Changes in the Coexpression of Innate Immunity Genes During Persistent Islet Autoimmunity Are Associated With Progression of Islet Autoimmunity: Diabetes Autoimmunity Study in the Young (DAISY)

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 Diabetes Autoimmunity Study in the Young (DAISY) who developed IA, autoantibodies present on two or more visits. Illumina's NovaSeq 6000 was used to quantify gene expression in whole blood. With linear mixed models we 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 coexpression network analysis was used to identify coexpression 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 coexpressed 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 β-cell survival in a murine model. Overall, results provide evidence of alterations in expression of innate immune genes prior to onset of T1D. We identified individuals who developed IA between February 1994 and February 2019 in DAISY and underwent autoantibody testing at two or more visits (n = 214). We divided individuals into three IA progression phenotypes. The reverter group was defined as individuals who reverted for all autoantibodies (two or more consecutive visits in which no autoantibodies were detected), did not develop T1D, and were autoantibody negative for all autoantibodies at their last DAISY visit (n = 47). The maintainer group was defined as individuals who continued to test positive for autoantibodies and did not develop T1D during follow-up (n = 66). The progressor group was defined as individuals who developed T1D (n = 25). We selected venous blood samples from two visits (termed IA-1 and IA-2) that occurred after the onset of IA for mRNA sequencing. The IA-1 visit was selected as the first available visit after the onset of IA for all groups. In the progressor group, the visit that preceded clinical onset of T1D was selected as the IA-2 visit. In the maintainer and reverter groups, the IA-2 visit was selected as the visit where age was closest to median age in the progressor group at the IA-2 visit. We also included 12 control samples and 12 technical replicates.