Identifying potential drug targets for sepsis-related adult respiratory distress syndrome through comprehensive genetic analysis and druggability assessment.
Summary
Using multiple Mendelian randomization frameworks across >100,000 participants and >10,000 cis-eQTLs, the authors mapped 50 genes causally linked to sepsis-related ARDS and highlighted four druggable targets (PSMA4, PDK2, RPS18, NDUFV3). They also confirmed a causal relationship between sepsis and ARDS (beta 1.80, SE 0.36, P<0.001).
Key Findings
- Sepsis is causally associated with ARDS (beta 1.80, SE 0.36, P<0.001).
- SMR identified 677 cis-eQTL genes linked to sepsis; TSMR confirmed 72 as causally associated.
- Mediating and multivariate MR analyses implicated 50 cis-eQTL genes in sepsis-related ARDS.
- Four druggable targets were prioritized: PSMA4, PDK2, RPS18, and NDUFV3.
Clinical Implications
While not immediately practice-changing, the targets (PSMA4, PDK2, RPS18, NDUFV3) prioritize pathways for drug development and may inform biomarker-driven stratification in future trials.
Why It Matters
This work provides an actionable shortlist of causal genes and druggable targets for sepsis-related ARDS, offering a roadmap for preclinical validation and therapeutic development.
Limitations
- Relies on summary-level genetic data; residual pleiotropy and instrument validity may affect estimates.
- No functional or experimental validation of identified targets within the study.
Future Directions
Prioritize functional validation of PSMA4, PDK2, RPS18, and NDUFV3; develop perturbation models and early-phase trials to translate genetic causality into therapeutics.
Study Information
- Study Type
- Case-control
- Research Domain
- Pathophysiology
- Evidence Level
- III - Genetic association and Mendelian randomization analyses using case-control GWAS/eQTL summary data.
- Study Design
- OTHER