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Genetic association of HLA DQB1 with CD4+CD25+high T-cell apoptosis in type 1 diabetes

Genes & Immunity volume 10, pages 334–340 (2009)Cite this article

Abstract

Type 1 diabetes (T1D) has a strong genetic component and the major locus lies in the HLA DQB1 region. We found earlier an increased apoptosis with decreased viability and function of the CD4+CD25+high T-cell subset (Treg) in human subjects with recent-onset T1D and in multiple autoantibody-positive, high at-risk individuals. Tregs normally inhibit or delay onset of T1D in animal models and increased Treg apoptosis could bring on or accelerate disease from effector T-cell-mediated destruction of insulin-producing beta cells. In this study, we test the hypothesis that HLA DQB1 genotypes are associated with increased CD4+CD25+high T-cell apoptosis. HLA DQ-based genetic risk status was significantly associated with CD4+CD25+high T-cell apoptosis, after adjustment for age, gender and phenotypic status (n=83, F=4.04 (d.f.=3), P=0.01). Unaffected, autoantibody-negative high risk HLA DQB1 control subjects showed increased CD4+CD25+high apoptosis levels compared with low risk HLA DQB1 control subjects (n=26, P=0.002), confirming that the association precedes disease. The association of specific HLA DQB1 genotypes with Treg apoptosis was also tested, showing significance for HLA DQB1*0302, DQB1*0201 and HLA DQB1*0602 alleles. Our study shows an association of HLA DQB1 genotypes with CD4+CD25+high T-cell apoptosis, which implicates CD4+CD25+high T-cell apoptosis as a new intermediate trait for T1D.

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Acknowledgements

The authors thank Karen Zeqiri, Hope Albertz, Jeffrey Woodliff and Corbett Reinbold for technical support. This project was funded by the Children's Hospital of Wisconsin, Clinical Research Institute and General Clinical Research Center grant M01 RR00058 from the National Center for Research Resources, National Institutes of Health. The funding source did not have any role in study design, collection of data, analysis and interpretation of results. The authors declare no competing interests.

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Authors and Affiliations

  1. Department of Pediatrics, Max McGee National Center for Juvenile Diabetes and Human Molecular Genetic Center, Medical College of Wisconsin, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI, USA

    S Glisic, M Klinker, J Waukau, P Jailwala, S Jana, J Basken & S Ghosh

  2. Division of Biostatistics and Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI, USA

    T Wang

  3. Department of Pediatric Endocrinology and Metabolism, Children's Hospital of Wisconsin Diabetes Center, Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, WI, USA

    R Alemzadeh

  4. Pacific Northwest Diabetes Research Institute, Seattle, WA, USA

    W Hagopian

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  1. S Glisic
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Correspondence to S Ghosh.

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

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Glisic, S., Klinker, M., Waukau, J. et al. Genetic association of HLA DQB1 with CD4+CD25+high T-cell apoptosis in type 1 diabetes. Genes Immun 10, 334–340 (2009). https://doi.org/10.1038/gene.2009.14

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