General anesthesia induces acute cell-free DNA methylation changes in peripheral blood.

IF 2.1 3区 医学 Q3 RESPIRATORY SYSTEM Journal of thoracic disease Pub Date : 2024-11-30 Epub Date: 2024-11-13 DOI:10.21037/jtd-24-476
Wenhua Liang, Xin Liu, Zhuxing Chen, Haixuan Wang, Ziwen Yu, Chunyan Li, Hao Yang, Jinsheng Tao, Hui Li, Zhiwei Chen, Jian-Bing Fan, Jianxing He
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Abstract

Background: Short-term and long-term adverse events could occur after general anesthesia (GA) and the specific mechanism driving these effects has not yet been well-characterized. In this study, we aimed to evaluate the global effect of GA on DNA methylation in the cell-free DNA (cfDNA) of surgical lung-nodule patients.

Methods: This large retrospective cohort study enrolled 1,006 surgical lung nodule patients (529 pre-anesthesia, and 477 post-anesthesia). Methylation profiles of the cfDNA isolated from plasma were analyzed by targeted bisulfite sequencing using an enrichment panel covering 12,899 biologically informative methylation regions and 105,844 CpG sites.

Results: By comparing the pre-anesthesia to the post-anesthesia group, a total of 4,562 differentially methylated regions (DMRs) were identified as GA-induced DMRs. Pathway enrichment analysis annotated with cellular processes including pattern specification process, head/heart/bone/tissues development and morphogenesis pathways, cell-adhesion, extra-cellular matrix (ECM) remodeling pathways, and signaling pathways including PI3K-AKT pathway, Ca2+ dependent pathway and RAS/extracellular signal-regulated kinase (RAS/ERK) signaling pathway. Prediction models using 20 DMR markers were derived using Random Forest, which could accurately predict biochemical indicators for post-operative abnormal coagulation function including activated-partial-thromboplastin-time [APTT, area under curve (AUC) 0.81], international normalized ratio (INR, AUC 0.87), D-dimer (AUC 0.82), neutrophil (AUC 0.84) and monocyte (AUC 0.79). Low methylation level in one of the top DMR markers, cg02032606 (DLX-4 gene), was found to be associated with worse overall survival in both lung adenocarcinoma and squamous carcinoma patients.

Conclusions: This study demonstrated that GA could result in acute DNA methylation changes, which were associated with tissue damage and repair responses. These GA-induced methylation changes were associated with postoperative coagulation functions and could serve as a promising predictive biomarker for coagulation disorders after surgery.

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全身麻醉会诱发外周血中无细胞 DNA 甲基化的急性变化。
背景:全身麻醉(GA)后可能会出现短期和长期的不良反应,而导致这些影响的具体机制尚未得到很好的描述。在这项研究中,我们旨在评估 GA 对手术肺结核患者无细胞 DNA(cfDNA)中 DNA 甲基化的总体影响:这项大型回顾性队列研究共纳入了 1006 例手术肺结节患者(529 例麻醉前,477 例麻醉后)。研究人员使用一个涵盖 12,899 个生物信息甲基化区域和 105,844 个 CpG 位点的富集面板,对从血浆中分离出的 cfDNA 的甲基化图谱进行了定向亚硫酸氢盐测序分析:结果:通过比较麻醉前组和麻醉后组,共发现4,562个差异甲基化区域(DMRs)为GA诱导的DMRs。通路富集分析注释了细胞过程,包括模式规范过程、头/心/骨/组织发育和形态发生通路、细胞粘附、细胞外基质(ECM)重塑通路,以及信号通路,包括PI3K-AKT通路、Ca2+依赖通路和RAS/细胞外信号调节激酶(RAS/ERK)信号通路。利用随机森林(Random Forest)技术得出了使用 20 个 DMR 标志物的预测模型,该模型可准确预测术后凝血功能异常的生化指标,包括活化部分凝血活酶时间(APTT,曲线下面积(AUC)0.81]、国际标准化比值(INR,AUC 0.87)、D-二聚体(AUC 0.82)、中性粒细胞(AUC 0.84)和单核细胞(AUC 0.79)。研究发现,在肺腺癌和鳞癌患者中,顶级 DMR 标记之一 cg02032606(DLX-4 基因)的甲基化水平较低与总生存期较差有关:本研究表明,GA 可导致急性 DNA 甲基化变化,这与组织损伤和修复反应有关。这些GA诱导的甲基化变化与术后凝血功能有关,可作为术后凝血功能障碍的预测性生物标志物。
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来源期刊
Journal of thoracic disease
Journal of thoracic disease RESPIRATORY SYSTEM-
CiteScore
4.60
自引率
4.00%
发文量
254
期刊介绍: The Journal of Thoracic Disease (JTD, J Thorac Dis, pISSN: 2072-1439; eISSN: 2077-6624) was founded in Dec 2009, and indexed in PubMed in Dec 2011 and Science Citation Index SCI in Feb 2013. It is published quarterly (Dec 2009- Dec 2011), bimonthly (Jan 2012 - Dec 2013), monthly (Jan. 2014-) and openly distributed worldwide. JTD received its impact factor of 2.365 for the year 2016. JTD publishes manuscripts that describe new findings and provide current, practical information on the diagnosis and treatment of conditions related to thoracic disease. All the submission and reviewing are conducted electronically so that rapid review is assured.
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