The Role of Autoantibodies to Zinc Transporter 8 in Prediction of Type 1 Diabetes in Relatives: Lessons from the European Nicotinamide Diabetes Intervention Trial (ENDIT) Cohort

Context: Antibodies to islet autoantigens are detectable many years before clinical onset of type 1 diabetes and can be used to identify individuals at increased risk of diabetes. Zinc transporter 8 is a recently identified islet autoantigen. Objective: Our aim was to determine whether addition of zinc transporter 8 autoantibodies (ZnT8A) improved prediction of type 1 diabetes in a well-characterized cohort of islet cell antibody (ICA)-positive first-degree relatives. We were particularly interested in the role of ZnT8A in prediction in antibody-positive relatives with intermediate and low overall risk of diabetes. Participants and Methods: ZnT8A were assayed in baseline samples from 526 ICA-positive first-degree relatives randomized in the European Nicotinamide Diabetes Intervention Trial. Antibodies to insulin, glutamate decarboxylase, islet antigen-2 (IA-2A) and IA-2β (IA-2βA), and human leukocyte antigen type had been previously determined. Risk of diabetes was assessed by survival analysis. Results: Of 221 ZnT8A-positive individuals, 113 developed diabetes during follow-up (5-yr cumulative risk, 55%). In multivariate models based on other autoantibodies, ZnT8A improved prediction in relatives at low genetic risk of diabetes (P = 0.030) and over age 20 yr (P = 0.026), but not in those with ICA alone or with one additional autoantibody (P = 0.696), IA-2A-negative relatives (P = 0.361), those at high or intermediate genetic risk, or younger relatives. Conclusions: ZnT8A are useful additional risk markers in relatives at low genetic risk of diabetes and older individuals, but they add relatively little in younger populations because of the precise prediction possible with current autoantibody combinations.