Genomic and GEO data integration identifies PDGFB as a potential therapeutic target for sepsis.
Total: 73.0Innovation: 8Impact: 7Rigor: 7Citation: 7
Summary
By integrating druggable genome annotations, large blood eQTLs, and sepsis GWAS with replication and colocalization, this study nominates PDGFB as a causally supported and low–on-target-risk therapeutic target for sepsis. GEO transcriptomics confirm PDGFB downregulation in sepsis.
Key Findings
- Discovery MR identified 26 blood-expressed drug targets (PFDR<0.05), with PDGFB and BPI replicated.
- Colocalization provided strong support for PDGFB (PPH4>0.75) as a causal sepsis locus.
- Phenome-wide MR suggested low risk of adverse effects when targeting PDGFB; GEO datasets confirmed PDGFB downregulation in sepsis.
Clinical Implications
Encourages preclinical validation and potential repurposing or development of PDGFB-modulating agents for sepsis; informs precision medicine strategies.
Why It Matters
Provides a human genetics–anchored, target-prioritization pipeline and a concrete target (PDGFB) to propel translational sepsis therapeutics.
Limitations
- MR relies on instrumental variable assumptions and blood eQTLs may not capture tissue/cell-type specificity in sepsis.
- No functional or clinical intervention data yet to confirm target validity.
Future Directions
Functional validation of PDGFB in relevant immune and endothelial cells, pharmacologic modulation in animal sepsis models, and exploration of drug repurposing opportunities.
Study Information
- Study Type
- Genetic causal inference (Mendelian randomization)
- Research Domain
- Treatment
- Evidence Level
- III - Observational genetic causal inference with replication and colocalization
- Study Design
- OTHER