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Progression from islet autoimmunity to clinical type 1 diabetes is influenced by genetic factors: results from the prospective TEDDY study
  1. Andreas Beyerlein1,
  2. Ezio Bonifacio2,3,
  3. Kendra Vehik4,
  4. Markus Hippich1,
  5. Christiane Winkler1,3,
  6. Brigitte I Frohnert5,
  7. Andrea K Steck5,
  8. William A Hagopian6,
  9. Jeffrey P Krischer4,
  10. Åke Lernmark7,
  11. Marian J Rewers5,
  12. Jin-Xiong She8,
  13. Jorma Toppari9,10,
  14. Beena Akolkar11,
  15. Stephen S Rich12,
  16. Anette-G Ziegler1,3
  17. the TEDDY Study Group
  1. 1Institute of Diabetes Research, Helmholtz Zentrum München, and Forschergruppe Diabetes, Technical University of Munich, at Klinikum rechts der Isar, Munich-Neuherberg, Germany
  2. 2DFG Center for Regenerative Therapies Dresden, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
  3. 3Forschergruppe Diabetes eV at Helmholtz Zentrum München, Munich-Neuherberg, Germany
  4. 4Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
  5. 5Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, Colorado, USA
  6. 6Pacific Northwest Diabetes Research Institute, Seattle, Washington, USA
  7. 7Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmo, Sweden
  8. 8Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
  9. 9Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, Turku University Hospital, Turku, Finland
  10. 10Department of Physiology, University of Turku, Turku, Finland
  11. 11National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA
  12. 12Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA
  1. Correspondence to Dr Anette-G Ziegler, Institute of Diabetes Research, Helmholtz Zentrum München, Munich-Neuherberg, 85764, Germany; anette-g.ziegler{at}helmholtz-muenchen.de

Abstract

Background Progression time from islet autoimmunity to clinical type 1 diabetes is highly variable and the extent that genetic factors contribute is unknown.

Methods In 341 islet autoantibody-positive children with the human leucocyte antigen (HLA) DR3/DR4-DQ8 or the HLA DR4-DQ8/DR4-DQ8 genotype from the prospective TEDDY (The Environmental Determinants of Diabetes in the Young) study, we investigated whether a genetic risk score that had previously been shown to predict islet autoimmunity is also associated with disease progression.

Results Islet autoantibody-positive children with a genetic risk score in the lowest quartile had a slower progression from single to multiple autoantibodies (p=0.018), from single autoantibodies to diabetes (p=0.004), and by trend from multiple islet autoantibodies to diabetes (p=0.06). In a Cox proportional hazards analysis, faster progression was associated with an increased genetic risk score independently of HLA genotype (HR for progression from multiple autoantibodies to type 1 diabetes, 1.27, 95% CI 1.02 to 1.58 per unit increase), an earlier age of islet autoantibody development (HR, 0.68, 95% CI 0.58 to 0.81 per year increase in age) and female sex (HR, 1.94, 95% CI 1.28 to 2.93).

Conclusions Genetic risk scores may be used to identify islet autoantibody-positive children with high-risk HLA genotypes who have a slow rate of progression to subsequent stages of autoimmunity and type 1 diabetes.

  • diabetes
  • diagnostics tests
  • epidemiology
  • immunology (including allergy)

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Footnotes

  • Contributors AB (guarantor) analysed the data and wrote the first and final draft of the manuscript together with EB and A-GZ. KV, MH, CW, BIF, AKS, WAH, JPK, ÅL, MJR, J-XS, JT, BA and SSR contributed to the interpretation of the results, reviewed the manuscript and contributed to subsequent drafts.

  • Funding This study was funded by U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, UC4 DK106955 and contract no HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Child Health and Human Development (NICHD), National Institute of Environmental Health Sciences (NIEHS), Juvenile Diabetes Research Foundation (JDRF), and the Centers for Disease Control and Prevention (CDC). This work was supported in part by the NIH/NCATS Clinical and Translational Science Awards to the University of Florida (UL1 TR000064) and the University of Colorado (UL1 TR001082).

  • Competing interests A patent has been applied for (LU100334) with the title ‘Method the risk to develop type 1 diabetes’ by Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt. EB, A-GZ and CW are among the inventors. The patent includes the genetic score that is examined in the manuscript.

  • Patient consent Not required.

  • Ethics approval The study was approved by local institutional review boards and is monitored by an external advisory board established by the US National Institutes of Health.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement The program code and the data can be provided upon reasonable request.

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