Journal
DIABETES CARE
Volume 43, Issue 9, Pages 2066-2073Publisher
AMER DIABETES ASSOC
DOI: 10.2337/dc19-2547
Keywords
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Categories
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases [U01-DK-63829, U01-DK-63861, U01-DK-63821, U01-DK-63865]
- National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases [HHSN267200700014C]
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
- National Institute of Environmental Health Sciences
- JDRF
- Centers for Disease Control and Prevention
- National Institutes of Health National Center for Advancing Translational Sciences Clinical and Translational Science Awards [UL1-TR-000064, UL1-TR-001082]
- [U01-DK-63863]
- [U01-DK-63836]
- [U01-DK-63790]
- [U01-DK-100238]
- [U01-DK-106955]
- [U01-DK-112243]
- [U01-DK-117483]
- [U01-DK-95300]
- [UC4-DK-63829]
- [UC4-DK-63861]
- [UC4-DK-63821]
- [UC4-DK-63865]
- [UC4-DK-63863]
- [UC4-DK-63836]
- [UC4-DK-95300]
- [UC4-DK-100238]
- [UC4-DK-106955]
- [UC4-DK-112243]
- [UC4-DK-117483]
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OBJECTIVE The first-appearing beta-cell autoantibody has been shown to influence risk of type 1 diabetes (T1D). Here, we assessed the risk of autoantibody spreading to the second-appearing autoantibody and further progression to clinical disease in The Environmental Determinants of Diabetes in the Young (TEDDY) study. RESEARCH DESIGN AND METHODS Eligible children with increased HLA-DR-DQ genetic risk for T1D were followed quarterly from age 3 months up to 15 years for development of a single first-appearing autoantibody (GAD antibody [GADA], insulin autoantibody [IAA], or insulinoma antigen-2 autoantibody [IA-2A]) and subsequent development of a single second-appearing autoantibody and progression to T1D. Autoantibody positivity was defined as positivity for a specific autoantibody at two consecutive visits confirmed in two laboratories. Zinc transporter 8 autoantibody (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 hazard ratio [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 T1D compared with children who remained positive for a single autoantibody, e.g., 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), or 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 T1D as compared with 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 T1D. CONCLUSIONS The hierarchical order of distinct autoantibody spreading was independent of the first-appearing autoantibody type and was age-dependent and augmented the risk of progression to T1D.
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