Causal Relationship Between Blood Metabolites and Prostate Cancer Risk: A Two-Sample Mendelian Randomization Study

Area of Science:

• Metabolomics and Cancer Epidemiology
• Genetic Epidemiology
• Biochemistry and Oncology

Background:

• Emerging evidence suggests links between blood metabolite levels and prostate cancer (PCa) development.
• The causal nature of these associations remains largely undetermined.
• Understanding these relationships is crucial for identifying novel PCa biomarkers and therapeutic targets.

Purpose of the Study:

• To investigate potential causal associations between blood metabolites and prostate cancer (PCa) risk.
• To identify specific blood metabolites that may influence PCa development.
• To assess potential pleiotropic effects of identified metabolites through phenome-wide analysis.

Main Methods:

• A two-sample Mendelian randomization (MR) analysis was performed using genetic instruments for 514 and 490 metabolites.
• Data were sourced from large-scale genome-wide association studies (GWAS) of European ancestry individuals (INTERVAL/EPIC-Norfolk and Canadian Longitudinal Study on Aging).
• Summary statistics for PCa risk (122,188 cases, 604,640 controls) were analyzed using inverse-variance weighted methods, MR-Egger, and MR-PRESSO for sensitivity.

Main Results:

• The MR analysis identified 107 unique blood metabolites significantly associated with PCa risk.
• Forty-three of these associations were consistently replicated using genetic instruments from two independent datasets.
• Phenome-wide MR analysis explored potential off-target effects relevant to PCa interventions.

Conclusions:

• This study provides robust evidence for potential causal roles of specific blood metabolites in prostate cancer (PCa) etiology.
• The findings highlight 43 consistently associated metabolites warranting further investigation as potential biomarkers or therapeutic targets.
• Further research is needed to validate these causal links and explore their clinical implications in PCa.