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Genetic scores to stratify risk of developing multiple islet autoantibodies and type 1 diabetes : A prospective study in children

Bonifacio, Ezio ; Beyerlein, Andreas ; Hippich, Markus ; Winkler, Christiane ; Vehik, Kendra LU ; Weedon, Michael N. ; Laimighofer, Michael ; Hattersley, Andrew T. ; Krumsiek, Jan and Frohnert, Brigitte I. , et al. (2018) In PLoS Medicine 15(4).
Abstract

Background: Around 0.3% of newborns will develop autoimmunity to pancreatic beta cells in childhood and subsequently develop type 1 diabetes before adulthood. Primary prevention of type 1 diabetes will require early intervention in genetically at-risk infants. The objective of this study was to determine to what extent genetic scores (two previous genetic scores and a merged genetic score) can improve the prediction of type 1 diabetes. Methods and findings: The Environmental Determinants of Diabetes in the Young (TEDDY) study followed genetically at-risk children at 3- to 6-monthly intervals from birth for the development of islet autoantibodies and type 1 diabetes. Infants were enrolled between 1 September 2004 and 28 February 2010 and... (More)

Background: Around 0.3% of newborns will develop autoimmunity to pancreatic beta cells in childhood and subsequently develop type 1 diabetes before adulthood. Primary prevention of type 1 diabetes will require early intervention in genetically at-risk infants. The objective of this study was to determine to what extent genetic scores (two previous genetic scores and a merged genetic score) can improve the prediction of type 1 diabetes. Methods and findings: The Environmental Determinants of Diabetes in the Young (TEDDY) study followed genetically at-risk children at 3- to 6-monthly intervals from birth for the development of islet autoantibodies and type 1 diabetes. Infants were enrolled between 1 September 2004 and 28 February 2010 and monitored until 31 May 2016. The risk (positive predictive value) for developing multiple islet autoantibodies (pre-symptomatic type 1 diabetes) and type 1 diabetes was determined in 4,543 children who had no first-degree relatives with type 1 diabetes and either a heterozygous HLA DR3 and DR4-DQ8 risk genotype or a homozygous DR4-DQ8 genotype, and in 3,498 of these children in whom genetic scores were calculated from 41 single nucleotide polymorphisms. In the children with the HLA risk genotypes, risk for developing multiple islet autoantibodies was 5.8% (95% CI 5.0%–6.6%) by age 6 years, and risk for diabetes by age 10 years was 3.7% (95% CI 3.0%–4.4%). Risk for developing multiple islet autoantibodies was 11.0% (95% CI 8.7%–13.3%) in children with a merged genetic score of >14.4 (upper quartile; n = 907) compared to 4.1% (95% CI 3.3%–4.9%, P < 0.001) in children with a genetic score of ≤14.4 (n = 2,591). Risk for developing diabetes by age 10 years was 7.6% (95% CI 5.3%–9.9%) in children with a merged score of >14.4 compared with 2.7% (95% CI 1.9%–3.6%) in children with a score of ≤14.4 (P < 0.001). Of 173 children with multiple islet autoantibodies by age 6 years and 107 children with diabetes by age 10 years, 82 (sensitivity, 47.4%; 95% CI 40.1%–54.8%) and 52 (sensitivity, 48.6%, 95% CI 39.3%–60.0%), respectively, had a score >14.4. Scores were higher in European versus US children (P = 0.003). In children with a merged score of >14.4, risk for multiple islet autoantibodies was similar and consistently >10% in Europe and in the US; risk was greater in males than in females (P = 0.01). Limitations of the study include that the genetic scores were originally developed from case–control studies of clinical diabetes in individuals of mainly European decent. It is, therefore, possible that it may not be suitable to all populations. Conclusions: A type 1 diabetes genetic score identified infants without family history of type 1 diabetes who had a greater than 10% risk for pre-symptomatic type 1 diabetes, and a nearly 2-fold higher risk than children identified by high-risk HLA genotypes alone. This finding extends the possibilities for enrolling children into type 1 diabetes primary prevention trials.

