Ma Jiawei, Fu Lu, Lu Zhonghua, Sun Yun
The First Department of Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.
Department of Critical Care Medicine, Wuxi No. 2 People's Hospital, Wuxi 214002, China.
ACS Omega. 2024 May 23;9(22):23864-23872. doi: 10.1021/acsomega.4c01934. eCollection 2024 Jun 4.
The current investigation deployed Mendelian randomization (MR) to elucidate the causal relationship between circulating proteins and sepsis. A rigorous two-sample MR analysis evaluated the effect of plasma proteins on the sepsis susceptibility. To affirm the integrity of MR findings, a suite of supplementary analyses, including Bayesian colocalization, Steiger filtering, the assessment of protein-altering polymorphisms, and the correlation between expression quantitative trait loci and protein quantitative trait loci (pQTLs), was employed. The study further integrated the examination of protein-protein interactions and pathway enrichment, along with the identification of pharmacologically actionable targets, to advance our comprehension and outline potential sepsis therapies. Subsequent analyses leveraging -pQTLs within MR studies unveiled noteworthy relationships: 94 specific proteins exhibited significant links with sepsis-related 28 day mortality, while 96 distinct proteins correlated with survival outcomes in sepsis. Furthermore, incorporating both - and -pQTLs in MR investigations revealed more comprehensive findings, associating 201 unique proteins with sepsis-related 28 day mortality and 199 distinct proteins with survival outcomes in sepsis. Markedly, colocalization analyses confirmed that eight of these proteins exhibited prominent evidence for colocalization, emphasizing their potential criticality in sepsis pathophysiology. Further in silico analyses were conducted to delineate putative regulatory networks and to highlight prospective drug targets among these proteins. Employing the MR methodology has shed light on plasma proteins implicated in the etiopathogenesis of sepsis. This novel approach unveiled numerous biomarkers and targets, providing a scientific rationale for the development of new therapeutic strategies and prophylactic measures against sepsis.
当前的研究采用孟德尔随机化（MR）方法来阐明循环蛋白与败血症之间的因果关系。一项严格的两样本MR分析评估了血浆蛋白对败血症易感性的影响。为了确认MR结果的完整性，采用了一系列补充分析，包括贝叶斯共定位、施泰格滤波、蛋白质改变多态性评估以及表达定量性状位点与蛋白质定量性状位点（pQTL）之间的相关性分析。该研究进一步整合了蛋白质-蛋白质相互作用和通路富集分析，以及药理学可作用靶点的鉴定，以加深我们的理解并勾勒出潜在的败血症治疗方法。随后在MR研究中利用-pQTLs进行的分析揭示了值得注意的关系：94种特定蛋白与败血症相关的28天死亡率存在显著关联，而96种不同蛋白与败血症的生存结果相关。此外，在MR研究中纳入-pQTLs和-pQTLs揭示了更全面的结果，201种独特蛋白与败血症相关的28天死亡率相关，199种不同蛋白与败血症的生存结果相关。值得注意的是，共定位分析证实其中8种蛋白表现出明显的共定位证据，强调了它们在败血症病理生理学中的潜在重要性。进一步进行了计算机模拟分析，以描绘假定的调控网络并突出这些蛋白中的潜在药物靶点。采用MR方法揭示了与败血症发病机制相关的血浆蛋白。这种新方法揭示了众多生物标志物和靶点，为开发针对败血症的新治疗策略和预防措施提供了科学依据。
