Sims Emily K, Cuthbertson David, Ferrat Lauric A, Bosi Emanuele, Evans-Molina Carmella, DiMeglio Linda A, Nathan Brandon M, Ismail Heba M, Jacobsen Laura M, Redondo Maria J, Oram Richard A, Sosenko Jay M
Department of Pediatrics, Wells Center for Pediatric Research, Division of Pediatric Endocrinology and Diabetology, Indiana University School of Medicine, Indianapolis, IN, USA.
Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
Diabetologia. 2025 May;68(5):993-1004. doi: 10.1007/s00125-025-06382-x. Epub 2025 Feb 28.
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.
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.
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.
目的/假设：准确了解1型糖尿病风险对于优化咨询、监测和干预至关重要，然而，即使在既定的分期分类中，个体临床疾病发生的时间也存在差异。先前的研究已将IA-2A阳性与1型糖尿病进展加快相关联，但尚未对在自身抗体阳性的自然病程中筛查IA-2A阳性的影响进行全面评估。在一项大型自然病程研究中，我们探讨了IA-2A在1型糖尿病既定阶段内及不同阶段是否始终与更高的进展风险相关。
对1型糖尿病预防研究的1型糖尿病试验网途径中纵向随访的1型糖尿病患者的成年和儿童自身抗体阴性（n=192）及自身抗体阳性（n=4577）亲属的基因、自身抗体和代谢数据进行分析。采用Cox回归按自身抗体谱和疾病阶段比较临床糖尿病的累积发病率。
与IA-2A阴性个体相比，IA-2A阳性个体在单自身抗体阳性（5年风险增加5.3倍）、1期（5年风险增加2.2倍）和2期（5年风险增加1.3倍）1型糖尿病类别中具有更高的遗传风险评分和临床进展风险。与自身抗体阴性、另一单自身抗体阳性及IA-2A 1期个体相比，IA-2A单自身抗体阳性个体的代谢功能障碍和糖尿病进展增加。单IA-2A类别中风险最高的个体包括儿童（风险比14.2[95%置信区间1.9,103.1]，p=0.009）、IA-2A滴度高于中位数的个体（风险比3.5[95%置信区间1.9,6.6]，p<0.001）、遗传风险评分高的个体（风险比1.4[95%置信区间1.2,1.6]，p<0.001）和HLA DR4阳性状态的个体（风险比3.7[95%置信区间1.6,8.3]，p=0.002）。在考虑所有自身抗体阳性个体时，血糖正常的IA-2A个体和血糖异常的IA-2A个体的进展风险相似。
结论/解读：IA-2A阳性在1型糖尿病发展的整个自然病程中始终与进展风险增加相关。IA-2A单自身抗体阳性个体比符合1期标准但为IA-2A阴性的个体具有更高的疾病进展风险。应考虑将IA-2A状态纳入自身抗体阳性个体监测策略的方法。
