DataSheet_1_FCGR2C: An emerging immune gene for predicting sepsis outcome.pdf

BackgroundSepsis is a life-threatening disease associated with immunosuppression. Immunosuppression could ultimately increase sepsis mortality. This study aimed to identify the prognostic biomarkers related to immunity in sepsis.
MethodsPublic datasets of sepsis downloaded from the Gene Expression Omnibus (GEO) database were divided into the discovery cohort and the first validation cohort. We used R software to screen differentially expressed genes (DEGs) and analyzed DEGs’ functional enrichment in the discovery dataset. Immune-related genes (IRGs) were filtered from the GeneCards website. A Lasso regression model was used to screen candidate prognostic genes from the intersection of DEGs and IRGs. Then, the candidate prognostic genes with significant differences were identified as prognostic genes in the first validation cohort. We further validated the expression of the prognostic genes in the second validation cohort of 81 septic patients recruited from our hospital. In addition, we used four immune infiltration methods (MCP-counter, ssGSEA, ImmuCellAI, and CIBERSORT) to analyze immune cell composition in sepsis. We also explored the correlation between the prognostic biomarker and immune cells.
ResultsFirst, 140 genes were identified as prognostic-related immune genes from the intersection of DEGs and IRGs. We screened 18 candidate prognostic genes in the discovery cohort with the lasso regression model. Second, in the first validation cohort, we identified 4 genes (CFHR2, FCGR2C, GFI1, and TICAM1) as prognostic immune genes. Subsequently, we found that FCGR2C was the only gene differentially expressed between survivors and non-survivors in 81 septic patients. In the discovery and first validation cohorts, the AUC values of FCGR2C were 0.73 and 0.67, respectively. FCGR2C (AUC=0.84) had more value than SOFA (AUC=0.80) and APACHE II (AUC=0.69) in evaluating the prognosis of septic patients in our recruitment cohort. Moreover, FCGR2C may be closely related to many immune cells and functions, such as B cells, NK cells, neutrophils, cytolytic activity, and inflammatory promotion. Finally, enrichment analysis showed that FCGR2C was enriched in the phagosome signaling pathway.
ConclusionFCGR2C could be an immune biomarker associated with prognosis, which may be a new direction of immunotherapy to reduce sepsis mortality.

背景 脓毒症（Sepsis）是一种危及生命的疾病，与免疫抑制密切相关。免疫抑制最终可能升高脓毒症患者的病死率。本研究旨在筛选与脓毒症免疫相关的预后生物标志物。
方法 本研究从基因表达综合数据库（Gene Expression Omnibus, GEO）下载脓毒症公共数据集，并将其划分为发现队列与首批验证队列。我们使用R软件筛选差异表达基因（differentially expressed genes, DEGs），并对发现数据集内的DEGs进行功能富集分析。从GeneCards数据库中筛选免疫相关基因（immune-related genes, IRGs）。通过Lasso回归模型从DEGs与IRGs的交集基因中筛选候选预后基因。随后在首批验证队列中，将存在显著表达差异的候选预后基因鉴定为核心预后基因。本研究进一步纳入本医院招募的81例脓毒症患者作为第二验证队列，以验证核心预后基因的表达水平。此外，我们采用四种免疫浸润分析方法（MCP-counter、ssGSEA、ImmuCellAI及CIBERSORT）分析脓毒症患者的免疫细胞组成，并探究预后生物标志物与免疫细胞之间的相关性。
结果 首先，从DEGs与IRGs的交集中共鉴定出140个与预后相关的免疫基因。通过Lasso回归模型在发现队列中筛选得到18个候选预后基因。其次，在首批验证队列中，我们鉴定出4个预后免疫基因，分别为CFHR2、FCGR2C、GFI1及TICAM1。随后在81例脓毒症患者中发现，FCGR2C是唯一在存活者与非存活者之间存在表达差异的基因。在发现队列与首批验证队列中，FCGR2C的曲线下面积（Area Under Curve, AUC）分别为0.73与0.67。在本研究招募的队列中，FCGR2C（AUC=0.84）在评估脓毒症患者预后方面的价值优于序贯器官衰竭评分（Sequential Organ Failure Assessment, SOFA, AUC=0.80）与急性生理学与慢性健康状况评分系统Ⅱ（Acute Physiology and Chronic Health Evaluation Ⅱ, APACHE II, AUC=0.69）。此外，FCGR2C可能与多种免疫细胞及免疫功能密切相关，例如B细胞、NK细胞、中性粒细胞、细胞溶解活性及炎症促进过程。最后，富集分析结果显示FCGR2C富集于吞噬体（phagosome）信号通路中。
结论 FCGR2C可作为与预后相关的免疫生物标志物，有望成为降低脓毒症病死率的免疫治疗新方向。