Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 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

Ezio Bonifacio  1 , Andreas Beyerlein  2   3   4 , Markus Hippich  2   3   4 , Christiane Winkler  2   3   4 , Kendra Vehik  5 , Michael N Weedon  6 , Michael Laimighofer  7 , Andrew T Hattersley  6 , Jan Krumsiek  7 , Brigitte I Frohnert  8 , Andrea K Steck  8 , William A Hagopian  9 , Jeffrey P Krischer  5 , Åke Lernmark  10 , Marian J Rewers  8 , Jin-Xiong She  11 , Jorma Toppari  12   13 , Beena Akolkar  14 , Richard A Oram  6   15   16 , Stephen S Rich  17 , Anette-G Ziegler  2   3   4 ; TEDDY Study Group
Affiliations

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

Ezio Bonifacio et al. PLoS Med. .

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.

PubMed Disclaimer

Conflict of interest statement

I have read the journal’s policy and the authors of this manuscript have the following competing interests: A patent has been applied for (EP17178396/LU100334) with the title "Method the risk to develop type 1 diabetes" by Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH). EB, AGZ, CW and JK are one of the inventors. The patent includes the genetic score that is examined in the manuscript. RAO has a personal funding from Diabetes UK to study the biology of Type 1 diabetes (this includes a research grant to work on genetic risk scores in Type 1 diabetes). RAO has a UK Medical Research Council confidence in concept grant to turn a type 1 diabetes genetic risk score into a diagnostic test for clinical practice. AB, MH, KV, MNW, ML, ATH, BIF, AKS, WAH, JPK, AL, MJR, JXS, JT, BA, SSR have declared that no other competing interests exist.

Figures

Fig 1
Fig 1. Flow diagram of the TEDDY study participants included in this analysis.
Fig 2
Fig 2. Cumulative risks of 1 or more islet autoantibody, multiple islet autoantibody, and type 1 diabetes in TEDDY children with the HLA DR3/DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotype.
The cumulative risk for 1 or more islet autoantibodies (A), multiple islet autoantibodies (B), and type 1 diabetes (C) for TEDDY children (y-axis) is shown relative to the age of the children (x-axis) and was calculated using the Kaplan–Meier method. The shaded area represents the 95% confidence interval of the cumulative risk. The numbers at risk indicate the number of children included in the analysis at each age.
Fig 3
Fig 3. Merged genetic score in TEDDY children according to their islet autoantibody outcome, geographic location, and sex.
Islet autoantibody outcome (A); geographic location (B); sex (C). Red horizontal lines indicate the median genetic score value in each group.
Fig 4
Fig 4. Cumulative risks of 1 or more islet autoantibody, multiple islet autoantibody, and type 1 diabetes development in TEDDY children with the HLA DR3/DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotype stratified by their merged score.
The cumulative risk of developing 1 or more islet autoantibodies (A), multiple islet autoantibodies (B), and type 1 diabetes (C) (y-axis) is shown relative to age in years (x-axis) and was calculated using the Kaplan–Meier method. Curves are shown for children with genetic scores in the upper (orange line), lower (green line), and 2 middle (blue line) quartiles. The shaded areas represent the 95% confidence interval of the cumulative risk. The numbers at risk indicate the number of children included in the analysis at each age.
Fig 5
Fig 5. Cumulative risks and the proportion of cases identified for 1 or more islet autoantibodies, multiple islet autoantibodies, and type 1 diabetes in TEDDY children with the HLA DR3/DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotype according to increasing thresholds of the merged genetic score.
Cumulative risk for developing islet autoantibodies by age 6 years and diabetes by age 10 years (A) and the proportion of cases positive for islet autoantibodies by age 6 years and diabetes by age 10 years (sensitivity; B) in TEDDY children with the HLA DR3/DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotype stratified by their merged genetic score. The risk and sensitivity are shown for each increment in the genetic score by the 5th percentile of scores in the TEDDY children, ranging from >12.1 (the 5th percentile of children) to >15.4 (the 95th percentile of children). The risk and sensitivity are shown for the development of 1 or more islet autoantibodies (left panels), multiple islet autoantibodies (middle panels), and type 1 diabetes (right panels). Error bars indicate 95% confidence intervals.
See this image and copyright information in PMC

References

    1. Du Toit G, Roberts G, Sayre PH, Bahnson HT, Radulovic S, Santos AF, et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med. 2015;372:803–13. doi: 10.1056/NEJMoa1414850 - DOI - PMC - PubMed
    1. Krischer JP, Lynch KF, Schatz DA, Ilonen J, Lernmark Å, Hagopian WA, et al. The 6 year incidence of diabetes-associated autoantibodies in genetically at-risk children: the TEDDY study. Diabetologia. 2015;58:980–7. doi: 10.1007/s00125-015-3514-y - DOI - PMC - PubMed
    1. Knip M, Åkerblom HK, Becker D, Dosch HM, Dupre J, Fraser W, et al. Hydrolyzed infant formula and early β-cell autoimmunity: a randomized clinical trial. JAMA. 2014;311:2279–87. doi: 10.1001/jama.2014.5610 - DOI - PMC - PubMed
    1. Bonifacio E, Ziegler AG, Klingensmith G, Schober E, Bingley PJ, Rottenkolber M, et al. Effects of high dose oral insulin on immune responses in children at high risk for type 1 diabetes: the Pre-POINT randomized clinical trial. JAMA. 2015;313:1541–9. doi: 10.1001/jama.2015.2928 - DOI - PubMed
    1. Vriezinga SL, Auricchio R, Bravi E, Castillejo G, Chmielewska A, Crespo Escobar P, et al. Randomized feeding intervention in infants at high risk for celiac disease. N Engl J Med. 2014;371(14):1304–15. doi: 10.1056/NEJMoa1404172 - DOI - PubMed

Publication types