Abstract
Sepsis remains a major global concern and is associated with high mortality and morbidity despite improvements in its management. Markers currently in use have shortcomings such as a lack of specificity and failures in the early detection of sepsis. In this study, we aimed to identify key genes involved in the molecular mechanisms of sepsis and search for potential new biomarkers and treatment targets for sepsis using bioinformatics analyses. Three datasets (GSE95233, GSE57065, and GSE28750) associated with sepsis were downloaded from the public functional genomics data repository Gene Expression Omnibus. Differentially expressed genes (DEGs) were identified using R packages (Affy and limma). Functional enrichment of the DEGs was analyzed with the DAVID database. Protein-protein interaction networks were derived using the STRING database and visualized using Cytoscape software. Potential biomarker genes were analyzed using receiver operating characteristic (ROC) curves in the R package (pROC). The three datasets included 156 whole blood RNA samples from 89 sepsis patients and 67 healthy controls. Between the two groups, 568 DEGs were identified, among which 315 were upregulated and 253 were downregulated in the septic group. These genes were enriched for pathways mainly involved in the innate immune response, T-cell biology, antigen presentation, and natural killer cell function. ROC analyses identified nine genes—LRG1, ELANE, TP53, LCK, TBX21, ZAP70, CD247, ITK, and FYN—as potential new biomarkers for sepsis. Real-time PCR confirmed that the expression of seven of these genes was in accordance with the microarray results. This study revealed imbalanced immune responses at the transcriptomic level during early sepsis and identified nine genes as potential biomarkers for sepsis.
Highlights
Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection
Gene Ontology (GO) annotation analysis showed enrichment of Differentially expressed genes (DEGs) involved in inflammatory responses such as the innate response, T-cell receptor pathway, and antigen processing and presentation (Figure 2(a))
It should be noted that the expression levels of most of these genes demonstrated by real-time PCR corresponded to the patterns observed by microarray analyses, while two genes (LRG1, TP53) showed no significant difference
Summary
Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Despite advances in critical care management over the past few years, sepsis is still associated with high mortality and morbidity worldwide [1]. It has been reported that sepsis causes 30 million episodes and 6 million deaths per year globally. The early diagnosis of sepsis is necessary to provide timely treatment. For example, CRP, PCT, and IL-6, have intrinsic shortcomings such as a lack of specificity and failures in the early detection of sepsis [2]. Many researchers are committed to exploring new biomarkers for sepsis. Studies have found that serum levels of presepsin, soluble urokinase plasminogen activator receptor, and soluble triggering receptor expressed on myeloid cell 1, as well as the expression of CD64, are upregulated among sepsis patients. Despite the increase in different potential biomarkers, such efforts have not yet yielded satisfactory results, which warrants further validation
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