Identification of novel protein biomarkers and drug targets for functional dyspepsia by integrating human plasma proteome with genome

This study aimed to identify novel therapeutic targets for functional dyspepsia (FD) using Mendelian randomization (MR) and assess the feasibility of candidate drugs for FD treatment. MR analysis was employed to identify cis-acting protein quantitative trait loci (cis-pQTLs) significantly associated with FD. Initial MR analysis was conducted using the TwoSample MR software package. Cochran Q-test and MR-Egger intercept test were applied to evaluate potential heterogeneity and horizontal pleiotropy, respectively. Cis-pQTLs exhibiting consistent effect estimates in the same direction were prioritized. Subsequent analyses included gene ontology enrichment, Kyoto Encyclopedia of Genes and Genomes enrichment, and protein-protein interaction network construction. Potential therapeutic compounds were predicted using the Drug Signatures Database, followed by molecular docking to evaluate their binding affinities with the target protein. The analysis identified 10 cis-pQTLs causally linked to FD. Certain cis-pQTLs were associated with a reduced risk of FD (odds ratio < 1), while others were associated with an increased risk (odds ratio > 1). Specific cis-pQTLs were identified whose corresponding protein levels serve as established diagnostic biomarkers for disease risk and pathological status. Five potential therapeutic drugs for FD were predicted through this integrated approach. Among the candidate drugs, Esculetin demonstrated notable pharmacological activities, including antioxidant and anti-inflammatory effects. Scopoletin exhibited a bidirectional modulatory effect on smooth muscle contraction, suggesting potential benefits in improving gastrointestinal motility. These 2 compounds represent the most promising candidates for FD therapy. This study delineated a rigorous multi-omics integration pipeline to identify potential therapeutic targets and drugs for FD. These findings provide new insights for developing therapeutic agents against FD.