ABSTRACT: Introduction. Epigenetic modifications have been implicated to mediate several complications of diabetes mellitus (DM), especially nephropathy and retinopathy. Our aims were to ascertain if epigenetic alterations in whole blood discriminate among DM patients with normal, delayed and rapid gastric emptying (GE). Methods. Using ChIP-seq (Chromatin immunoprecipitation combined with next generation sequencing) assays, we compared the genome-wide enrichment of three histone modifications (ie, H3K4me3, H3K9ac and H3K27ac) in buffy coats from 20 DM patients with normal (n=6), delayed (n=8), or rapid (n=6) GE. Results. Between DM patients with delayed versus normal GE, there were 108 and 54 genes that were differentially-bound (FDR < 0.05) with H3K27ac and H3K9ac; 100 genes were differentially bound with H3K9ac in patients with rapid versus normal GE. The differentially bound genes with H3K27ac were functionally linked to the type 2 immune response, particularly Th2 cell activation and function (eg, CCR3, CRLF2, CXCR4, IL5RA, and IL1RL1) and glucose homeostasis (FBP-1, PDE4A, CMKLR1). For H3K9ac, the differentially occupied genes were related to T cell development and function (eg, ICOS and CCR3) and innate immunity (RELB, CD300LB, CLEC2D). Compared to normal, rapid GE had differential H3K9ac peaks at the promoter site of diverse immunity-related genes (eg, TNFRSF25 and CXCR4) and genes related to insulin resistance and glucose metabolism. The motif analysis disclosed enrichment of binding sites for several transcription factors relevant to the pathogenesis and complications of DM. Conclusions. GE disturbances in DM are associated with epigenetic alterations that may serve as biomarkers and provide clues to the pathogenesis
