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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

Research output: Contribution to journalArticle

  • TEDDY Study Group
  • 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
Original languageEnglish
Pages (from-to)847-857
Number of pages11
JournalDiabetes
Volume68
Issue number4
DOIs
DateAccepted/In press - 4 Jan 2019
DatePublished (current) - 1 Apr 2019

Abstract

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.

Additional information

© 2019 by the American Diabetes Association.

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