554 T1D patients and 841 controls without HLA matching. Electrophoretic mobility shift assay was used to show a functional effect of an associated SNP. Seven SNPs showed evidence of association in the initial discovery experiment. Upon replication, only rs419434 (upstream HLA-DOA gene) remained significant. A functional variant (rs432375) in complete LD with rs419434 was shown to affect USF-1 binding and could be responsible for the association signal in the region. We have identified a new susceptibility locus within the MHC with a modest contribution to T1D (OR=1.93; CI: 1.52–2.44; P=10−8) that is independent of HLA-DRB1 locus.

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Acknowledgements

This work was partially funded by CIBER de Diabetes y Enfermedades metabólicas (CIBERDEM) and Research Project grants 05/2291 from Instituto de Salud Carlos III (LC) and 2005/111039 from the Basque Department of Health (AMA). IS and AC-R are predoctoral fellows supported by grants from the University of the Basque Country and the Spanish Ministry of Education, respectively. JRB is co-funded by the I3SNS Program of the Spanish Ministry of Health (CES05/036).

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Author notes

  1. L Castaño and J R Bilbao: These authors contributed equally to this work.

Authors and Affiliations

  1. Endocrinology and Diabetes Research Group—CIBERDEM, Hospital de Cruces and University of the Basque Country School of Medicine, Bilbao, Spain

    I Santin, A Castellanos-Rubio, G Gutierrez, S Gaztambide, I Rica, L Castaño & J R Bilbao

  2. CIC bioGUNE Research Center, Derio, Bizkaia, Spain,

    A M Aransay

  3. Histocompatibility Department, Centro de Transfusiones de la Comunidad de Madrid, Madrid, Spain

    J L Vicario

  4. Children's Hospital Oakland Research Institute, Oakland, CA, USA

    J A Noble

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  1. I Santin
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  2. A Castellanos-Rubio
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  3. A M Aransay
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  4. G Gutierrez
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  6. I Rica
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  7. J L Vicario
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  8. J A Noble
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  9. L Castaño
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  10. J R Bilbao
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Corresponding authors

Correspondence to L Castaño or J R Bilbao.

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

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Santin, I., Castellanos-Rubio, A., Aransay, A. et al. Exploring the diabetogenicity of the HLA-B18-DR3 CEH: independent association with T1D genetic risk close to HLA-DOA. Genes Immun 10, 596–600 (2009). https://doi.org/10.1038/gene.2009.41

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