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

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.