Attenuated humoral responses in HLA-A*24-positive individuals at risk of type 1 diabetes

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.