Transfusion Strategies are Associated with Epigenetic Changes Following Blunt Trauma.

INTRODUCTION: Epigenetics has been identified in multiple diseases. The effect of transfusion strategy on epigenetics is unknown. We hypothesized that expression of epigenetic regulating genes would be associated with resuscitation strategy following blunt trauma.

METHODS: Retrospective study using the inflammation in host response to injury (glue grant) dataset. Volume transfused over 24 h of packed red blood cells (PRBC), fresh frozen plasma (FFP), platelets (PLT) as well as crystalloids was extracted along with leucocyte microarray data of genes with known epigenetic modulating activity from day 1 after injury.Principal component analysis (PCA) was used to identify principal components (PC) within the transcriptomic dataset. Multiple regression associated these with volume of blood products and crystalloids while controlling for confounders. Genes co-expressed with genes central genes in the identified PCs were furthermore subjected to pathway analysis using the reactome database.

RESULTS: PCA identified seven components. PRBC and crystalloid volumes were positively associated with PC1, implicating histone acetylation (HAT1), DNA and histone methylation (KDM6B, SET1DB) and histone phosphorylation (RPS6KA5). Conversely, PLT volume was negatively associated with PC1,5 and 6, implicating DNA methylation (DNMT1) as well as histone acetylation (HAT1) and phosphorylation (RPSKA3).FFP was negatively associated with PC3, implicating histone methylation (SETD1B) and phosphorylation (RPS6KA5).Co-expression network analysis identified downstream pathways relevant to inflammation and the innate immune response, including Toll-like receptor, interleukin and mitogen activated protein kinase activation.

CONCLUSIONS: Resuscitation strategy was associated with epigenetic transcriptomic alterations, especially for PRBC and PLT transfusions. Downstream effects may include pertubations of pathways involved in immune signaling and cellular survival.