Evolution of islet autoantibodies in the Environmental Determinants of Islet Autoimmunity (ENDIA) prospective cohort

Abstract

AIMS/HYPOTHESIS: Islet autoantibodies herald early type 1 diabetes. However, less is known of the evolution of autoantibodies to the islet autoantigen ZnT8. Our primary aim was to characterise the development of islet autoantibodies in a pregnancy-birth at-risk cohort and to provide new knowledge about ZnT8A. METHODS: Islet autoantibodies were measured every 3-6 months in 1277/1473 children with a first-degree relative with type 1 diabetes who were followed prospectively from pregnancy in the Environmental Determinants of Islet Autoimmunity (ENDIA) cohort for 7.0 (IQR 5.8-8.3) years. Islet autoantibodies were also measured in the mothers and/or in cord blood in 901 pregnancies with type 1 diabetes. RESULTS: The development of persistent IAA reached a probability of 0.02 by 2 years of age. A combination of IAA- and GADA-first, GADA-first and ZnT8A-first all reached a similar probability by 5 years of age. ZnT8A appeared as the first islet autoantibody, alone or in combination, in 43 (32%) of the 134/1473 children with persistent islet autoantibodies. Persistent single ZnT8A, detected only by ELISA, usually appeared after 4 years of age. ZnT8A that progressed to multiple islet autoantibodies or type 1 diabetes were detected in younger children (p=0.006) and in multiple assay formats. ZnT8A were confirmed in additional assay formats when present with multiple islet autoantibodies, but not when remaining as a single islet autoantibody, unlike IAA and GADA. Maternal islet GADA were detected until 15 months of age and transmission of any islet antibody/autoantibody did not relate to islet autoantibody development in the offspring (χ(2)=3.32, df=2, p=0.19). CONCLUSIONS/INTERPRETATION: Persistent single ZnT8A, which are detected only by ELISA and no other test format, appear not to confer an increased risk of progression to type 1 diabetes.