Changes in the Co-Expression of Innate Immunity Genes During Persistent Islet Autoimmunity are Associated with Progression of Islet Autoimmunity: The 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 DAISY who developed IA, autoantibodies present on two or more visits. Illumina’s NovaSEQ 600TM 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.