Jody Ye1, Anna E Long1, James A Pearson1, Hazel Taylor2, Polly J Bingley1, Alistair J K Williams1, Kathleen M Gillespie3. 1. Diabetes and Metabolism, School of Clinical Sciences, University of Bristol, Level 2 Learning and Research Building, Southmead Hospital, Bristol, BS10 5NB, UK. 2. Research Design Service-South West, Education Centre, University Hospitals Bristol NHS Foundation Trust, Bristol, UK. 3. Diabetes and Metabolism, School of Clinical Sciences, University of Bristol, Level 2 Learning and Research Building, Southmead Hospital, Bristol, BS10 5NB, UK. k.m.gillespie@bristol.ac.uk.
Abstract
AIMS/HYPOTHESIS: The rate of progression from islet autoimmunity to clinical type 1 diabetes depends on the rate of beta cell destruction. The HLA-A*24 gene is associated with early diabetes onset, but previous studies have shown attenuated humoral responses to islet antigens in individuals with both recent and long-standing type 1 diabetes carrying HLA-A*24. We aimed to establish whether HLA-A*24 is also associated with attenuated humoral responses in individuals at high risk of type 1 diabetes. METHODS: We established HLA-A*24, DQ and rs9258750 (an HLA-A*24 tagged single-nucleotide polymorphism) genotype, as well as GAD, zinc transporter 8 (ZnT8), insulin, islet antigen-2 (IA-2), and IA-2β autoantibody status in 373 islet cell antibody-positive first-degree relatives participating in the European Nicotinamide Diabetes Intervention Trial. RESULTS: Univariate regression analyses showed that humoral responses to GAD, ZnT8 and insulin were less common in relatives carrying HLA-A*24. The prevalence of GAD and ZnT8 autoantibodies remained negatively associated with HLA-A*24 and rs9258750 after adjusting for age, sex, proband relationship and HLA class II genotype. CONCLUSIONS/ INTERPRETATION: HLA-A*24 is associated with attenuated humoral responses in individuals at high risk of type 1 diabetes, and this may reflect a distinct phenotype of rapid beta cell loss.
AIMS/HYPOTHESIS: The rate of progression from islet autoimmunity to clinical type 1 diabetes depends on the rate of beta cell destruction. The HLA-A*24 gene is associated with early diabetes onset, but previous studies have shown attenuated humoral responses to islet antigens in individuals with both recent and long-standing type 1 diabetes carrying HLA-A*24. We aimed to establish whether HLA-A*24 is also associated with attenuated humoral responses in individuals at high risk of type 1 diabetes. METHODS: We established HLA-A*24, DQ and rs9258750 (an HLA-A*24 tagged single-nucleotide polymorphism) genotype, as well as GAD, zinc transporter 8 (ZnT8), insulin, islet antigen-2 (IA-2), and IA-2β autoantibody status in 373 islet cell antibody-positive first-degree relatives participating in the European NicotinamideDiabetes Intervention Trial. RESULTS: Univariate regression analyses showed that humoral responses to GAD, ZnT8 and insulin were less common in relatives carrying HLA-A*24. The prevalence of GAD and ZnT8 autoantibodies remained negatively associated with HLA-A*24 and rs9258750 after adjusting for age, sex, proband relationship and HLA class II genotype. CONCLUSIONS/ INTERPRETATION:HLA-A*24 is associated with attenuated humoral responses in individuals at high risk of type 1 diabetes, and this may reflect a distinct phenotype of rapid beta cell loss.
Entities:
Keywords:
Autoantibodies; HLA-A*24; Type 1 diabetes
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