Exploring the causal role of plasma metabolites and metabolite ratios in prostate cancer: a two-sample Mendelian randomization study

作者：Changzhou Feng, Haining Li, Chu Zhang, Ying Zhou, Huanhuan Zhang, Ping Zheng, Shaolin Zhao, Lei Wang, Jin Yang · 发表于：Frontiers in Molecular Biosciences · 年份：2025 · DOI：10.3389/fmolb.2024.1406055 · 被引用次数：5 · 研究领域：Ferroptosis and cancer prognosis、Metabolomics and Mass Spectrometry Studies、Glutathione Transferases and Polymorphisms

Background Prostate cancer (PCa), the most prevalent malignant neoplasm in males, involves complex biological mechanisms and risk factors, many of which remain unidentified. By employing a novel two-sample Mendelian randomization (MR) approach, this study aims to elucidate the causal relationships between the circulating metabolome and PCa risk, utilizing comprehensive data on genetically determined plasma metabolites and metabolite ratios. Methods For the MR analysis, we utilized data from the GWAS Catalog database to analyze 1,091 plasma metabolites and 309 ratios in relation to PCa outcomes within two independent GWAS datasets. The inverse variance weighted (IVW) method was the primary approach for determining the existence of the causal relationship, supplemented by additional MR methods for heterogeneity, pleiotropy, and cross-validation. The false discovery rate (FDR) and Bonferroni correction were applied to identify the most significant causative associations. Additionally, reverse MR and Steiger filtering were conducted to ascertain whether PCa influenced the observed metabolite levels. Furthermore, metabolic pathway analysis was conducted with MetaboAnalyst 6.0 software. Results In the MR analysis, our findings reveal three overlapped metabolite ratios (arginine to glutamate, phosphate to uridine, and glycerol to mannitol/sorbitol) inversely associated with PCa risk. Following FDR correction (FDR < 0.05), cysteinylglycine disulfide was identified as a potenti...