Multiomic Mendelian randomization-based insights into the role of neutrophil extracellular trap-related genes in sepsis

Objective: This study aims to elucidate the role of neutrophil extracellular trap-related genes (NRGs) in sepsis risk using a multiomic Mendelian randomization (MR) approach, leveraging genetic variants as instrumental variables to investigate the causal relationships between NRGs and sepsis. Methods: We systematically identified 69 NRGs through literature and database reviews. Genetic data for sepsis cases and controls were extracted from the IEU OpenGWAS Project database. Expression quantitative trait loci (eQTLs), methylation quantitative trait loci (mQTLs), and protein quantitative trait loci (pQTLs) associated with NRGs were obtained from the eQTLGen Consortium, mQTL meta-analysis, and deCODE Genetics datasets, respectively. We employed inverse variance-weighted method, supplemented by MR-Egger regression, weighted median, and Bayesian colocalization analysis, to identify genes significantly associated with sepsis risk. Results: Four genes (CXCR1, CXCR2, ENTPD4, and MAPK3) were significantly associated with sepsis risk. Three CpG sites associated with these genes were identified through mQTL-based MR analysis, and ten proteins showed significant associations with sepsis risk in pQTL-based MR analysis. Summary-data-based MR and colocalization analyses confirmed a causal relationship between CXCR2 and sepsis, unaffected by pleiotropy. The DNA methylation level at cg06547715, located in the CXCR2 enhancer region, was inversely correlated with CXCR2 expression and sepsis risk, suggesting that the DNA methylation status of CXCR2 may modulate gene expression, influencing sepsis risk. Conclusion: Our findings indicate that NRGs, particularly CXCR2, play a crucial role in sepsis susceptibility and highlight the potential of NRGs as therapeutic targets. Targeting CXCR2 and its regulatory mechanisms may offer a new avenue for sepsis management, contributing to the theoretical understanding of sepsis pathogenesis and paving the way for future research into precision medicine for sepsis.