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

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Neutrophil extracellular traps (NETs) have been implicated in the pathogenesis of sepsis, yet the precise role of NET-related genes (NRGs) remains unclear. This study employed a multiomic Mendelian randomization (MR) approach, leveraging genetic variants as instrumental variables to investigate the relationships between NRGs and sepsis risk. We systematically identified 69 NRGs based on literature and database reviews. Utilizing the IEU OpenGWAS Project database, we extracted genetic data for sepsis cases and controls. Expression quantitative trait loci, 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 the inverse variance-weighted method, supplemented by MR-Egger regression, weighted median, and Bayesian colocalization analysis, and identified four genes (CXCR1, CXCR2, ENTPD4, and MAPK3) significantly associated with sepsis risk. Three CpG sites associated with these genes were identified through mQTL-based MR analysis. Additionally, ten proteins showed significant associations with sepsis risk in pQTL-based MR analysis. Summary-data-based MR and colocalization analyses confirmed the causal relationship between CXCR2 and sepsis, which remained unaffected by pleiotropy. The DNA methylation level at cg06547715, located in the CXCR2 enhancer region, was inversely correlated with CXCR2 expression and sepsis risk. These findings suggest that NRGs, particularly CXCR2, play a crucial role in sepsis susceptibility and that the DNA methylation status of CXCR2 may modulate gene expression, influencing sepsis risk. This study provides novel insights into the molecular epidemiology of sepsis and highlights the potential of NRGs as therapeutic targets. Targeting CXCR2 and its regulatory mechanisms may offer a new avenue for sepsis management. These findings contribute to the theoretical understanding of sepsis pathogenesis and pave the way for future research into precision medicine for sepsis.