Abstract
BACKGROUND: Sepsis-related adult respiratory distress syndrome (ARDS) is a life-threatening condition characterised by a high mortality rate. This underscores the pressing requirement to identify and develop potential therapeutic targets for the severe condition. This study investigated the genetic predisposition to sepsis-related ARDS in this study. METHODS: We utilised summary-based Mendelian randomisation (SMR), two-sample MR (TSMR), mediating MR, and multivariate MR (MVMR) analysis to explore the genetic susceptibility of sepsis-related ARDS by integrating over 10 000 cis-expression quantitative trait loci (cis-eQTLs) and over 100 000 participants. Subsequently, we performed drug target analysis to identify potentially druggable cis-eQTL genes. RESULTS: The SMR analysis identified 677 cis-eQTL genes associated with sepsis. Further TSMR validation filtered 72 cis-eQTL genes causally associated with sepsis. Sepsis was causally associated with ARDS (beta = 1.80, standard error (SE) = 0.36, P < 0.001). After conducting the mediating MR and MVMR analysis, 50 cis-eQTL genes were reported to be causally associated with sepsis-related ARDS. Subsequent drug target analysis confirmed the role of four targets (PSMA4, PDK2, RPS18, and NDUFV3) as druggable genes for sepsis-related ARDS. CONCLUSIONS: Through an extensive analysis, we identified potential drug targets for sepsis-related ARDS. Additional research is imperative to substantiate our discoveries and to pave the way for the development of novel pharmaceuticals aimed at these specific targets.