Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL
Forschergruppe Diabetes e.V., Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany.
Diabetes Care. 2020 Sep;43(9):2066-2073. doi: 10.2337/dc19-2547. Epub 2020 Jul 8.
The first-appearing β-cell autoantibody has been shown to influence risk of type 1 diabetes (T1D). Here, we assessed the risk of autoantibody spreading to the second-appearing autoantibody and further progression to clinical disease in The Environmental Determinants of Diabetes in the Young (TEDDY) study.
Eligible children with increased HLA-DR-DQ genetic risk for T1D were followed quarterly from age 3 months up to 15 years for development of a single first-appearing autoantibody (GAD antibody [GADA], insulin autoantibody [IAA], or insulinoma antigen-2 autoantibody [IA-2A]) and subsequent development of a single second-appearing autoantibody and progression to T1D. Autoantibody positivity was defined as positivity for a specific autoantibody at two consecutive visits confirmed in two laboratories. Zinc transporter 8 autoantibody (ZnT8A) was measured in children who developed another autoantibody.
There were 608 children who developed a single first-appearing autoantibody (IAA, = 282, or GADA, = 326) with a median follow-up of 12.5 years from birth. The risk of a second-appearing autoantibody was independent of GADA versus IAA as a first-appearing autoantibody (adjusted hazard ratio [HR] 1.12; 95% CI 0.88-1.42; = 0.36). Second-appearing GADA, IAA, IA-2A, or ZnT8A conferred an increased risk of T1D compared with children who remained positive for a single autoantibody, e.g., IAA or GADA second (adjusted HR 6.44; 95% CI 3.78-10.98), IA-2A second (adjusted HR 16.33; 95% CI 9.10-29.29; < 0.0001), or ZnT8A second (adjusted HR 5.35; 95% CI 2.61-10.95; < 0.0001). In children who developed a distinct second autoantibody, IA-2A (adjusted HR 3.08; 95% CI 2.04-4.65; < 0.0001) conferred a greater risk of progression to T1D as compared with GADA or IAA. Additionally, both a younger initial age at seroconversion and shorter time to the development of the second-appearing autoantibody increased the risk for T1D.
The hierarchical order of distinct autoantibody spreading was independent of the first-appearing autoantibody type and was age-dependent and augmented the risk of progression to T1D.
已证明首次出现的β细胞自身抗体影响 1 型糖尿病（T1D）的风险。在此，我们评估了在环境决定青少年糖尿病（TEDDY）研究中，自身抗体向第二个自身抗体扩散以及进一步发展为临床疾病的风险。
从 3 个月大到 15 岁，对具有 T1D 高 HLA-DR-DQ 遗传风险的合格儿童进行每季度一次的随访，以观察单一首次出现的自身抗体（谷氨酸脱羧酶抗体[GADA]、胰岛素自身抗体[IAA]或胰岛素瘤抗原-2 自身抗体[IA-2A]）的发展情况，以及随后出现的第二个自身抗体以及向 T1D 的进展情况。自身抗体阳性定义为在两个实验室两次连续检查中均为阳性的特定自身抗体阳性。在出现另一种自身抗体的儿童中测量锌转运蛋白 8 自身抗体（ZnT8A）。
共有 608 名儿童出现了单一的首次出现的自身抗体（IAA， = 282，或 GADA， = 326），从出生起中位随访时间为 12.5 年。出现第二种自身抗体的风险与首次出现的 GADA 与 IAA 无关（调整后的危险比[HR] 1.12；95%CI 0.88-1.42； = 0.36）。与仍保持单一自身抗体阳性的儿童相比，第二次出现 GADA、IAA、IA-2A 或 ZnT8A 的儿童患 T1D 的风险增加，例如第二次出现 IAA 或 GADA（调整后的 HR 6.44；95%CI 3.78-10.98）、IA-2A 第二次出现（调整后的 HR 16.33；95%CI 9.10-29.29； < 0.0001）或 ZnT8A 第二次出现（调整后的 HR 5.35；95%CI 2.61-10.95； < 0.0001）。在出现第二种自身抗体的儿童中，IA-2A（调整后的 HR 3.08；95%CI 2.04-4.65； < 0.0001）进展为 T1D 的风险高于 GADA 或 IAA。此外，初次血清转换年龄较小和到第二个自身抗体出现的时间较短都会增加 T1D 的风险。
不同自身抗体扩散的层次顺序与首次出现的自身抗体类型无关，而是与年龄相关，并增加了向 T1D 进展的风险。
