Identification of therapeutic targets for neonatal respiratory distress: A systematic druggable genome-wide Mendelian randomization.

Currently, there remains a significant gap in effective pharmacologic interventions for neonatal respiratory distress syndrome (NRDS). To address this critical unmet medical need, we aimed to systematically identify novel therapeutic targets and preventive strategies through comprehensive integration and analysis of multiple publicly accessible datasets. In this study, we employed an integrative approach combining druggable genome data, cis-expression quantitative trait loci (cis-eQTL) from human blood and lung tissues, and genome-wide association study summary statistics for neonatal respiratory distress. We performed two-sample Mendelian randomization (TSMR) analysis to investigate potential causal relationships between druggable genes and neonatal respiratory distress. To strengthen causal inference, we performed Bayesian co-localization analyses. Furthermore, we conducted phenome-wide Mendelian randomization (Phe-MR) to systematically evaluate potential side effects and alternative therapeutic indications associated with the identified candidate drug targets. Finally, we interrogated existing drug databases to identify actionable pharmacological agents targeting the identified genes. All 3 genes (LTBR, NAAA, CSNK1G2) were analyzed by Bayesian co-localization (PH4 > 75%). CSNK1G2 (lung eQTL, odds ratio [OR]: 0.419, 95% CI: 0.185-0.948, P = .037; blood eQTL, OR: 4.255, 95% CI: 1.346-13.455, P = .014; Gtex whole blood eQTL, OR: 4.966, 95% CI: 1.104-22.332, P = .037). LTBR (lung eQTL, OR: 0.550, 95% CI: 0.354-0.856, P = .008; blood eQTL, OR: 0.347, 95% CI: 0.179-0.671, P = .002; Gtex whole blood eQTL, OR: 0.059, 95% CI: 0.0.007-0.478, P = .008). NAAA (lung eQTL, OR: 0.717, 95% CI: 0.555-0.925, P = .011; Gtex whole blood eQTL, OR: 0.660, 95% CI: 0.476-0.913, P = .012). Drug repurposing analyses support the possibility that etanercept and asciminib hydrochloride may treat neonatal respiratory distress by activating LTBR. This study demonstrated that LTBR, NAAA, and CSNK1G2 may serve as promising biomarkers and therapeutic targets for NRDS.