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Islet Autoimmunity and HLA Markers of Presymptomatic and Clinical Type 1 Diabetes: Joint Analyses of Prospective Cohort Studies in Finland, Germany, Sweden, and the U.S.

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posted on 25.06.2021, 14:31 by Vibha Anand, Ying Li, Bin Liu, Mohamed Ghalwash, Eileen Koski, Kenney Ng, Jessica L. Dunne, Josefine Jönsson, Christiane Winkler, Mikael Knip, Jorma Toppari, Jorma Ilonen, Michael B. Killian, Brigitte I. Frohnert, Markus Lundgren, Anette-Gabriele Ziegler, William Hagopian, Riitta Veijola, Marian Rewers, the T1DI Study Group
OBJECTIVE: To combine prospective cohort studies, by including HLA harmonization, and to estimate risk of islet autoimmunity and progression to clinical diabetes.

RESEARCH DESIGN AND METHODS: Prospective cohorts in Finland, Germany, Sweden and the US have followed 24,662 children at increased genetic risk for development of islet autoantibodies and type 1 diabetes. Following harmonization, the outcomes were analyzed in 16,709 infants-toddlers enrolled by age 2.5 years.

RESULTS: In the infant-toddler cohort, 1413 (8.5%) developed at least one autoantibody confirmed at two or more consecutive visits (seroconversion), 865 (5%) developed multiple autoantibodies, and 655 (4%) progressed to diabetes. The 15-year cumulative incidence of diabetes varied in children with one, two or three autoantibodies at seroconversion: 45% (95% CI 40-52%), 85% (78-90%), and 92% (85-97%), respectively. Among those with single autoantibody, their status two years after seroconversion predicted diabetes risk: 12% (10-25%) if reverting to autoantibody negative, 30% (20-40%) if retaining single autoantibody, and 82% (80-95%) if developing multiple autoantibodies. HLA-DR-DQ affected the risk of confirmed seroconversion and progression to diabetes in children with stable single autoantibody. Their 15-year diabetes incidence for higher vs. lower risk genotypes was 40% (28-50%) vs. 12% (5-38%). The rate of progression to diabetes was inversely related to age at development of multiple autoantibodies ranging from 20%/year to 6%/year in children developing multi-positivity ≤2 years or >7.4 years, respectively.

CONCLUSIONS: The number of islet autoantibodies at seroconversion reliably predicts 15-year type 1 diabetes risk. In children retaining single autoantibody, HLA-DR-DQ genotypes can further refine risk of progression.

Funding

This work was supported by funding from JDRF (IBM: 1-RSC-2017-368-I-X, 1-IND-2019-717-I-X), (DAISY: 1-SRA-2019-722-I-X, 1-RSC-2017-517-I-X, 5-ECR-2017-388-A-N), (DiPiS: 1-SRA-2019-720-I-X, 1-RSC-2017-526-I-X), (DIPP: 1-RSC-2018-555-I-X), (DEW-IT: 1-SRA-2019-719-I-X, 1-RSC-2017-516-I-X) as well as NIH (DAISY: DK032493, DK032083, DK104351; and DK116073; DiPiS: DK26190 and the CDC (DEW-IT: UR6/CCU017247). The DIPP study was funded by JDRF (grants 1-SRA-2016-342-M-R, 1-SRA-2019-732-M-B); European Union (grant BMH4-CT98-3314); Novo Nordisk Foundation; Academy of Finland (Decision No 292538 and Centre of Excellence in Molecular Systems Immunology and Physiology Research 2012-2017, Decision No. 250114); Special Research Funds for University Hospitals in Finland; Diabetes Research Foundation, Finland; and Sigrid Juselius Foundation, Finland. The BABYDIAB study was funded by the German Federal Ministry of Education and Research to the German Center for Diabetes Research. The DiPiS study was funded by Swedish Research Council (grant no. 14064), Swedish Childhood Diabetes Foundation, Swedish Diabetes Association, Nordisk Insulin Fund, SUS funds, Lion Club International, district 101-S, The royal Physiographic society, Skåne County Council Foundation for Research and Development as well as LUDC-IRC/EXODIAB funding from the Swedish foundation for strategic research (Dnr IRC15-0067) and Swedish research council (Dnr 2009-1039). Additional funding for DEW-IT was provided by the Hussman Foundation and by the Washington State Life Science Discovery Fund.

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