High-affinity ZnT8 autoantibodies by electrochemiluminescence assay improve risk prediction for type 1 diabetes.

BACKGROUND The risk of progression to type 1 diabetes (T1D) in subjects positive only for ZnT8 autoantibody (ZnT8A) is currently not known. METHODS We developed an electrochemiluminescence (ECL) assay to detect high-affinity ZnT8A and validated it in three populations: 302 patients newly diagnosed with T1D, 135 non-diabetic children positive for ZnT8A by standard radio-binding assay (RBA) among 23400 children screened by the Autoimmunity Screening for Kids (ASK), and 123 non-diabetic children multiple autoantibody positive or single ZnT8A positive by RBA participating in the Diabetes Autoimmunity Study in the Young (DAISY). RESULTS In 302 patients with T1D at diagnosis, the positivity for ZnT8A was 62% in both RBA and ECL. Among ASK 135 participants positive for RBA-ZnT8A, 64 were detected ZnT8A as the only islet autoantibody. Of these 64, only 9 were confirmed by ECL-ZnT8A, found to be of high affinity with increased T1D risk. Overall positive predictive value of ECL-ZnT8A for T1D risk was 87.1%, significantly higher than that of RBA-ZnT8A (53.5%, P<0.0001). In DAISY, 11/2547 children who had no positivity previously detected for other islet autoantibodies were identified as single ZnT8A by RBA; of these, three were confirmed positive by ECL-ZnT8A and all three progressed to clinical T1D. CONCLUSIONS Large proportion of ZnT8A by RBA are single ZnT8A with low T1D risk while ZnT8A by ECL were of high-affinity and high prediction for T1D development.