Identification of novel plasma proteins as potential therapeutic targets for benign prostatic hyperplasia: a proteome-wide association study.

Background: Benign prostatic hyperplasia (BPH) represents a prevalent age-related disorder with suboptimal pharmacological management. To systematically identify plasma proteins causally linked to BPH pathogenesis and therapeutic potential, we conducted a proteome-wide association study (PWAS) integrated with multi-omics analytical approaches. Methods: Genome-wide association study (GWAS) datasets of bioavailable testosterone (BAT) and BPH were harmonized by multi-trait analysis of GWAS (MTAG) to enhance discovery power. Subsequent proteomic integration encompassed PWAS, two-sample Mendelian randomization (MR), and Bayesian colocalization analyses, complemented by pathway enrichment evaluation. Validation was performed using conventional BPH GWAS data. Results: This integrative analysis identified 25 plasma proteins exhibiting significant associations with BPH risk (adjusted P<0.05), including two proteins (AIF1 and RSPO3) independently validated in the conventional BPH GWAS dataset. MR analyses established causal relationships for 18 proteins (adjusted P<0.05), with Bayesian colocalization confirming shared causal variants between BPH and key proteins AIF1 [posterior probability 4 (PP4) =0.999], RSPO3 (PP4 =0.714), and COL2A1 (PP4 =0.920). Pathway analysis revealed enrichment in inflammatory signaling and extracellular matrix remodeling. Conclusions: This first PWAS investigation of BPH delineates a panel of circulating proteins with mechanistic and therapeutic implications, particularly highlighting AIF1 and RSPO3 as priority candidates for functional validation and drug development.