Integrative Multi-Omics Analysis of Circulating Biomarkers Reveals Targetable Pathways in Pelvic Organ Prolapse

Area of Science:

• Biomedical research
• Genetics
• Metabolomics

Background:

• Pelvic Organ Prolapse (POP) is a common condition with complex underlying mechanisms.
• Understanding the molecular drivers of POP is crucial for developing effective treatments.

Purpose of the Study:

• To investigate plasma proteins and metabolites causally linked to POP.
• To explore the molecular mechanisms of POP using a proteo-metabolomic Mendelian Randomization (MR) framework.

Main Methods:

• Utilized a large-scale proteomic genome-wide association study (GWAS) dataset for MR analysis.
• Performed colocalization and independent cohort replication to validate genetic associations.
• Employed a two-step MR approach to identify metabolites associated with soluble Tie2 (sTie2) and characterized plasma metabolomics in POP patients.

Main Results:

• Identified 11 plasma proteins potentially causally linked to POP, with soluble Tie2 (sTie2) as a key candidate.
• Confirmed elevated sTie2 levels in POP patients and identified 27 metabolites associated with sTie2.
• Discovered a significant association between paraxanthine and POP susceptibility, with caffeine metabolism enriched in POP plasma.

Conclusions:

• Proposed a novel sTie2-paraxanthine axis as a potential driver of POP.
• Indicated that vascular signaling and metabolic regulation contribute to pelvic floor degeneration.
• Highlighted sTie2 and paraxanthine as potential therapeutic targets for POP pathogenesis.