Islet autoantibody level distribution in Type 1 diabetes and their association with genetic and clinical characteristics

Positivity for islet autoantibodies is used for diagnosis of type 1 diabetes. However, the importance of the autoantibody level at diagnosis of type 1 diabetes is not clear. Here, we assessed the association of glutamate decarboxylase (GADA), islet antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A) autoantibody levels, measured using radiobinding assays, on genetic and clinical characteristics at diagnosis of 1536 participants with diabetes who were positive for these autoantibodies. We show that GADA and IA-2A levels had bimodal distributions, but ZnT8A level did not. The comparison of genetic and clinical characteristics between high and low level categories showed high GADA level was associated with older age at diagnosis, female sex and HLA-DR3-DQ2, whereas high IA-2A level was associated with younger age of diagnosis, ZnT8A positivity and HLA-DR4-DQ8. We replicated our findings in an independent cohort of 427 people with type 1 diabetes where autoantibodies were measured using enzyme-linked immunosorbent assays. In conclusion, Islet autoantibody levels provide additional information over positivity in type 1 diabetes at diagnosis. The bimodality of islet autoantibody levels highlights the novel aspect of heterogeneity of type 1 diabetes which may have implications on prediction, treatment and prognosis.Islet autoantibodies are commonly used in the diagnosis and prediction of type 1 diabetes. They are well established as the biomarkers of the underlying autoimmune pathogenesis (1). Autoantibodies to islet cell antigen (ICA), glutamate decarboxylase (GADA), islet antigen-2 (IA-2A), insulin (IAA) and zinc transporter 8 (ZnT8A) are the most commonly used islet autoantibodies at diagnosis (2). As detectable islet autoantibodies overlap between health and disease, a test is usually considered positive for a given islet autoantibody when the antibody level is higher than a 97.5–99th centile of a control population (3; 4). In routine clinical practice, quantitative islet autoantibody results are usually interpreted as positive or negative, and the level of the islet autoantibody, is not thought to be clinically meaningful.Islet autoantibody levels may provide additional information over positivity in type 1 diabetes at diagnosis. Similar to type 1 diabetes, autoantibodies to a specific antigen are commonly used for diagnosis in many other autoimmune diseases (such as TSH receptor antibodies in Graves’ disease and Rheumatoid Factor and Citrullinated Protein in rheumatoid arthritis). For Graves’ disease and rheumatoid arthritis, along with autoantibody positivity for these antigens, autoantibody level at diagnosis is associated with disease severity, prognosis and treatment success (5; 6). Multiple studies have shown a role for islet autoantibody level in the prediction of onset of type 1 diabetes, those with a higher levels of IA-2A, IAA and ICA have an increased risk of developing type 1 diabetes in at-risk populations (1; 7-9). However, it is not clear if the islet autoantibody level at diagnosis of type 1 diabetes, in addition to its interpretation as ‘positive’, is associated with the clinical phenotype similar to other autoimmune diseases.In this study, we undertook an analysis of GADA, IA-2A and ZnT8A levels at diagnosis in a large cohort of participants with type 1 diabetes, assessing the association of islet autoantibody levels on genetic and clinical characteristics at diagnosis in people with type 1 diabetes.