Hierarchical Order of Distinct Autoantibody Spreading and Progression to Type 1 Diabetes in the TEDDY Study

Diabetes Care. 2020 Sep;43(9):2066-2073. doi: 10.2337/dc19-2547. Epub 2020 Jul 8.

Abstract

Objective: The first-appearing β-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Autoantibodies / blood*
  • Autoantibodies / immunology
  • Child
  • Child, Preschool
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / pathology*
  • Disease Progression
  • Female
  • Follow-Up Studies
  • Genetic Predisposition to Disease
  • Glutamate Decarboxylase / immunology
  • HLA-DQ Antigens / genetics
  • HLA-DR Antigens / genetics
  • Humans
  • Infant
  • Insulin Antibodies / blood
  • Male
  • Risk Factors
  • Seroconversion / physiology*
  • Zinc Transporter 8 / immunology

Substances

  • Autoantibodies
  • HLA-DQ Antigens
  • HLA-DR Antigens
  • Insulin Antibodies
  • Zinc Transporter 8
  • Glutamate Decarboxylase

Associated data

  • figshare/10.2337/figshare.12302405