Emily K. Sims, David Cuthbertson, Lauric A. Ferrat, Emanuele Bosi, Carmella Evans-Molina, Linda A. DiMeglio, Brandon M. Nathan, Heba M. Ismail, Laura M. Jacobsen, Maria J. Redondo, Richard A. Oram, Jay M. Sosenko
{"title":"IA-2A positivity increases risk of progression within and across established stages of type 1 diabetes","authors":"Emily K. Sims, David Cuthbertson, Lauric A. Ferrat, Emanuele Bosi, Carmella Evans-Molina, Linda A. DiMeglio, Brandon M. Nathan, Heba M. Ismail, Laura M. Jacobsen, Maria J. Redondo, Richard A. Oram, Jay M. Sosenko","doi":"10.1007/s00125-025-06382-x","DOIUrl":null,"url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>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.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Genetic, autoantibody and metabolic data from adult and paediatric autoantibody-negative (<i>n</i>=192) and autoantibody-positive (<i>n</i>=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.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Compared with IA-2A<sup>−</sup> individuals, IA-2A<sup>+</sup> 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<sup>−</sup> stage 1 individuals. Individuals at highest risk within the single-IA-2A<sup>+</sup> category included children (HR 14.2 [95% CI 1.9, 103.1], <i>p</i>=0.009), individuals with IA-2A titres above the median (HR 3.5 [95% CI 1.9, 6.6], <i>p</i><0.001), individuals with high genetic risk scores (HR 1.4 [95% CI 1.2,1.6], <i>p</i><0.001) and individuals with <i>HLA DR4</i>-positive status (HR 3.7 [95% CI 1.6, 8.3], <i>p</i>=0.002). When considering all autoantibody-positive individuals, progression risk was similar for euglycaemic IA-2A<sup>+</sup> individuals and dysglycaemic IA-2A<sup>−</sup> individuals.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>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<sup>−</sup>. Approaches to incorporate IA-2A<sup>+</sup> status into monitoring strategies for autoantibody-positive individuals should be considered.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\n","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"10 1","pages":""},"PeriodicalIF":8.4000,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Diabetologia","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00125-025-06382-x","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍：
Diabetologia, the authoritative journal dedicated to diabetes research, holds high visibility through society membership, libraries, and social media. As the official journal of the European Association for the Study of Diabetes, it is ranked in the top quartile of the 2019 JCR Impact Factors in the Endocrinology & Metabolism category. The journal boasts dedicated and expert editorial teams committed to supporting authors throughout the peer review process.
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