The longitudinal loss of islet autoantibody responses from diagnosis of type 1 diabetes occurs progressively over follow-up and is determined by low autoantibody titres, early-onset, and genetic variants
Claire Williams, Rana Fareed, Georgina Mortimer, Rachel J. Aitken, Isabel Wilson, Gabriel George, Kathleen M. Gillespie, Alistair J.K. Williams, The BOX Study Group, Chitrabhanu Ballav, Atanu Dutta, Michelle Russell‐Taylor, Rachel Besser, James Bursell, Shanthi Chandran, Sejal Patel, Anne Smith, Manohara Kenchaiah, Gomathi Margabanthu, Foteini Kavvoura, Chandan Yaliwal, Anna E. Long
Abstract
The clinical usefulness of post-diagnosis islet autoantibody levels is unclear and factors that drive autoantibody persistence are poorly defined in type 1 diabetes (T1D). Our aim was to characterise the longitudinal loss of islet autoantibody responses after diagnosis in a large, prospectively sampled UK cohort. Participants with T1D [n = 577] providing a diagnosis sample [range -1.0 to 2.0 years] and at least one post-diagnosis sample (<32.0 years) were tested for autoantibodies to glutamate decarboxylase 65 (GADA), islet antigen-2 (IA-2A), and zinc transporter 8 (ZnT8A). Select HLA and non-HLA SNPs were considered. Non-genetic and genetic factors were assessed by multivariable logistic regression models for autoantibody positivity at initial sampling and autoantibody loss at final sampling. For GADA, IA-2A, and ZnT8A, 70.8%, 76.8%, and 40.1%, respectively, remained positive at the final sampling. Non-genetic predictors of autoantibody loss were low baseline autoantibody titres (P < 0.0001), longer diabetes duration (P < 0.0001), and age-at-onset under 8 years (P < 0.01--0.05). Adjusting for non-genetic covariates, GADA loss was associated with low-risk HLA class II genotypes (P = 0.005), and SNPs associated with autoimmunity RELA/11q13 (P = 0.017), LPP/3q28 (P = 0.004), and negatively with IFIH1/2q24 (P = 0.018). IA-2A loss was not associated with genetic factors independent of other covariates, while ZnT8A loss was associated with the presence of HLA A*24 (P = 0.019) and weakly negatively with RELA/11q13 (P = 0.049). The largest longitudinal study of islet autoantibody responses from diagnosis of T1D shows that autoantibody loss is heterogeneous and influenced by low titres at onset, longer duration, earlier age-at-onset, and genetic variants. These data may inform clinical trials where post-diagnosis participants are recruited.