ARG1 as a promising biomarker for sepsis diagnosis and prognosis: evidence from WGCNA and PPI network

Abstract

Background Sepsis is a life-threatening multi-organ dysfunction caused by the dysregulated host response to infection. Sepsis remains a major global concern with high mortality and morbidity, while management of sepsis patients relies heavily on early recognition and rapid stratification. This study aims to identify the crucial genes and biomarkers for sepsis which could guide clinicians to make rapid diagnosis and prognostication. Methods Preliminary analysis of multiple global datasets, including 170 samples from patients with sepsis and 110 healthy control samples, revealed common differentially expressed genes (DEGs) in peripheral blood of patients with sepsis. After Gene Oncology (GO) and pathway analysis, the Weighted Gene Correlation Network Analysis (WGCNA) was used to screen for genes most related with clinical diagnosis. Also, the Protein-Protein Interaction Network (PPI Network) was constructed based on the DEGs and the hub genes were found. The results of WGCNA and PPI network were compared and one shared gene was discovered. Then more datasets of 728 experimental samples and 355 control samples were used to prove the diagnostic and prognostic value of this gene. Last, we used real-time PCR to confirm the bioinformatic results. Results Four hundred forty-four common differentially expressed genes in the blood of sepsis patients from different ethnicities were identified. Fifteen genes most related with clinical diagnosis were found by WGCNA, and 24 hub genes with most node degrees were identified by PPI network. ARG1 turned out to be the unique overlapped gene. Further analysis using more datasets showed that ARG1 was not only sharply up-regulated in sepsis than in healthy controls, but also significantly high-expressed in septic shock than in non-septic shock, significantly high-expressed in severe or lethal sepsis than in uncomplicated sepsis, and significantly high-expressed in non-responders than in responders upon early treatment. These all demonstrate the performance of ARG1 as a key biomarker. Last, the up-regulation of ARG1 in the blood was confirmed experimentally. Conclusions We identified crucial genes that may play significant roles in sepsis by WGCNA and PPI network. ARG1 was the only overlapped gene in both results and could be used to make an accurate diagnosis, discriminate the severity and predict the treatment response of sepsis.

Curculigoside, a traditional Chinese medicine monomer, ameliorates oxidative stress in Alzheimer's disease mouse model via suppressing ferroptosis

“…Our analysis using WGCNA indicated that the yellow module in GSE5281 and the blue module in GSE144194 were the most relevant to AD and ferroptosis, suggesting that potential drug targets could be explored in these modules. Previous studies have typically selected the top 10–20 hub genes for qPCR verification, which represent about 20% of all genes in the screened modules (Liu et al, 2019; Liu, Chen, & Lu, 2021; Zeng et al, 2021; Zhang et al, 2022). However, our aim was to identify one or two target genes related to AD and ferroptosis, so we expanded the screening range of hub genes to the top 20%–35% of all genes in the two modules.…”

The ‘analysis of gene expression and biomarkers for point-of-care decision support in Sepsis‘ study; temporal clinical parameter analysis and validation of early diagnostic biomarker signatures for severe inflammation andsepsis-SIRS discrimination

“…Providing external validation to our findings, several genes, such as CD177, ARG1 (arginase), MMP9, OLAH and ADM have been described previously as having important inflammatory roles in sepsis ( 16 , 29 , 41 , 42 , 44 , 51 – 71 ). ARG1 in particular has been identified by other groups as a good biomarker for sepsis diagnosis ( 64 ), specifically associated with neutrophil activity ( 72 ) a component of which may be from a myeloid-derived suppressor cell (MDSC) phenotype ( 60 ). These have been postulated to promote immune-suppression during sepsis and may also serve the same function in SIRS due to surgery or trauma ( 73 , 74 ), perhaps due to arginase suppression of T-cell function ( 55 , 56 , 63 , 75 ).…”

A Meta-Analysis of Whole Blood Transcriptome Reveals Association of Increased Neutrophil Activity and T cell Suppression in Sepsis

“…Upregulation of ARG1 on neutrophils in sepsis worsen the immunosuppression by suppressing T-lymphocytes. It impairs the function of T-cells by downregulating T-cell receptor (TCR) associated CD3G and CD3E chains leading to immunosuppressive state [42].…”