Integrative Genomics Reveals Causal Pleiotropy and Therapeutic Opportunities at the Interface of Acute Pancreatitis and Infection

Zou, Bo and Jiang, Hao and Ruan, Jingsheng and Yang, Daifeng and Chen, Xing and Cai, Shanshan and Yi, Xinglin (2025) Integrative Genomics Reveals Causal Pleiotropy and Therapeutic Opportunities at the Interface of Acute Pancreatitis and Infection. Journal of Hepato‐Biliary‐Pancreatic Sciences. ISSN 1868-6974

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Abstract

Background: Understanding the genetic links between acute pancreatitis (AP) and its infectious comorbidities is crucial for prognosis and therapy, yet remains underexplored. Methods: We conducted a comprehensive post‐GWAS analysis using large‐scale summary statistics for AP and 16 infectious diseases. To pinpoint pleiotropic genes, we integrated multi‐omics data via transcriptome‐wide and proteome‐wide association studies, and resolved cell‐type‐specific effects using single‐cell analysis. Extensive locus colocalization analyses were performed to validate our findings by estimating the probability of shared causal variants. Results: This computational discovery phase prioritized 29 high‐confidence pleiotropic genes, including established loci (SPINK1, CRP) and novel candidates (ERBB2, ALDH2, FLOT1). To functionally validate and contextualize these findings, we performed bulk transcriptomic analysis on peripheral blood from AP patients and employed gsMap, a spatial GWAS mapping algorithm, to integrate our genetic data with transcriptomics from a murine AP model, comparing pathological versus normal tissue. These analyses confirmed that the identified genes are dynamically regulated in a severity‐dependent manner in patients and are activated within specific pathological niches in pancreatic tissue. Conclusion: In conclusion, this study provides a genetic map linking AP and its infectious comorbidities, offering insights into potential prevention strategies and highlighting novel therapeutic targets for further investigation and validation.