Longitudinal changes in gene expression during islet autoimmunity (IA) may provide insight into biological processes that explain progression to type 1 diabetes (T1D). We identified individuals from DAISY who developed IA, autoantibodies present on two or more visits. Illumina's NovaSEQ 600™ was used to quantify gene expression in whole blood. Linear mixed models tested for changes in expression after IA that differed across individuals who progressed to T1D (progressors, n=25), reverted to an autoantibody negative stage (reverters, n=47), or maintained IA positivity but did not develop T1D (maintainers, n=66). Weighted gene co-expression network analysis was used to identify co-expression modules. Gene Ontology pathway analysis of the top 150 differentially expressed genes (nominal p<0.01) identified significantly enriched pathways including leukocyte activation involved in immune response, innate immune response, and regulation of immune response. We identified a module of 14 co-expressed genes with roles in the innate immunity. The hub gene, LTF, is known to have immunomodulatory properties. Another gene within the module, CAMP, is potentially relevant based on its role in promoting beta cell survival in a murine model. Overall, results provide evidence of alterations in expression of innate immune genes prior to onset of T1D.

中文翻译：

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持续性胰岛自身免疫期间先天免疫基因共表达的变化与胰岛自身免疫的进展有关：年轻人的糖尿病自身免疫研究 (DAISY)

胰岛自身免疫 (IA) 期间基因表达的纵向变化可能有助于深入了解解释进展为 1 型糖尿病 (T1D) 的生物学过程。我们从 DAISY 中确定了患有 IA 的个体，在两次或多次就诊时存在自身抗体。Illumina 的 NovaSEQ 600™ 用于量化全血中的基因表达。线性混合模型测试了 IA 后表达的变化，这些变化在进展为 T1D（进展者，n=25）、恢复到自身抗体阴性阶段（恢复者，n=47）或保持 IA 阳性但未发展为 T1D 的个体之间存在差异。维护者，n = 66）。加权基因共表达网络分析用于识别共表达模块。前 150 个差异表达基因的 Gene Ontology 通路分析（标称 p＜0. 01) 确定了显着丰富的途径，包括参与免疫反应、先天免疫反应和免疫反应调节的白细胞活化。我们确定了一个由 14 个共表达基因组成的模块，这些基因在先天免疫中发挥作用。已知中枢基因 LTF 具有免疫调节特性。该模块中的另一个基因 CAMP 可能基于其在小鼠模型中促进 β 细胞存活的作用而相关。总体而言，结果提供了 T1D 发病前先天免疫基因表达改变的证据。基于其在小鼠模型中促进 β 细胞存活的作用，可能具有相关性。总体而言，结果提供了 T1D 发病前先天免疫基因表达改变的证据。基于其在小鼠模型中促进 β 细胞存活的作用，可能具有相关性。总体而言，结果提供了 T1D 发病前先天免疫基因表达改变的证据。