What factors influence the persistence of autoantibodies to zinc transporter 8 (ZnT8A) in type 1 diabetes after diagnosis

Background: Autoantibodies to zinc transporter 8 (ZnT8A) are usually the last autoantibody specificity to appear in the preclinical phase of type 1 diabetes (T1D). Little is known about the factors that influence autoantibody profiles and the continuation of the autoimmune response post-diagnosis. Here we have measured ZnT8A longitudinally in individuals from diagnosis with a maximum time frame of 32 years.

Methods: Radiobinding assays were used to test for ZnT8A positivity (arginine (R) and tryptophan (W) specific) in individuals with T1D [n=213; 108 males; median age at diagnosis 10.19yrs (range 0.7-21yrs)] participating in the Bart’s-Oxford family study who had a first sample close to diabetes onset available [median time from diagnosis, 0yrs (range -0.9 to 2.0yrs)] and at least 1 sample post-diagnosis [median follow-up, 9.0yrs (range 1.9-32.2yrs)]. Genetic data were already available. Univariable relationships were investigated by Chi-squared tests followed by multivariable logistic regression models.

Results: Of 213 individuals studied, 150 had lost ZnT8A by the time of the last available sample with the probability of ZnT8A loss influenced by ZnT8A level at diagnosis (P<0.001). In a model excluding genetic determinants, those diagnosed under 10 years were more likely to lose ZnT8A than those diagnosed over 10 years of age (P=0.06). The level of ZnT8A at diagnosis (P<0.001) was positively associated and time from diagnosis (P<0.001) negatively associated with ZnT8A persistence. When SLC30A8 and HLA Class II genotypes were included in the model, time from diagnosis and ZnT8A level at diagnosis remained significantly associated with ZnT8A loss, although the association of age at DX was lost. SLC30A8 genotype may also influence ZnT8A loss (P=0.075), such that the T allele (ZnT8W) was associated with antibody persistence, an effect not explained by the epitope specificity of ZnT8A. Overall, the principal predictor of a persistent ZnT8A response was a high ZnT8A titre at diagnosis.