Genomic and GEO data integration identifies PDGFB as a potential therapeutic target for sepsis.

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We integrated data from the druggable genome, expression quantitative trait loci (eQTLs) from human blood, and genome-wide association studies on sepsis. Mendelian randomization (MR) was employed to investigate causal relationships between drug target genes and sepsis. The eQTLGen Consortium data served as the discovery set and was validated using genotype-tissue expression (GTEx) eQTLs. Sensitivity and colocalization analyses were conducted to support causal inferences. Additionally, phenome-wide MR (Phe-MR) was used to assess potential side effects of druggable genes. The expression levels of the target genes were validated using the GSE154918 dataset. In the discovery MR analysis phase, we identified 26 potential targets with significant expression in blood (PFDR < 0.05). PDGFB and BPI were further validated in the replication MR analysis. Colocalization analysis provided strong evidence (PPH4 > 0.75) supporting PDGFB as a therapeutic candidate for sepsis. Phe-MR analysis suggested that targeting PDGFB is unlikely to cause adverse effects. PDGFB downregulation was confirmed in sepsis groups via the GEO dataset. PDGFB is identified as a promising druggable target for sepsis treatment, supported by strong evidence of its therapeutic potential.", "claims": [{"id": "claim-method", "statement": "Subsequently, we performed a two-sample MR analysis to assess the causal impact of blood eQTLs on sepsis and performed replication and validation studies.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:40221544", "locator": "sections[2] \"Methods\" paragraph 4", "quote": "Subsequently, we performed a two-sample MR analysis to assess the causal impact of blood eQTLs on sepsis and performed replication and validation studies."}], "state": "complete"}, {"id": "claim-data-access", "statement": "All data generated or analyzed during this study are included in this published article and its additional files.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:40221544", "locator": "sections[23] \"Data availability\" paragraph 2", "quote": "All data generated or analyzed during this study are included in this published article and its additional files."}], "state": "complete"}, {"id": "claim-target-result", "statement": "PDGFB is identified as a promising druggable target for sepsis treatment, supported by strong evidence of its therapeutic potential.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:40221544", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "PDGFB is identified as a promising druggable target for sepsis treatment, supported by strong evidence of its therapeutic potential."}, {"asset": "source:pmid:40221544", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "Colocalization analysis provided strong evidence (PPH4 > 0.75) supporting PDGFB as a therapeutic candidate for sepsis."}, {"asset": "source:pmid:40221544", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "PDGFB and BPI were further validated in the replication MR analysis."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "PDGFB is identified as a promising druggable target for sepsis treatment, supported by strong evidence of its therapeutic potential.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:40221544"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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