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Hierarchical order of distinct autoantibody spreading and progression to type 1 diabetes in the TEDDY Study

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posted on 08.07.2020 by Kendra Vehik, Ezio Bonifacio, Ake Lernmark, Liping Yu, Alistair Williams, Desmond Schatz, Marian Rewers, Jin-Xiong She, Jorma Toppari, William Hagopian, Beena Akolkar, Anette G. Ziegler, Jeffrey P. Krischer, the TEDDY Study Group
Objective: The first-appearing β-cell autoantibody has been shown to influence risk of type 1 diabetes. Here, we assessed risk of autoantibody spreading to the second-appearing autoantibody and further progression to clinical disease in the Environmental Determinants of Diabetes in the Young study.

Research Design and Methods: Eligible children with increased HLA-DR-DQ genetic risk for type 1 diabetes were followed quarterly from age 3 months up to 15 years for development of a single first-appearing autoantibody (GADA, IAA or IA-2A) and subsequent development of a single second-appearing autoantibody and progression to type 1 diabetes. Autoantibody positivity was defined as positivity for a specific autoantibody at two consecutive visits confirmed in two laboratories. ZnT8A was measured in children who developed another autoantibody.

Results: There were 608 children who developed a single first-appearing autoantibody (IAA, n=282 or GADA, n=326) with a median follow-up of 12.5 years from birth. The risk of a second-appearing autoantibody was independent of GADA versus IAA as a first-appearing autoantibody (adjusted-HR=1.12, 95%CI=0.88-1.42, P=0.36). Second-appearing GADA, IAA, IA-2A or ZnT8A conferred an increased risk of type 1 diabetes compared to children who remained single autoantibody positive (IAA- or GADA-second: adjusted-HR=6.44 95%CI=3.78-10.98; IA-2A-second: adjusted-HR=16.33 95%CI=9.10-29.29, P<0.0001; ZnT8A-second: adjusted-HR=5.35 95%CI=2.61-10.95, P<0.0001). In children who developed a distinct second autoantibody, IA-2A (adjusted-HR=3.08 95%CI=2.04-4.65, P<0.0001) conferred a greater risk of progression to type 1 diabetes as compared to GADA or IAA. Additionally, both a younger initial age at seroconversion and shorter time to the development of the second-appearing autoantibody increased the risk for type 1 diabetes.

Conclusions: The hierarchical order of distinct autoantibody spreading was independent of the first-appearing autoantibody type, age-dependent and augmented the risk of progression to type 1 diabetes.


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), National Institute of Allergy and Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Environmental Health Sciences (NIEHS), Juvenile Diabetes Research Foundation (JDRF), and Centers for Disease Control and Prevention (CDC). This work supported in part by the NIH/NCATS Clinical and Translational Science Awards to the University of Florida (UL1 TR000064) and the University of Colorado (UL1 TR001082).