Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
J Clin Endocrinol Metab. 2022 Feb 17;107(3):e935-e946. doi: 10.1210/clinem/dgab816.
To evaluate the role of autoantibodies to N-terminally truncated glutamic acid decarboxylase GAD65(96-585) (t-GADA) as a marker for type 1 diabetes (T1D) and to assess the potential human leukocyte antigen (HLA) associations with such autoantibodies.
In this cross-sectional study combining data from the Finnish Pediatric Diabetes Register, the Type 1 Diabetes Prediction and Prevention study, the DIABIMMUNE study, and the Early Dietary Intervention and Later Signs of Beta-Cell Autoimmunity study, venous blood samples from 760 individuals (53.7% males) were analyzed for t-GADA, autoantibodies to full-length GAD65 (f-GADA), and islet cell antibodies. Epitope-specific GAD autoantibodies were analyzed from 189 study participants.
T1D had been diagnosed in 174 (23%) participants. Altogether 631 (83%) individuals tested positive for f-GADA and 451 (59%) for t-GADA at a median age of 9.0 (range 0.2-61.5) years. t-GADA demonstrated higher specificity (46%) and positive predictive value (30%) for T1D than positivity for f-GADA alone (15% and 21%, respectively). Among participants positive for f-GADA, those who tested positive for t-GADA carried more frequently HLA genotypes conferring increased risk for T1D than those who tested negative for t-GADA (77% vs 53%; P < 0.001).
Autoantibodies to N-terminally truncated GAD improve the screening for T1D compared to f-GADA and may facilitate the selection of participants for clinical trials. HLA class II-mediated antigen presentation of GAD(96-585)-derived or structurally similar peptides might comprise an important pathomechanism in T1D.
评估谷氨酸脱羧酶 GAD65（96-585）（t-GADA）N 端截断自身抗体作为 1 型糖尿病（T1D）标志物的作用，并评估此类自身抗体与人类白细胞抗原（HLA）的潜在关联。
在这项结合了芬兰儿科糖尿病登记处、1 型糖尿病预测和预防研究、DIABIMMUNE 研究以及早期饮食干预和胰岛细胞自身免疫的后期标志物研究数据的横断面研究中，对来自 760 名个体（53.7%为男性）的静脉血样本进行 t-GADA、全长 GAD65（f-GADA）自身抗体和胰岛细胞抗体分析。从 189 名研究参与者中分析了表位特异性 GAD 自身抗体。
174 名（23%）参与者被诊断为 T1D。总共 631 名（83%）个体在中位年龄为 9.0 岁（范围 0.2-61.5 岁）时检测到 f-GADA 阳性，451 名（59%）个体检测到 t-GADA 阳性。与仅 f-GADA 阳性相比，t-GADA 对 T1D 的特异性（46%）和阳性预测值（30%）更高（分别为 15%和 21%）。在 f-GADA 阳性的参与者中，与 t-GADA 阴性者相比，t-GADA 阳性者更常携带增加 T1D 风险的 HLA 基因型（77%比 53%；P < 0.001）。
与 f-GADA 相比，N 端截断的 GAD 自身抗体可提高 T1D 的筛查效率，并且可能有助于选择参与者参加临床试验。HLA Ⅱ类介导的 GAD（96-585）衍生或结构相似肽的抗原呈递可能构成 T1D 的重要发病机制。
