High titre and older age-at-onset are predictors of persistent autoantibody responses to major autoantigens in type 1diabetes modulated by HLA variants

Aim: Autoantibody persistence after diagnosis may reflect ongoing beta cell destruction, but little is known about the factors influencing this. In individuals with type 1 diabetes followed prospectively, we investigated genetic and non-genetic determinants of autoantibody persistence, considering three major autoantibodies to glutamate decarboxylase (GADA), islet antigen 2 (IA-2A), and zinc transporter 8 (ZnT8A). Methods: In total, 583 individuals with type 1 diabetes [324 males; median age at onset 10.73 years (0.74-54.6 years)] who had a diagnosis sample [median 0 years (-1-2 years)] and at least one sample post-diagnosis (2-32.2 years) were tested for GADA, IA-2A, and ZnT8A. Multivariate logistic regression models were applied and corrected for autoantibody titre at onset, age at onset, and final sampling time from diagnosis, as quartiles. Type 1 diabetes-associated HLA Class I (A*24, B*18, B*39) and Class II (DR3/DR4) were considered in those for whom data were available. Results: Of those positive at onset, 67.6%, 72.9%, and 40% remained positive at final sampling for GADA, IA-2A, and ZnT8A, respectively. Principal predictors of autoantibody persistence were high titres at onset (p<0.0001) and older age-at-onset above 10 years (p<0.01-0.05). GADA persistence was negatively associated with low-risk HLA Class II genotypes (p=0.004). IA-2A persistence was not associated with HLA Class I or II genotypes. ZnT8A persistence was associated with the absence of Class I A*24 (p=0.016) and moderate-risk HLA class II genotypes (p=0.024). Conclusions: Autoantibodies can persist for many years after type 1 diabetes onset. The main predictors of autoantibody persistence are high baseline autoantibody titre and onset over 10 years of age with smaller antigen-specific effects exhibited by certain type 1 diabetes-associated alleles.