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

The TEDDY study group

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)847-857
Number of pages11
JournalDiabetes
Volume68
Issue number4
DOIs
StatePublished - Apr 1 2019

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Type 1 Diabetes Mellitus
Population
Genetic Predisposition to Disease
Autoimmunity
Autoantibodies
Genotype
Genes
Parturition

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Genetic contribution to the divergence in type 1 diabetes risk between children from the general population and children from affected families. / The TEDDY study group.

In: Diabetes, Vol. 68, No. 4, 01.04.2019, p. 847-857.

Research output: Contribution to journalArticle

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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.",
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T1 - Genetic contribution to the divergence in type 1 diabetes risk between children from the general population and children from affected families

AU - The TEDDY study group

AU - Hippich, Markus

AU - Beyerlein, Andreas

AU - Hagopian, William A.

AU - Krischer, Jeffrey P.

AU - Vehik, Kendra

AU - Knoop, Jan

AU - Winker, Christiane

AU - Toppari, Jorma

AU - Lernmark, Åke

AU - Rewers, Marian J.

AU - Steck, Andrea K.

AU - She, Jin Xiong

AU - She, Jin-Xiong

AU - Robertson, Catherine C.

AU - Onengut-Gumuscu, Suna

AU - Rich, Stephen S.

AU - Bonifacio, Ezio

AU - Ziegler, Anette G.

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N2 - 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.

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