Islet Autoantibody Level Distribution in Type 1 Diabetes and Their Association With Genetic and Clinical Characteristics

Abstract Context The importance of the autoantibody level at diagnosis of type 1 diabetes (T1D) is not clear. Objective We aimed to assess the association of glutamate decarboxylase (GADA), islet antigen-2 (IA-2A), and zinc transporter 8 (ZnT8A) autoantibody levels with clinical and genetic characte...

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Published in:	The journal of clinical endocrinology and metabolism 2022-12, Vol.107 (12), p.e4341-e4349
Main Authors:	Grace, Sian Louise, Bowden, Jack, Walkey, Helen C, Kaur, Akaal, Misra, Shivani, Shields, Beverley M, McKinley, Trevelyan J, Oliver, Nick S, McDonald, Timothy J, Johnston, Desmond G, Jones, Angus G, Patel, Kashyap A
Format:	Article
Language:	eng
Subjects:	Autoantibodies Autoimmunity Clinical Enzyme-linked immunosorbent assay Enzymes Genetic aspects Genetic research Glutamate Glutamate decarboxylase Hemoglobin Histocompatibility antigens HLA histocompatibility antigens
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Summary:	Abstract Context The importance of the autoantibody level at diagnosis of type 1 diabetes (T1D) is not clear. Objective We aimed to assess the association of glutamate decarboxylase (GADA), islet antigen-2 (IA-2A), and zinc transporter 8 (ZnT8A) autoantibody levels with clinical and genetic characteristics at diagnosis of T1D. Methods We conducted a prospective, cross-sectional study. GADA, IA-2A, and ZnT8A were measured in 1644 individuals with T1D at diagnosis using radiobinding assays. Associations between autoantibody levels and the clinical and genetic characteristics for individuals were assessed in those positive for these autoantibodies. We performed replication in an independent cohort of 449 people with T1D. Results GADA and IA-2A levels exhibited a bimodal distribution at diagnosis. High GADA level was associated with older age at diagnosis (median 27 years vs 19 years, P = 9 × 10−17), female sex (52% vs 37%, P = 1 × 10−8), other autoimmune diseases (13% vs 6%, P = 3 × 10−6), and HLA-DR3-DQ2 (58% vs 51%, P = .006). High IA-2A level was associated with younger age of diagnosis (median 17 years vs 23 years, P = 3 × 10−7), HLA-DR4-DQ8 (66% vs 50%, P = 1 × 10−6), and ZnT8A positivity (77% vs 52%, P = 1 × 10−15). We replicated our findings in an independent cohort of 449 people with T1D where autoantibodies were measured using enzyme-linked immunosorbent assays. Conclusion Islet autoantibody levels provide additional information over positivity in T1D at diagnosis. Bimodality of GADA and IA-2A autoantibody levels highlights the novel aspect of heterogeneity of T1D. This may have implications for T1D prediction, treatment, and pathogenesis.
ISSN:	0021-972X 1945-7197