Plasma proteomic signatures predict incident benign prostatic hyperplasia: a prospective cohort study of 20 996 men

Clinical Snapshot

Key Findings

• P Value: FDR <0.05 for 92 significant proteins

• Effect Size: Three-protein signature: TSPAN1 HR=1.24, KLK3 HR=1.34 (risk factors), EDA2R HR=0.83 (protective)

• Primary Outcome: Incident benign prostatic hyperplasia over median 13.38 years

• Nnt Or Sensitivity: AUC 0.71 indicates moderate discriminative ability for BPH prediction

• Confidence Interval: AUC 0.71 (95% CI 0.69-0.73)

Clinical Application

Requires specialised proteomic testing platforms (Olink) not routinely available in clinical practice Limited immediate applicability - proteomic testing not PBS-funded for BPH screening. Would require validation in Australian population and cost-effectiveness analysis before clinical implementation Middle-aged and elderly men without existing BPH, particularly those of European ancestry given UK Biobank demographics

Abstract

BACKGROUND: Benign prostatic hyperplasia (BPH) is a prevalent disease in elderly men. However, the plasma proteomic signatures for incident BPH are absent, hindering early prediction and risk stratification. We aimed to identify plasma proteins associated with incident BPH and the implicated biological pathways. METHODS: This prospective cohort was constructed based on the UK Biobank, enrolling 20 996 BPH-free males at baseline. We used the Olink Explore platform to determine the abundances of 2920 plasma proteins. We used Cox regression models to evaluate associations and the Extreme Gradient Boosting model to perform feature selection and predictive modelling. We performed pathway enrichment and Mendelian randomisation analyses to elucidate the molecular pathways involved and assess causality. RESULTS: During the median follow-up period of 13.38 years, 2405 incident BPH cases were recorded. Cox regression identified 92 plasma proteins significantly associated with BPH risk (false discovery rate <0.05). Extreme Gradient Boosting model prioritised a three-protein signature: TSPAN1 (hazard ratio (HR) = 1.24) and KLK3 (HR = 1.34) as risk factors, and EDA2R (HR = 0.83) as a protective factor. This three-protein panel achieved an AUC of 0.71 (95% confidence interval = 0.69-0.73) for predicting BPH onset. Enrichment analysis revealed the associated proteins were mainly involved in immune-inflammatory pathways and stromal remodelling. As revealed by Mendelian randomisation, TSPAN1 and KLK3 were causally associated with incident BPH. CONCLUSIONS: We identified a three-protein panel (TSPAN1, KLK3, EDA2R) which can predict incident BPH. The findings highlight potential targets for non-invasive risk assessment and therapy.

References

1. 1.Li, H., Zhang, Y., Chen, L., Yuan, J., Qin, F., Wang, X., & Xiong, Y. (2026). Plasma proteomic signatures predict incident benign prostatic hyperplasia: a prospective cohort study of 20 996 men. Journal of Global Health. https://doi.org/10.2147/JIR.S431049