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PLoS Medicine
volume
15
issue
4
article number
e1002548
publisher
Public Library of Science (PLoS)
external identifiers
  • pmid:29614081
  • scopus:85046033349
ISSN
1549-1676
DOI
10.1371/journal.pmed.1002548
language
English
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yes
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fc25a019-7a2f-4589-a599-b2f1806a6e9e
date added to LUP
2018-05-22 08:21:31
date last changed
2024-04-15 06:58:18
@article{fc25a019-7a2f-4589-a599-b2f1806a6e9e,
  abstract     = {{<p>Background: Around 0.3% of newborns will develop autoimmunity to pancreatic beta cells in childhood and subsequently develop type 1 diabetes before adulthood. Primary prevention of type 1 diabetes will require early intervention in genetically at-risk infants. The objective of this study was to determine to what extent genetic scores (two previous genetic scores and a merged genetic score) can improve the prediction of type 1 diabetes. Methods and findings: The Environmental Determinants of Diabetes in the Young (TEDDY) study followed genetically at-risk children at 3- to 6-monthly intervals from birth for the development of islet autoantibodies and type 1 diabetes. Infants were enrolled between 1 September 2004 and 28 February 2010 and monitored until 31 May 2016. The risk (positive predictive value) for developing multiple islet autoantibodies (pre-symptomatic type 1 diabetes) and type 1 diabetes was determined in 4,543 children who had no first-degree relatives with type 1 diabetes and either a heterozygous HLA DR3 and DR4-DQ8 risk genotype or a homozygous DR4-DQ8 genotype, and in 3,498 of these children in whom genetic scores were calculated from 41 single nucleotide polymorphisms. In the children with the HLA risk genotypes, risk for developing multiple islet autoantibodies was 5.8% (95% CI 5.0%–6.6%) by age 6 years, and risk for diabetes by age 10 years was 3.7% (95% CI 3.0%–4.4%). Risk for developing multiple islet autoantibodies was 11.0% (95% CI 8.7%–13.3%) in children with a merged genetic score of &gt;14.4 (upper quartile; n = 907) compared to 4.1% (95% CI 3.3%–4.9%, P &lt; 0.001) in children with a genetic score of ≤14.4 (n = 2,591). Risk for developing diabetes by age 10 years was 7.6% (95% CI 5.3%–9.9%) in children with a merged score of &gt;14.4 compared with 2.7% (95% CI 1.9%–3.6%) in children with a score of ≤14.4 (P &lt; 0.001). Of 173 children with multiple islet autoantibodies by age 6 years and 107 children with diabetes by age 10 years, 82 (sensitivity, 47.4%; 95% CI 40.1%–54.8%) and 52 (sensitivity, 48.6%, 95% CI 39.3%–60.0%), respectively, had a score &gt;14.4. Scores were higher in European versus US children (P = 0.003). In children with a merged score of &gt;14.4, risk for multiple islet autoantibodies was similar and consistently &gt;10% in Europe and in the US; risk was greater in males than in females (P = 0.01). Limitations of the study include that the genetic scores were originally developed from case–control studies of clinical diabetes in individuals of mainly European decent. It is, therefore, possible that it may not be suitable to all populations. Conclusions: A type 1 diabetes genetic score identified infants without family history of type 1 diabetes who had a greater than 10% risk for pre-symptomatic type 1 diabetes, and a nearly 2-fold higher risk than children identified by high-risk HLA genotypes alone. This finding extends the possibilities for enrolling children into type 1 diabetes primary prevention trials.</p>}},
  author       = {{Bonifacio, Ezio and Beyerlein, Andreas and Hippich, Markus and Winkler, Christiane and Vehik, Kendra and Weedon, Michael N. and Laimighofer, Michael and Hattersley, Andrew T. and Krumsiek, Jan and Frohnert, Brigitte I. and Steck, Andrea K. and Hagopian, William A. and Krischer, Jeffrey P. and Lernmark, Åke and Rewers, Marian J. and She, Jin Xiong and Toppari, Jorma and Akolkar, Beena and Oram, Richard A. and Rich, Stephen S. and Ziegler, Anette G.}},
  issn         = {{1549-1676}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{4}},
  publisher    = {{Public Library of Science (PLoS)}},
  series       = {{PLoS Medicine}},
  title        = {{Genetic scores to stratify risk of developing multiple islet autoantibodies and type 1 diabetes : A prospective study in children}},
  url          = {{http://dx.doi.org/10.1371/journal.pmed.1002548}},
  doi          = {{10.1371/journal.pmed.1002548}},
  volume       = {{15}},
  year         = {{2018}},
}