Classification of subtypes and identification of dysregulated genes in sepsis

Ran Tong; Xianfei Ding; Fengyu Liu; Hongyi Li; Huan Liu; Heng Song; Yuze Wang; Xiaojuan Zhang; Shaohua Liu; Tongwen Sun

doi:10.3389/fcimb.2023.1226159

Classification of subtypes and identification of dysregulated genes in sepsis

Front Cell Infect Microbiol. 2023 Aug 21:13:1226159. doi: 10.3389/fcimb.2023.1226159. eCollection 2023.

Authors

Ran Tong^{1

2

3}, Xianfei Ding^{1

2}, Fengyu Liu^{1

2}, Hongyi Li^{1

2}, Huan Liu^{1

2}, Heng Song^{1

2

3}, Yuze Wang^{1

2}, Xiaojuan Zhang^{1

2}, Shaohua Liu^{1

2}, Tongwen Sun^{1

2

3}

Affiliations

¹ General Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Henan Engineering Research Center for Critical Care Medicine, Zhengzhou, Henan, China.
² Zhengzhou Key Laboratory of Sepsis, Zhengzhou, Henan, China.
³ Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.

Abstract

Background: Sepsis is a clinical syndrome with high mortality. Subtype identification in sepsis is meaningful for improving the diagnosis and treatment of patients. The purpose of this research was to identify subtypes of sepsis using RNA-seq datasets and further explore key genes that were deregulated during the development of sepsis.

Methods: The datasets GSE95233 and GSE13904 were obtained from the Gene Expression Omnibus database. Differential analysis of the gene expression matrix was performed between sepsis patients and healthy controls. Intersection analysis of differentially expressed genes was applied to identify common differentially expressed genes for enrichment analysis and gene set variation analysis. Obvious differential pathways between sepsis patients and healthy controls were identified, as were developmental stages during sepsis. Then, key dysregulated genes were revealed by short time-series analysis and the least absolute shrinkage and selection operator model. In addition, the MCPcounter package was used to assess infiltrating immunocytes. Finally, the dysregulated genes identified were verified using 69 clinical samples.

Results: A total of 898 common differentially expressed genes were obtained, which were chiefly related to increased metabolic responses and decreased immune responses. The two differential pathways (angiogenesis and myc targets v2) were screened on the basis of gene set variation analysis scores. Four subgroups were identified according to median expression of angiogenesis and myc target v2 genes: normal, myc target v2, mixed-quiescent, and angiogenesis. The genes CHPT1, CPEB4, DNAJC3, MAFG, NARF, SNX3, S100A9, S100A12, and METTL9 were recognized as being progressively dysregulated in sepsis. Furthermore, most types of immune cells showed low infiltration in sepsis patients and had a significant correlation with the key genes. Importantly, all nine key genes were highly expressed in sepsis patients.

Conclusion: This study revealed novel insight into sepsis subtypes and identified nine dysregulated genes associated with immune status in the development of sepsis. This study provides potential molecular targets for the diagnosis and treatment of sepsis.

Keywords: biomarker; dysregulated genes; immune cell infiltration; sepsis; subtypes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Division
Databases, Factual
Humans
RNA-Binding Proteins
Sepsis*

Substances

CPEB4 protein, human
RNA-Binding Proteins

Grants and funding

This study was supported by the Fund of National Natural Science Foundation of China (Grant No. U2004110, 82172129, 82202370); The central government guides local science and technology development funds (Grant No. Z20221343037); The 2021 youth talent promotion project in Henan Province (Grant No.2021HYTP053); Medical Science and Technology Tackling Plan Provincial and Ministerial Major Projects of Henan Province (Grant No. SBGJ202101015), and 2021 joint construction project of Henan Medical Science and technology breakthrough plan (Grant No. LHGJ20210299); The Excellent Youth Science Foundation of Henan Province (Grant No. 232300421048).