Institute of Neurology, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China.
mBio. 2019 Aug 6;10(4):e01663-19. doi: 10.1128/mBio.01663-19.
Increasing evidence has indicated that single nucleotide polymorphisms (SNPs) are related to the susceptibility of sepsis and might provide potential evidence for the mechanisms of sepsis. Our recent preliminary study showed that the ADAM10 genetic polymorphism was clinically associated with the development of sepsis, and little is known about the underlying mechanism. The aim of this study was to confirm the association between the ADAM10 promoter rs653765 G→A polymorphism and the progression of sepsis and to discover the underlying mechanism. Clinical data showed that the rs653765 G→A polymorphism was positively correlated with the development of sepsis, as evidenced by a multiple-center case-control association study with a large sample size, and showed that EGR1 and ADAM10 levels were associated well with the different subtypes of sepsis patients. results demonstrated that the rs653765 G→A variants could functionally modulate ADAM10 promoter activity by altering the binding of the EGR1 transcription factor (TF) to the ADAM10 promoter, affecting the transcription and translation of the gene. Electrophoretic mobility shift assay (EMSA) followed by chromatin immunoprecipitation (ChIP) assay indicated the direct interaction. Functional studies further identified that the EGR1/ADAM10 pathway is important for the inflammatory response. EGR1 intervention decreased host proinflammatory cytokine secretion and rescued the survival and tissue injury of the mouse endotoxemia model. Sepsis is characterized as life-threatening organ dysfunction, with unacceptably high mortality. Evidence has indicated that functional SNPs within inflammatory genes are associated with susceptibility, progression, and prognosis of sepsis. These mechanisms on which these susceptible sites depended often suggest the key pathogenesis and potential targets in sepsis. In the present study, we confirmed that a functional variant acts as an important genetic factor that confers the progression of sepsis in a large sample size and in multiple centers and revealed that the variants modulate the EGR1/ADAM10 pathway and influence the severity of sepsis. We believe that we provide an important insight into this new pathway involving the regulation of inflammatory process of sepsis based on the clinical genetic evidence, which will enhance the understanding of nosogenesis of sepsis and provide the potential target for inflammation-related diseases.
越来越多的证据表明，单核苷酸多态性（SNP）与脓毒症的易感性有关，可能为脓毒症的发病机制提供潜在的证据。我们最近的初步研究表明，ADAM10 基因多态性与脓毒症的发生发展有关，但潜在机制知之甚少。本研究旨在确认 ADAM10 启动子 rs653765 G→A 多态性与脓毒症进展的相关性，并发现其潜在机制。临床数据显示，rs653765 G→A 多态性与脓毒症的发生发展呈正相关，这一点通过一项具有较大样本量的多中心病例对照关联研究得到了证实，并且表明 EGR1 和 ADAM10 水平与不同亚型的脓毒症患者密切相关。研究结果表明，rs653765 G→A 变体可以通过改变 EGR1 转录因子（TF）与 ADAM10 启动子的结合，从而改变基因的转录和翻译，从而对 ADAM10 启动子活性进行功能性调节。电泳迁移率变动分析（EMSA）和染色质免疫沉淀（ChIP）分析表明存在直接相互作用。功能研究进一步确定了 EGR1/ADAM10 途径对炎症反应很重要。EGR1 干预可减少宿主促炎细胞因子的分泌，并挽救小鼠内毒素血症模型的存活和组织损伤。脓毒症的特点是危及生命的器官功能障碍，死亡率高得令人无法接受。有证据表明，炎症基因中的功能性 SNP 与脓毒症的易感性、进展和预后有关。这些易感位点所依赖的机制通常提示了脓毒症的关键发病机制和潜在靶点。在本研究中，我们在大样本量和多中心证实了一个功能性变体是脓毒症进展的重要遗传因素，并揭示了变体对 EGR1/ADAM10 途径的调节作用及其对脓毒症严重程度的影响。我们相信，基于临床遗传证据，我们为这一新的途径提供了一个重要的见解，该途径涉及脓毒症炎症过程的调节，这将有助于加深对脓毒症发病机制的理解，并为炎症相关疾病提供潜在的靶点。
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