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Does a central MHC gene in linkage disequilibrium with HLA-DRB1*0401 affect susceptibility to type 1 diabetes?

Genes & Immunity volume 6, pages 298–304 (2005)Cite this article

Abstract

Subtypes of HLA-DR4 are associated with susceptibility or protection against type 1 diabetes (T1DM). We addressed whether this reflects linkage disequilibrium with the true susceptibility locus by studying broader MHC haplotypes marked by alleles of HLA-B, IKBL (adjacent to TNFA) and complement C4. The study used a largely Caucasian cohort from Western Australia. HLA-DRB1*0401 and HLA-DRB1*0405 marked susceptibility to T1DM. In Caucasians, DRB1*0401 occurs predominantly in the 44.1 ancestral haplotype (AH; HLA-A2,B44, DRB1*0401,DQB1*0301) and the 62.1AH (HLA-A2,B15(62),DRB1*0401,DQB1*0302). HLA-B15 marked susceptibility and HLA-B44 marked with resistance to T1DM in patients and controls preselected for HLA-DRB1*0401. A gene between TNFA and HLA-B on the 8.1AH (HLA-A1,B8,;DR3,DQ2) modifies the effects of the class II alleles. Here, alleles characteristic of the 62.1AH (C4B3, IKBL+446*T and HLA-A2,B15) were screened in donors preselected for HLA-DRB1*0401. C4B3 was associated with diabetes, consistent with a diabetes gene telomeric of MHC class II. However, increases in carriage of IKBL+446*T and HLA-A2,B15 were marginal, as too few control subjects were available with the diabetogenic alleles. However, with these tools, selection of HLA-DRB1*0401, DQB1*0302 donors who are positive and negative for C4B3 will allow bidirectional mapping of diabetes genes in the central MHC.191 words

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Acknowledgements

We thank the staff of the Department of Clinical Immunology and Biochemical Genetics for HLA typing and Drs Tim Jones and Kim Stanton for recruitment of patients. This is publication 2004-32 of the Department of Clinical Immunology and Biochemical Genetics (RPH).

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Authors and Affiliations

  1. Department of Clinical Immunology and Biochemical Genetics, Royal Perth Hospital, Perth, Australia

    L Windsor, M Puschendorf, A Scott, D Sayer, C Witt, F Christiansen & P Price

  2. School of Surgery and Pathology, University of Western Australia, Nedlands, Australia

    L Windsor, R Allcock, A Scott, F Christiansen & P Price

  3. Centre Nationale de Genotypage, Batiment G2, Evry, France

    R Kucharzak & I Gut

  4. Department of Endocrinology, Royal Perth Hospital, Perth, Australia

    V McCann

  5. Department of Endocrinology, Princess Margaret Hospital, Subiaco, Australia

    E Davis

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  1. L Windsor
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  10. C Witt
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Correspondence to P Price.

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Windsor, L., Puschendorf, M., Allcock, R. et al. Does a central MHC gene in linkage disequilibrium with HLA-DRB1*0401 affect susceptibility to type 1 diabetes?. Genes Immun 6, 298–304 (2005). https://doi.org/10.1038/sj.gene.6364210

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