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

  • 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
Publishing year: 2019
Language: English
Pages: 847-857
Publication/Series: Diabetes
Volume: 68
Issue: 4
Document type: Journal article
Publisher: American Diabetes Association Inc.

Abstract english

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.


  • Endocrinology and Diabetes


  • Diabetes and Celiac Unit
  • ISSN: 0012-1797
E-mail: ake [dot] lernmark [at] med [dot] lu [dot] se

Principal investigator

Diabetes and Celiac Unit

+46 40 39 19 01

+46 70 616 47 79


Jan Waldenströms gata 35, Malmö


Lund University Diabetes Centre, CRC, SUS Malmö, Jan Waldenströms gata 35, House 91:12. SE-214 28 Malmö. Telephone: +46 40 39 10 00