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Anand, V.* ; Li, Y.* ; Liu, B.* ; Ghalwash, M.* ; Koski, E.* ; Ng, K.* ; Dunne, J.L.* ; Jönsson, J.* ; Winkler, C. ; Knip, M.* ; Toppari, J.* ; Ilonen, J.* ; Killian, M.B.* ; Frohnert, B.I.* ; Lundgren, M. ; Ziegler, A.-G. ; Hagopian, W.* ; Veijola, R.* ; Rewers, M.*

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.

Diabetes Care, DOI: 10.2337/dc20-1836 (2021)
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OBJECTIVE: To combine prospective cohort studies, by including HLA harmonization, and estimate risk of islet autoimmunity and progression to clinical diabetes. RESEARCH DESIGN AND METHODS: For prospective cohorts in Finland, Germany, Sweden, and the U.S., 24,662 children at increased genetic risk for development of islet autoantibodies and type 1 diabetes have been followed. Following harmonization, the outcomes were analyzed in 16,709 infants-toddlers enrolled by age 2.5 years. RESULTS: In the infant-toddler cohort, 1,413 (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 a single autoantibody, status 2 years after seroconversion predicted diabetes risk: 12% (10-25) if reverting to autoantibody negative, 30% (20-40) if retaining a 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 status. Their 15-year diabetes incidence for higher- versus 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% per year to 6% per year in children developing multipositivity in ≤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 a single autoantibody, HLA-DR-DQ genotypes can further refine risk of progression.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
ISSN (print) / ISBN 0149-5992
e-ISSN 1935-5548
Zeitschrift Diabetes Care
Verlag American Diabetes Association
Verlagsort Alexandria, Va.
Begutachtungsstatus Peer reviewed