Identification of Potential Therapeutic Targets for Sepsis Using Mendelian Randomization and Integrated eQTL/pQTL Analysis.

BACKGROUND

Sepsis significantly contributes to global morbidity, yet effective treatments remain limited. Mendelian randomization (MR), integrated with genetic data, offers promise for uncovering novel therapeutic targets.

METHODS

We utilized eQTL (eQTLGen) and pQTL (DECODE) data as exposures, and GWAS summaries for sepsis (UK Biobank, FinnGen) as outcomes. GEO datasets (GSE57065, GSE95233) underwent batch correction via PCA clustering using the "sva" R package. Differentially expressed genes (DEGs, |log2FC|>1, adjusted P<0.05) intersected with druggable genes were identified. MR analyses were performed using TwoSampleMR and MR-PRESSO, followed by drug-target predictions using DGIdb. Key genes (BCL6, PTX3, IL7R, BTN3A2, LGALS1) were validated experimentally through qRT-PCR and Western blot in a mouse sepsis model induced by cecal ligation and puncture (CLP).

RESULTS

Intersection analyses yielded 398 therapeutic candidates. MR revealed 6 genes and 21 proteins significantly associated with sepsis risk, including protective (eg, HDC, IFI27) and harmful factors (eg, CTSO, BTN3A2). Furthermore, 13 druggable genes correlated with sepsis-related factors, such as BTN3A2 with diabetes, and IL7R, BCL6, PTX3, among others, linked to vitamin D deficiency and cancer. DGIdb identified 34 potential drugs targeting these hub genes, with KEGG and GO analyses highlighting immune regulation and FoxO signaling pathways. qRT-PCR and Western blot confirmed consistent downregulation (BCL6, PTX3, IL7R) and upregulation (BTN3A2, LGALS1) at both mRNA and protein levels in septic mice compared to controls, supporting MR-based predictions.

CONCLUSION

We identified and experimentally validated 6 sepsis-associated genes and 21 proteins, providing crucial insights into potential therapeutic targets and enhancing understanding of the molecular pathogenesis of sepsis.