Identification of key pathogenic genes of sepsis based on the Gene Expression Omnibus database

Abstract

Sepsis is a life-threatening condition in which an uncontrolled inflammatory host response is triggered. The exact pathogenesis of sepsis remains unclear. The aim of the present study was to identify key genes that may aid in the diagnosis and treatment of sepsis. mRNA expression data from blood samples taken from patients with sepsis and healthy individuals was downloaded from the Gene Expression Omnibus database and differentially expressed genes (DEGs) between the two groups were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and protein-protein interaction (PPI) network construction, was performed to investigate the function of the identified DEGs. Furthermore, for validation of these results, the expression levels of several DEGs were analyzed by reverse transcription quantitative-polymerase chain reaction (RT-qPCR) in three patients with sepsis and three healthy blood samples to support the results obtained from the bioinformatics analysis. Receiver operating characteristic analyses were also used to analyze the diagnostic ability of the identified DEGs for sepsis. The results demonstrated that a total of 4,402 DEGs, including 1,960 upregulated and 2,442 downregulated genes, were identified between patients with sepsis and healthy individuals. KEGG pathway analysis revealed that 39 DEGs were significantly enriched in toll-like receptor signaling pathways. The top 20 upregulated and downregulated DEGs were used to construct the PPI network. Hub genes with high degrees, including interleukin 1 receptor-associated kinase 3 (IRAK3), S100 calcium-binding protein (S100)A8, angiotensin II receptor-associated protein (AGTRAP) and S100A9, were demonstrated to be associated sepsis. Furthermore, RT-qPCR results demonstrated that IRAK3, adrenomedullin (ADM), arachidonate 5-lipoxygenase (ALOX5), matrix metallopeptidase 9 (MMP9) and S100A8 were significantly upregulated, while ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1) was upregulated but not significantly, in blood samples from patients with sepsis compared with healthy individuals, which was consistent with bioinformatics analysis results. Therefore, AGTRAP, IRAK3, ADM, ALOX5, MMP9, S100A8 and ENTPD1 were identified to have potential diagnostic value in sepsis. In conclusion, dysregulated levels of the AGTRAP, IRAK3, ADM, ALOX5, MMP9, S100A8 and ENTPD1 genes may be involved in sepsis pathophysiology and may be utilized as potential diagnostic biomarkers or therapeutic targets.

DNA Methylation Analysis to Unravel Altered Genetic Pathways Underlying Early Onset and Late Onset Neonatal Sepsis. A Pilot Study

“…Interestingly, S100A8 is an alarmin related with immunosuppression, because it prevents the expansion of specific inflammatory monocyte populations in septic neonates ( 44 ). Of note, S100A8 participates in neutrophil chemotaxis and adhesion, and it is up-regulated in patients with sepsis ( 45 ), which is in agreement with the low methylation levels identified in its promoter found in our study.…”

Analysis of interleukin-1 receptor associated kinase-3 (IRAK3) function in modulating expression of inflammatory markers in cell culture models: A systematic review and meta-analysis

“…Identifying the time frames of these events in different cell models is relevant, as IRAK3 is involved in sepsis pathophysiology [ 14 , 135 ]. The dysregulated cytokine production responses of the first phase of sepsis that can cause organ injury or dysfunction are followed by immunosuppression characterized by irresponsiveness to repeated infections with pathogens [ 18 ].…”

“…Notably, IRAK3 plays a role in regulating immunosuppression in sepsis. IRAK3 mRNA expression is up-regulated in blood samples of patients with sepsis compared with healthy controls [ 14 ]. Clinical samples of sepsis patients show increased IRAK3 mRNA levels and significant decreases in TNF-α and IL-6 protein levels at 4h (IT) after ex vivo LPS challenge [ 89 ] or decreased TNF-α protein levels at IT or LT [ 88 ], whereas samples from healthy controls demonstrate the hyper-inflammatory phase of sepsis.…”

“…However, more recent studies show that NF-κB activity or inflammatory cytokine levels are increased in IRAK3 downregulation, demonstrating IRAK3 has an inhibitory role in inflammation [ 6 , 11 – 13 ]. As one of the crucial proteins regulating pathways of innate immune signalling [ 6 ], IRAK3 has been found to be associated with many significant diseases such as sepsis [ 14 ], cancer [ 15 ], and asthma [ 12 ] and is considered a promising biomarker candidate for diagnosis of these diseases and a potential therapeutic target. Therefore, the purpose of this review is to provide a greater understanding about IRAK3 function in inflammation based on systematic analysis of quantitative data reported in published studies until now.…”

Screening and identification of key gene in sepsis development

“…In addition, some recent studies also found the hub-gene from microarray technology. Lu et al [ 16 ] identified 5 hub genes (IRAK3, ADM, ALOX5, MMP9, and S100A8) related to sepsis from 2 GEO datasets by developing an integrated method including DEG screen, pathway analysis, gene annotations, PPI networks. Wang et al [ 17 ] identified candidate biomarkers (Icam1 and Socs3) for sepsis from one GEO datasets by performing DEG, gene functional enrichment, and PPI network analyses, and validated their results with RT-qPCR.…”