Sims, Emily K.Cuthbertson, DavidFerrat, Lauric A.Bosi, EmanueleEvans‑Molina, CarmellaDiMeglio, Linda A.Nathan, Brandon M.Ismail, Heba M.Jacobsen, Laura M.Redondo, Maria J.Oram, Richard A.Sosenko, Jay M.2025-05-152025-05-152025Sims EK, Cuthbertson D, Ferrat LA, et al. IA-2A positivity increases risk of progression within and across established stages of type 1 diabetes. Diabetologia. 2025;68(5):993-1004. doi:10.1007/s00125-025-06382-xhttps://hdl.handle.net/1805/48146Aims/hypothesis: Accurate understanding of type 1 diabetes risk is critical for optimisation of counselling, monitoring and interventions, yet even within established staging classifications, individual time to clinical disease varies. Previous work has associated IA-2A positivity with increased type 1 diabetes progression but a comprehensive assessment of the impact of screening for IA-2A positivity across the natural history of autoantibody positivity has not been performed. We asked whether IA-2A would consistently be associated with higher risk of progression within and across established stages of type 1 diabetes in a large natural history study. Methods: Genetic, autoantibody and metabolic data from adult and paediatric autoantibody-negative (n=192) and autoantibody-positive (n=4577) relatives of individuals with type 1 diabetes followed longitudinally in the Type 1 Diabetes TrialNet Pathway to Prevention Study were analysed. Cox regression was used to compare cumulative incidences of clinical diabetes by autoantibody profiles and disease stages. Results: Compared with IA-2A- individuals, IA-2A+ individuals had higher genetic risk scores and clinical progression risk within single-autoantibody-positive (5.3-fold increased 5 year risk), stage 1 (2.2-fold increased 5 year risk) and stage 2 (1.3-fold increased 5 year risk) type 1 diabetes categories. Individuals with single-autoantibody positivity for IA-2A showed increased metabolic dysfunction and diabetes progression compared with people who were autoantibody negative, those positive for another single autoantibody, and IA-2A- stage 1 individuals. Individuals at highest risk within the single-IA-2A+ category included children (HR 14.2 [95% CI 1.9, 103.1], p=0.009), individuals with IA-2A titres above the median (HR 3.5 [95% CI 1.9, 6.6], p<0.001), individuals with high genetic risk scores (HR 1.4 [95% CI 1.2,1.6], p<0.001) and individuals with HLA DR4-positive status (HR 3.7 [95% CI 1.6, 8.3], p=0.002). When considering all autoantibody-positive individuals, progression risk was similar for euglycaemic IA-2A+ individuals and dysglycaemic IA-2A- individuals. Conclusions/interpretation: IA-2A positivity is consistently associated with increased progression risk throughout the natural history of type 1 diabetes development. Individuals with single-autoantibody positivity for IA-2A have a greater risk of disease progression than those who meet stage 1 criteria but who are IA-2A-. Approaches to incorporate IA-2A+ status into monitoring strategies for autoantibody-positive individuals should be considered.en-USAttribution-NonCommercial-NoDerivatives 4.0 InternationalAutoantibodiesIA-2AIslet antigen-2Precision medicinePredictionProgressionStratificationType 1 diabetesArticle