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An Age-Related Exponential Decline in the Risk of Multiple Islet Autoantibody Seroconversion During Childhood

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posted on 01.03.2021, 15:56 by Ezio Bonifacio, Andreas Weiß, Christiane Winkler, Markus Hippich, Marian J. Rewers, Jorma Toppari, Åke Lernmark, Jin-Xiong She, William A. Hagopian, Jeffrey P. Krischer, Kendra Vehik, Desmond A. Schatz, Beena Akolkar, Anette-Gabriele Ziegler, the TEDDY Study Group
Objective. Islet autoimmunity develops prior to clinical type 1 diabetes and includes multiple and single autoantibody phenotypes. The objective was to determine age-related risks of islet autoantibodies that reflect etiology and improve screening for pre-symptomatic type 1 diabetes.

Research Design and Methods. The Environmental Determinants of Diabetes in the Young study prospectively followed 8,556 genetically at-risk children at 3–6-month intervals from birth for the development of islet autoantibodies and type 1 diabetes. The age-related change in the risk of developing islet autoantibodies was determined using landmark and regression models.

Results. The 5-year risk of developing multiple islet autoantibodies was 4.3% (95% confidence interval, 3.8–4.7) at 7.5 months of age and declined to 1.1% (95% confidence interval, 0.8–1.3) at a landmark age of 6.25 years (P<0.0001). Risk decline was slight or absent in single insulin- and GAD-autoantibody phenotypes. The influence of sex, HLA and other susceptibility genes on risk subsided with increasing age and was abrogated by age six years. Highest sensitivity and positive predictive value of multiple islet autoantibody phenotypes for type 1 diabetes was achieved by autoantibody screening at 2 years and again at 5–7 years of age.

Conclusions. The risk of developing islet autoimmunity declines exponentially with age and the influence of major genetic factors on this risk is limited to the first few years of life.

Funding

TEDDY Study was funded by U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, UC4 DK106955, UC4 DK112243, UC4 DK117483, and Contract No. HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Institute of Environmental Health Sciences (NIEHS), the Centers for Disease Control and Prevention (CDC), and the JDRF, and in part by the NIH/NCATS Clinical and Translational Science Awards to the University of Florida (UL1 TR000064) and the University of Colorado (UL1 TR002535). This work was also supported by funds from the German Federal Ministry of Education and Research (FKZ: 01KX1818) and grants awarded to the German Center for Diabetes Research (DZD e.V.).

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