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PLoS Med. 2018 Apr 3;15(4):e1002548. doi: 10.1371/journal.pmed.1002548. eCollection 2018 Apr.

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

Author information

1
DFG-Center for Regenerative Therapies Dresden, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
2
Institute of Diabetes Research, Helmholtz Zentrum München, Munich, Germany.
3
Forschergruppe Diabetes, Technical University of Munich, Klinikum Rechts der Isar, Munich, Germany.
4
Forschergruppe Diabetes e.V. at Helmholtz Zentrum München, Munich, Germany.
5
Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America.
6
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, United Kingdom.
7
Institute of Computational Biology, Helmholtz Zentrum München, Munich, Germany.
8
Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado, United States of America.
9
Pacific Northwest Diabetes Research Institute, Seattle, Washington, United States of America.
10
Department of Clinical Sciences, Clinical Research Centre, Skåne University Hospital, Lund University, Malmo, Sweden.
11
Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia, United States of America.
12
Department of Pediatrics, Turku University Hospital, Turku, Finland.
13
Department of Physiology, University of Turku, Turku, Finland.
14
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
15
Clinical Islet Transplant Program, University of Alberta, Edmonton, Alberta, Canada.
16
National Institute for Health Research, Exeter Clinical Research Facility, Exeter, United Kingdom.
17
Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, United States of America.

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 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.

PMID:
29614081
PMCID:
PMC5882115
DOI:
10.1371/journal.pmed.1002548
[Indexed for MEDLINE]
Free PMC Article

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