Epigenome Wide DNA Methylation Profiling of Sepsis and the Critical Illness Phenotype
CCCF ePoster library. Binnie A. 11/09/18; 233353; 120
Alexandra Binnie
Alexandra Binnie
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Epigenetic alterations may provide important insights into the regulation of gene expression in critical illness and the genetic pathways that drive the critical illness phenotype. In a pilot study of whole blood DNA methylation profiling in critically-ill septic and non-septic patients we identified 668 differentially methylated regions (DMRs) corresponding to 443 unique differentially-methylated genes (DMGs). Analysis of transcriptomic data from eight human sepsis cohorts reveals that DMGs are overrepresented amongst genes showing differential expression in response to sepsis, with 81% of DMGs showing significant expression change in at least one dataset. Functional analysis of all DMGs showed enrichment for antigen processing and presentation, methyltransferase activity, cell adhesion proteins, and cell junction proteins as well as metal-binding proteins. A text-mining tool, the “SepsisScore”, was created to identify DMGs previously associated with sepsis in the literature. Top-ranked DMGs included complement component 3, angiopoietin 2, myeloperoxidase, HLA-A, HLA-DRB1, HLA-C, and HLA-DQB1. Intriguingly, a large number of genes are both differentially-methylated and differentially-expressed in sepsis yet do not appear in the sepsis literature. Weighted gene correlation network analysis (WGCNA) using the same patient dataset identifies gene methylation modules associated with important clinical traits in both septic and non-septic patients – these include multiple organ dysfunction score, need for vasopressors, length of ICU stay and length of hospital stay. Thus, DNA methylation profiling of whole blood is a powerful new method for characterizing critically ill patients and may have utility as both a diagnostic and prognostic tool.


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