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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

, ; Hippich, Markus; Beyerlein, Andreas; Hagopian, William A.; Krischer, Jeffrey P.; Vehik, Kendra LU ; Knoop, Jan; Winker, Christiane; Toppari, Jorma and Lernmark, Åke LU , et al. (2019) In Diabetes 68(4). p.847-857
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... (More)

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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Contribution to journal
publication status
published
subject
in
Diabetes
volume
68
issue
4
pages
11 pages
publisher
American Diabetes Association Inc.
external identifiers
  • scopus:85063639692
ISSN
0012-1797
DOI
10.2337/db18-0882
language
English
LU publication?
yes
id
12eabb8e-bafe-4699-be1c-b06e0c545e62
date added to LUP
2019-04-09 14:37:23
date last changed
2019-04-30 04:10:53
@article{12eabb8e-bafe-4699-be1c-b06e0c545e62,
  abstract     = {<p>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.</p>},
  author       = {,  and Hippich, Markus and Beyerlein, Andreas and Hagopian, William A. and Krischer, Jeffrey P. and Vehik, Kendra and Knoop, Jan and Winker, Christiane and Toppari, Jorma and Lernmark, Åke and Rewers, Marian J. and Steck, Andrea K. and She, Jin Xiong and Akolkar, Beena and Robertson, Catherine C. and Onengut-Gumuscu, Suna and Rich, Stephen S. and Bonifacio, Ezio and Ziegler, Anette G.},
  issn         = {0012-1797},
  language     = {eng},
  number       = {4},
  pages        = {847--857},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {Genetic contribution to the divergence in type 1 diabetes risk between children from the general population and children from affected families},
  url          = {http://dx.doi.org/10.2337/db18-0882},
  volume       = {68},
  year         = {2019},
}