IA-2A positivity increases risk of progression within and across established stages of type 1 diabetes
dc.contributor.author | Sims, Emily K. | |
dc.contributor.author | Cuthbertson, David | |
dc.contributor.author | Ferrat, Lauric A. | |
dc.contributor.author | Bosi, Emanuele | |
dc.contributor.author | Evans‑Molina, Carmella | |
dc.contributor.author | DiMeglio, Linda A. | |
dc.contributor.author | Nathan, Brandon M. | |
dc.contributor.author | Ismail, Heba M. | |
dc.contributor.author | Jacobsen, Laura M. | |
dc.contributor.author | Redondo, Maria J. | |
dc.contributor.author | Oram, Richard A. | |
dc.contributor.author | Sosenko, Jay M. | |
dc.contributor.department | Pediatrics, School of Medicine | |
dc.date.accessioned | 2025-05-15T10:04:14Z | |
dc.date.available | 2025-05-15T10:04:14Z | |
dc.date.issued | 2025 | |
dc.description.abstract | Aims/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. | |
dc.eprint.version | Final published version | |
dc.identifier.citation | Sims 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-x | |
dc.identifier.uri | https://hdl.handle.net/1805/48146 | |
dc.language.iso | en_US | |
dc.publisher | Springer | |
dc.relation.isversionof | 10.1007/s00125-025-06382-x | |
dc.relation.journal | Diabetologia | |
dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 International | en |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
dc.source | PMC | |
dc.subject | Autoantibodies | |
dc.subject | IA-2A | |
dc.subject | Islet antigen-2 | |
dc.subject | Precision medicine | |
dc.subject | Prediction | |
dc.subject | Progression | |
dc.subject | Stratification | |
dc.subject | Type 1 diabetes | |
dc.title | IA-2A positivity increases risk of progression within and across established stages of type 1 diabetes | |
dc.type | Article |