Identification of infants with increased type 1 diabetes genetic risk for enrollment into Primary Prevention Trials-GPPAD-02 study design and first results

Christiane Winkler^{1

2}, Florian Haupt^{1

2}, Martin Heigermoser¹, Jose Zapardiel-Gonzalo¹, Jasmin Ohli¹, Theresa Faure¹, Evdokia Kalideri¹, Angela Hommel³, Petrina Delivani³, Reinhard Berner⁴, Olga Kordonouri⁵, Frank Roloff⁵, Thekla von dem Berge⁵, Karin Lange⁶, Mariusz Oltarzewski⁷, Ryszard Glab⁷, Agnieszka Szypowska⁸, Matthew D Snape⁹, Manu Vatish¹⁰, John A Todd¹¹, Helena E Larsson^{12

13}, Anita Ramelius¹⁴, Jeanette Å Kördel¹⁴, Kristina Casteels^{15

16}, Jasmin Paulus¹⁵, Anette G Ziegler^{1

2

17}, Ezio Bonifacio³; GPPAD Study Group

Affiliations

¹ Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
² Forschergruppe Diabetes e.V. at Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
³ Faculty of Medicine, Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany.
⁴ Department of Pediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
⁵ Hannoversche Kinderheilanstalt, Kinder- und Jugendkrankenhaus AUF DER BULT, Hannover, Germany.
⁶ Department of Medical Psychology, Hannover Medical School, Hannover, Germany.
⁷ Institute of Mother and Child, Warsaw, Poland.
⁸ Department of Paediatrics, Medical University of Warsaw, Warsaw, Poland.
⁹ Department of Paediatrics, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.
¹⁰ Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford, UK.
¹¹ Nuffield Department of Medicine, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
¹² Unit for Pediatric Endocrinology, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden.
¹³ Department of Paediatrics, Skåne University Hospital, Malmö, Sweden.
¹⁴ Lund University, Lund, Sweden.
¹⁵ Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium.
¹⁶ Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
¹⁷ Forschergruppe Diabetes, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.

PMID: 31192505
PMCID: PMC6851563
DOI: 10.1111/pedi.12870

Randomized Controlled Trial

Identification of infants with increased type 1 diabetes genetic risk for enrollment into Primary Prevention Trials-GPPAD-02 study design and first results

Christiane Winkler et al. Pediatr Diabetes. 2019 Sep.

. 2019 Sep;20(6):720-727.

doi: 10.1111/pedi.12870. Epub 2019 Jun 13.

Authors

Affiliations

¹ Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
² Forschergruppe Diabetes e.V. at Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
³ Faculty of Medicine, Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany.
⁴ Department of Pediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
⁵ Hannoversche Kinderheilanstalt, Kinder- und Jugendkrankenhaus AUF DER BULT, Hannover, Germany.
⁶ Department of Medical Psychology, Hannover Medical School, Hannover, Germany.
⁷ Institute of Mother and Child, Warsaw, Poland.
⁸ Department of Paediatrics, Medical University of Warsaw, Warsaw, Poland.
⁹ Department of Paediatrics, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.
¹⁰ Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford, UK.
¹¹ Nuffield Department of Medicine, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
¹² Unit for Pediatric Endocrinology, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden.
¹³ Department of Paediatrics, Skåne University Hospital, Malmö, Sweden.
¹⁴ Lund University, Lund, Sweden.
¹⁵ Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium.
¹⁶ Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
¹⁷ Forschergruppe Diabetes, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.

PMID: 31192505
PMCID: PMC6851563
DOI: 10.1111/pedi.12870

Abstract

Primary prevention of type 1 diabetes (T1D) requires intervention in genetically at-risk infants. The Global Platform for the Prevention of Autoimmune Diabetes (GPPAD) has established a screening program, GPPAD-02, that identifies infants with a genetic high risk of T1D, enrolls these into primary prevention trials, and follows the children for beta-cell autoantibodies and diabetes. Genetic testing is offered either at delivery, together with the regular newborn testing, or at a newborn health care visits before the age of 5 months in regions of Germany (Bavaria, Saxony, Lower Saxony), UK (Oxford), Poland (Warsaw), Belgium (Leuven), and Sweden (Region Skåne). Seven clinical centers will screen around 330 000 infants. Using a genetic score based on 46 T1D susceptibility single-nucleotide polymorphisms (SNPs) or three SNPS and a first-degree family history for T1D, infants with a high (>10%) genetic risk for developing multiple beta-cell autoantibodies by the age of 6 years are identified. Screening from October 2017 to December 2018 was performed in 50 669 infants. The prevalence of high genetic risk for T1D in these infants was 1.1%. Infants with high genetic risk for T1D are followed up and offered to participate in a randomized controlled trial aiming to prevent beta-cell autoimmunity and T1D by tolerance induction with oral insulin. The GPPAD-02 study provides a unique path to primary prevention of beta-cell autoimmunity in the general population. The eventual benefit to the community, if successful, will be a reduction in the number of children developing beta-cell autoimmunity and T1D.

Keywords: beta-cell autoantibodies; genetic risk for type 1 diabetes; type 1 diabetes.

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Figures

**Figure 1**
(A) GPPAD‐02 study design and (B) Definition of increased genetic risk

**Figure 2**
Cumulative number of newborns/infants screened in the GPPAD‐02 study. Numbers are shown from the start of the study in October 2017. The red line represents the expected numbers and the blue line shows the actual number of screened infants

See this image and copyright information in PMC

References

1. Patterson CC, Harjutsalo V, Rosenbauer J, et al. Trends and cyclical variation in the incidence of childhood type 1 diabetes in 26 European centres in the 25 year period 1989‐2013: a multicentre prospective registration study. Diabetologia. 2019;62(3):408‐417. - PubMed
1. Ziegler AG, Rewers M, Simell O, et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA. 2013;309:2473‐2479. - PMC - PubMed
1. Ziegler AG, Nepom GT. Prediction and pathogenesis in type 1 diabetes. Immunity. 2010;32(4):468‐478. - PMC - PubMed
1. Bonifacio E. Predicting type 1 diabetes using biomarkers. Diabetes Care. 2015;38(6):989‐996. - PubMed
1. Bonifacio E, Beyerlein A, Hippich M, et al. Genetic scores to stratify risk of developing multiple islet autoantibodies and type 1 diabetes: a prospective study in children. PLoS Med. 2018;15(4):e1002548. - PMC - PubMed

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Identification of infants with increased type 1 diabetes genetic risk for enrollment into Primary Prevention Trials-GPPAD-02 study design and first results

Affiliations

Identification of infants with increased type 1 diabetes genetic risk for enrollment into Primary Prevention Trials-GPPAD-02 study design and first results

Authors

Affiliations

Abstract

Figures

References

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MeSH terms

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LinkOut - more resources

Full Text Sources

Medical