Integrated methylomic and transcriptomic characterisation of postoperative systemic inflammatory dysregulation (RNA EXPRESSION)

The inflammatory response to surgery is essential for healing and recovery, however hyperinflammation and altered immune competence increases the risk of inflammation mediated complications. We hypothesised that, in some patients, a state of postoperative systemic inflammatory dysregulation (PSID) exists increasing the risk or infection and sepsis, and that this will be associated with, and potentially predicted by, altered patterns of genome-wide peripheral blood mononuclear cell differential DNA methylation and gene expression. In this study we utilised phenotypic extremes of postoperative plasma C-reactive protein levels to define PSID, which manifested clinically in significantly higher rates of sepsis, complications and longer hospital stays following major abdominal surgery. We identified altered DNA methylation and differential gene expression in specific immune and metabolic pathways during PSID. Our findings suggest that dysregulation results in, or from, dramatic changes in differential DNA methylation and highlights potential targets for early detection and treatment. The combination of altered DNA methylation and gene expression confirms that dysregulation is mediated at multiple levels within specific gene sets and hence, non-specific anti-inflammatory treatments such as corticosteroids alone are unlikely to represent an effective therapeutic strategy. Overall design: In this study we have matched RNA-seq expression and EPIC methylation array data from patients before and after major abdominal surgery. There are two patient groups, those with low CRP after surgery (n= 25) and those with elevated CRP after surgery (n=21). The purpose is to understand the gene regulatory events that occur in patients with high CRP levels, as these patients are at a higher risk of adverse outcomes after surgery.

手术引发的炎症反应对于伤口愈合与术后恢复至关重要，然而过度炎症反应与免疫功能异常会增加炎症介导并发症的发生风险。我们提出假设：部分患者会出现术后全身炎症失调（postoperative systemic inflammatory dysregulation, PSID）状态，该状态会提升感染与脓毒症的发生风险；且该状态与全基因组水平外周血单个核细胞（peripheral blood mononuclear cell）的差异性DNA甲基化及基因表达模式改变相关，或可通过此类模式改变进行预测。本研究借助术后血浆C反应蛋白水平的表型极端值定义PSID；经临床验证，该状态患者在接受腹部大手术后，脓毒症、并发症发生率显著更高，且住院时长更长。我们在PSID状态下的特定免疫与代谢通路中，发现了DNA甲基化与基因表达的异常改变。本研究结果提示，炎症失调可引发差异性DNA甲基化的显著改变，或由此类改变所介导；同时本研究也为早期检测与干预提供了潜在靶点。DNA甲基化异常与基因表达改变的联合特征证实，炎症失调是在特定基因集的多个层面介导发生的；因此，仅使用糖皮质激素等非特异性抗炎治疗，难以成为有效的临床干预策略。研究整体设计：本研究整合了腹部大手术患者术前与术后的配对RNA-seq表达谱与EPIC甲基化芯片数据。本研究共纳入两组患者：术后C反应蛋白（CRP）水平较低组（n=25）与术后CRP水平升高组（n=21）。本研究旨在阐明CRP水平升高患者体内发生的基因调控事件——此类患者术后不良结局的发生风险显著更高。