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A strategy for combining minor genetic susceptibility genes to improve prediction of disease in type 1 diabetes

Genes & Immunity volume 13, pages 549–555 (2012)Cite this article

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Abstract

Genome-wide association studies have identified gene regions associated with type 1 diabetes. The aim of this study was to determine how the combined allele frequency of multiple susceptibility genes can stratify islet autoimmunity and/or type 1 diabetes risk. Children of parents with type 1 diabetes and prospectively followed from birth for the development of islet autoantibodies and diabetes were genotyped for single-nucleotide polymorphisms at 12 type 1 diabetes susceptibility genes (ERBB3, PTPN2, IFIH1, PTPN22, KIAA0350, CD25, CTLA4, SH2B3, IL2, IL18RAP, IL10 and COBL). Non-human leukocyte antigen (HLA) risk score was defined by the total number of risk alleles at these genes. Receiver operator curve analysis showed that the non-HLA gene combinations were highly effective in discriminating diabetes and most effective in children with a high-risk HLA genotype. The greatest diabetes discrimination was obtained by the sum of risk alleles for eight genes (IFIH1, CTLA4, PTPN22, IL18RAP, SH2B3, KIAA0350, COBL and ERBB3) in the HLA-risk children. Non-HLA-risk allele scores stratified risk for developing islet autoantibodies and diabetes, and progression from islet autoimmunity to diabetes. Genotyping at multiple susceptibility loci in children from affected families can identify neonates with sufficient genetic risk of type 1 diabetes to be considered for early intervention.

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Acknowledgements

We thank Annette Knopff, Stephanie Krause, Claudia Matzke, Marlon Scholz, Daniela Höfelmann, Jesse Hansen, Joanna Stock, Claudia Ramminger, Julia Schenkel, Nadine Bruckmeier, Nadja Kocher, Melanie Herbst and Ina Geisler for data collection and expert technical assistance, and Ramona Puff for laboratory management. We also thank all pediatricians and family doctors in Germany for participating in the BABYDIAB study. The work was supported by grants from the Kompetenznetz Diabetes mellitus (Competence Network for Diabetes mellitus) funded by the Federal Ministry of Education and Research (FKZ 01GI0805-07), the European Union (EP7-HEALTH-2007, DIAPREPP N202013) and the Juvenile Diabetes Research Fund (No 17-2012-16). EB is supported by the DFG Research Center and Cluster of Excellence—Center for Regenerative Therapies Dresden (FZ 111). JL is supported by the Finnish Foundation for Pediatric Research and Turku University Hospital Foundation. This study was supported in part by a grant from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD e.V.).

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Author notes

  1. E Bonifacio and A-G Ziegler: Joint senior authorship.

Authors and Affiliations

  1. Institute of Diabetes Research, Helmholtz Zentrum München and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität, München, Germany

    C Winkler, J Lempainen, P Achenbach, E Giannopoulou, M Bunk & A-G Ziegler

  2. Forschergruppe Diabetes e.V, Neuherberg, Germany

    C Winkler, P Achenbach, E Giannopoulou, M Bunk, E Bonifacio & A-G Ziegler

  3. Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Neuherberg, Germany

    J Krumsiek & F J Theis

  4. Department of Pediatrics, Immunogenetics Laboratory, University of Turku, Turku, Finland

    J Lempainen

  5. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany

    H Grallert

  6. Center for Regenerative Therapies-Dresden, Dresden University of Technology, Dresden, Germany

    E Bonifacio

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  1. C Winkler
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  2. J Krumsiek
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  8. F J Theis
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  9. E Bonifacio
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  10. A-G Ziegler
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Correspondence to E Bonifacio or A-G Ziegler.

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Winkler, C., Krumsiek, J., Lempainen, J. et al. A strategy for combining minor genetic susceptibility genes to improve prediction of disease in type 1 diabetes. Genes Immun 13, 549–555 (2012). https://doi.org/10.1038/gene.2012.36

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