Genomic and GEO data integration identifies PDGFB as a potential therapeutic target for sepsis

Abstract

Sepsis is a major contributor to global health loss, yet effective therapeutic options remain scarce. This study aims to identify potential therapeutic targets for sepsis. We integrated data from the druggable genome, expression quantitative trait loci (eQTLs) from human blood, and genome-wide association studies on sepsis. Mendelian randomization (MR) was employed to investigate causal relationships between drug target genes and sepsis. The eQTLGen Consortium data served as the discovery set and was validated using genotype-tissue expression (GTEx) eQTLs. Sensitivity and colocalization analyses were conducted to support causal inferences. Additionally, phenome-wide MR (Phe-MR) was used to assess potential side effects of druggable genes. The expression levels of the target genes were validated using the GSE154918 dataset. In the discovery MR analysis phase, we identified 26 potential targets with significant expression in blood (PFDR < 0.05). PDGFB and BPI were further validated in the replication MR analysis. Colocalization analysis provided strong evidence (PPH4 > 0.75) supporting PDGFB as a therapeutic candidate for sepsis. Phe-MR analysis suggested that targeting PDGFB is unlikely to cause adverse effects. PDGFB downregulation was confirmed in sepsis groups via the GEO dataset. PDGFB is identified as a promising druggable target for sepsis treatment, supported by strong evidence of its therapeutic potential.

Keywords: PDGFB; GEO database; Genomic; Mendelian randomization; Sepsis.

Fig. 1

Flow diagram of the study.

Fig. 2

Forest plots displaying the findings from the discovery phase for 26 significant genes.

Fig. 3

Volcano map of MR analysis in discovery phase. Significant genes are annotated and highlighted in green and pink. Genes with an OR greater than 1 are marked in pink and identified as risk genes for sepsis, while those with an OR less than 1 are marked in green and considered protective genes against sepsis. The horizontal dashed line indicates the p-value corresponding to FDR of 0.05.

Fig. 4

The results of colocalization. A strong colocalization signal between PDGFB and sepsis is shown. Instrumental variables and their chromosomal positions are visualized.

Fig. 5

Manhattan plot for MR results of whole phenome with blood PDGFB. The vertical axis shows the p-values in phenome-wide MR results. The horizontal axis represents the categorization of 775 disease traits from the UK Biobank, clustered into 17 categories. Points represent disease traits, with different colors indicating different MR results of expression. Disease traits with significant causal effects (FDR <0.05) are highlighted and marked.