SOX18-associated gene signature predicts sepsis outcome

Abstract

Objectives: Sepsis is a critical medical condition associated with an high mortality. Currently, there are no reliable diagnostic or prognostic biomarkers to evaluate sepsis outcomes. SRY (sex-determining region on the Y chromosome)-box transcription factor 18 (SOX18) is an endothelial barrier protective protein, and a decreased level of SOX18 expression is involved in disruption of human endothelial cell barrier integrity. Over-expression of SOX18 attenuates the bacterial lipopolysaccharide (LPS)-mediated disruption of the vascular barrier and is associated with favorable prognosis. The utility of SOX18-related genes as biomarkers in sepsis is uncertain.

Methods: Transcriptomic analysis was used to profile the PBMC samples of patients with sepsis across two Gene Expression Omnibus (GEO) datasets with survival data. An 84-gene signature was derived from discovery datasets that correlated with SOX18 gene expression and sepsis survival.

Results: Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed Th1 and Th2 cell differentiation, Cytokine-cytokine receptor interaction, and T cell receptor signaling pathways as the most significantly enriched KEGG pathways among 84 genes. A severity score based on the gene expression of 84 genes was allocated to each patient. A notable increase was detected in sepsis patients compared to healthy controls in both discovery and validation cohorts. SOX18-associated gene signature discriminated severe cases from mild cases and performed significantly better than both random 84-gene sets from whole genomes or sepsis survival-related genes. Furthermore, we obtained an 18-gene signature from screening these 84 genes in a LASSO model, which performed better in both discovery and validation cohorts.

Conclusions: Data support SOX18-associated gene signatures as a prognostic biomarker for sepsis.

Keywords: SOX18; gene signature; sepsis survival.

Figure 1

Discovery of SOX18 co-expressed genes and sepsis survival-related genes. A. Volcano plot showing DEGs among sepsis survivors and non-survivors. B. Enriched KEGG pathways among sepsis survival-related genes. C. Enriched TF target genes among SOX18 co-expressed genes; D. Enriched KEGG pathways among SOX18 co-expressed genes. E. Venn plot depicting sepsis survival and SOX18 co-expressed overlapping genes; F. Heat map revealing the 84-gene signature gene expression in the discovery cohort. Red represents increased gene expression, while blue represents decreased gene expression.

Figure 2

The 84-gene signature-based sepsis risk score. A. Enriched KEGG pathways among 84 genes; B. Box plot of the risk scores in non-survivors and survivors. C. PPI network for the 84-genes.

Figure 3

84-gene signature-based sepsis risk score differentiates non-survivors from survivors in both the discovery and validation cohort. A. ROC curves of the 84-gene signature in the discovery and validation cohorts. B. Density distribution plot of random gene signatures from the whole genome genes and only sepsis survival-related genes, the 84-gene signature-based AUC value was marked as red inverted triangle; C. PCA plot of the 84-gene signature for the discovery cohort and validation cohorts.

Figure 4

The 18-gene signature-based sepsis risk score. A. The gene signature screening of optical parameters in LASSO model; B. Box plot of the risk scores in non-survivors and survivors.

Figure 5

18-gene signature-based sepsis risk score differentiated non-survivors from survivors in both the discovery and validation cohort. A. ROC curves of the 18-gene signature in the discovery and validation cohorts. B. Density distribution plot of random gene signatures from the whole genome genes and only sepsis survival-related genes, the 18-gene signature-based AUC value was marked as red inverted triangle; C. PCA plot of the 18-gene signature for the discovery cohort and validation cohorts.