Major surgery induces acute changes in DNA methylation associated with activation of the immune response

Abstract

Background: Surgery is an invasive procedure evoking acute inflammatory and immune responses that are believed to mediate risk for postoperative complications including cognitive dysfunction and delirium. Although the specific mechanisms driving these responses have not been well-characterized, they are hypothesized to involve the epigenetic regulation of gene expression. We quantified genome-wide levels of DNA methylation in purified peripheral blood mononuclear cells (PBMCs) longitudinally collected from 55 elderly patients undergoing three types of major surgery (elective colorectal and hip replacement surgery, and emergency hip fracture surgery), comparing samples collected at baseline to those collected immediately post-operatively and at discharge from hospital. Results:Major surgery was associated with acute changes in DNA methylation at sites annotated to immune system genes, paralleling changes in serum-levels of markers including C-reactive protein (CRP) and Interleukin 6 (IL-6) measured in the same individuals.Although many of the observed changes in DNA methylation are consistent across the three types of surgery, there is notable heterogeneity between surgery types at certain loci. The acute changes in DNA methylation induced by surgery are relatively stable in the postoperative period, generally persisting until discharge from hospital. Conclusions:Our results highlight the dramatic alterations in gene regulation induced by invasive surgery, primarily reflecting upregulation of the immune system in response to trauma, wound healing and anaesthesia.