Genetic contribution to the divergence in type 1 diabetes risk between children from the general population and children from affected families

Research output: Contribution to journalArticle


The risk for autoimmunity and subsequently type 1 diabetes is 10-fold higher in children with a first-degree family history of type 1 diabetes (FDR children) than in children in the general population (GP children). We analyzed children with high-risk HLA genotypes (n = 4,573) in the longitudinal TEDDY birth cohort to determine how much of the divergent risk is attributable to genetic enrichment in affected families. Enrichment for susceptible genotypes of multiple type 1 diabetes–associated genes and a novel risk gene, BTNL2, was identified in FDR children compared with GP children. After correction for genetic enrichment, the risks in the FDR and GP children converged but were not identical for multiple islet autoantibodies (hazard ratio [HR] 2.26 [95% CI 1.6–3.02]) and for diabetes (HR 2.92 [95% CI 2.05–4.16]). Convergence varied depending upon the degree of genetic susceptibility. Risks were similar in the highest genetic susceptibility group for multiple islet autoantibodies (14.3% vs .12.7%) and diabetes (4.8% vs. 4.1%) and were up to 5.8-fold divergent for children in the lowest genetic susceptibility group, decreasing incrementally in GP children but not in FDR children. These findings suggest that additional factors enriched within affected families preferentially increase the risk of autoimmunity and type 1 diabetes in lower genetic susceptibility strata.


  • Markus Hippich
  • Andreas Beyerlein
  • William A. Hagopian
  • Jeffrey P. Krischer
  • Kendra Vehik
  • Jan Knoop
  • Christiane Winker
  • Jorma Toppari
  • Åke Lernmark
  • Marian J. Rewers
  • Andrea K. Steck
  • Jin Xiong She
  • Beena Akolkar
  • Catherine C. Robertson
  • Suna Onengut-Gumuscu
  • Stephen S. Rich
  • Ezio Bonifacio
  • Anette G. Ziegler
  • TEDDY Study Group
External organisations
  • Helmholtz Zentrum München
  • Klinikum rechts der Isar
  • Pacific Northwest Diabetes Research Institute
  • Turku University Hospital
  • University of Colorado
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • University of Virginia
  • Dresden University of Technology
  • University of South Florida
  • University of Turku
  • Augusta University
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
Original languageEnglish
Pages (from-to)847-857
Number of pages11
Issue number4
Publication statusPublished - 2019
Publication categoryResearch