Effect of the plasma metabolites, biomarkers, and inflammatory proteins on urolithiasis: insights from Mendelian randomization and mediation analysis

Urolithiasis represents a systemic disorder characterized by metabolic circulation issues and ongoing inflammation. The purpose of this research is to explore the relationships of causation among plasma metabolites, biomarkers, inflammatory proteins, and stones within the urinary system. We initially carried out a two-sample Mendelian randomization (MR) analysis to evaluate possible causal connections between 233 plasma metabolites and 35 biomarkers related to urolithiasis. The genetic association study (GWAS) data concerning plasma metabolites were derived from a 2024 publication in Nature, while data for biomarkers were collected from the UK Biobank. To determine causal relationships, we utilized several analytical techniques, including inverse variance weighting (IVW), MR-Egger, weighted median, and weighted mode. Furthermore, we conducted analyses for pleiotropy and heterogeneity to ensure the findings’ robustness. A Steiger analysis was used to explore the presence of any reverse causal relationships. Lastly, we conducted mediation analysis to elucidate how inflammatory proteins mediate the associations between plasma metabolites, biomarkers, and stones in the urinary system. Our research demonstrates causal connections between six plasma metabolites and six biomarkers related to upper urinary tract stones. Furthermore, we identified causal associations between ten plasma metabolites and four biomarkers linked to lower urinary tract stones. Most of these metabolites belong to lipid and lipoprotein classes, indicating that changes in blood lipid levels may influence stone formation. Finally, mediation analysis revealed 13 mediating relationships, including the mediating effects of six inflammatory proteins. Our results provide evidence for the causal links among plasma metabolites, biomarkers, and inflammatory proteins associated with urolithiasis. This provides new insights into the potential mechanisms underlying urinary system stone formation, contributing to their prevention, diagnosis, and treatment.