Causal relationships between plasma metabolites and prostate cancer: A Mendelian randomization study exploring immune and inflammatory mediators

Abstract

Background: Metabolic alterations and inflammatory processes contribute substantially to the pathogenesis of prostate cancer (PCa). This study used Mendelian randomization (MR) to investigate the causal relationships between plasma metabolites and PCa and to identify potential mediators, including immune cell traits and circulating inflammatory proteins.

Materials and methods: A 2-sample MR analysis was conducted using data from the Canadian Longitudinal Study on Aging and a diverse genome-wide association study of PCa. A total of 1400 plasma metabolites were analyzed. Single-nucleotide polymorphisms were carefully selected and refined using linkage disequilibrium clumping. The inverse variance weighting method was used for primary analysis, supplemented by sensitivity analyses, including MR-Egger, weighted median, and MR-Pleiotropy RESidual Sum and Outlier, to ensure the robustness of the results.

Results: Eight metabolites were significantly associated with PCa. Specifically, a higher phosphate-to-uridine ratio was associated with a decreased risk of PCa, whereas higher levels of N- acetyl-arginine were linked to an increased risk. Other significant metabolites included the phosphate-to-2′-deoxyuridine ratio; N6-methyl-lysine, N-acetyl-leucine, N- succinyl-phenylalanine, and cysteinylglycine disulfide levels; and the α-ketoglutarate-to-ornithine ratio. Sensitivity analyses and the MR-Steiger test confirmed the robustness and causal direction of these associations. In addition, further analysis indicated that certain metabolites may influence PCa risk by modulating the expression of inflammatory markers, such as leukemia inhibitory factor receptor, interleukin-8, and CD33-related markers.

Conclusions: This study identified plasma metabolites that exert causal effects on the risk of PCa and highlighted the mediating role of immune traits and inflammatory proteins. These findings underscore the complexity of the biological pathways involved and suggest potential targets for therapeutic interventions.

Keywords

Prostate cancer / Mendelian randomization / Plasma metabolites / Inflammation / Immune cell traits / Causal inference

Acknowledgments

We thank the participants and investigators who contributed to this study. We are also grateful to the Open GWAS and GWAS Catalog for providing the summary statistics used in this study.

Statement of ethics

In our center/institution, studies based on publicly available databases do not require ethical approval or informed consent. All procedures performed in this study in volving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Conflict of interest statement

JP is a member of Editorial Board of Current Urology and confirms no involvement in any stage of this article’s review process, ensuring unbiased editorial decision-making. The other authors declare no conflicts of interest.

Funding source

The present study was funded by the National Natural Science Foundation of China (Grant No. 82272689 to Jun P.); the Sanming Project of Medicine in Shenzhen (SZSM202011011 to Jun P.); the Shenzhen Medical Research Fund (A2302037 to Mengjun H.); the Research Start-up Fund of Part-time PI, SAHSYSU (ZSQYJZPI202003 to Jun P.); and the Guangdong Basic and Applied Basic Research Foundation (Grant No. 2021A151511-1052 to Jun P.).

Author contributions

MH, DN, JP: Conception of the study;

MH, DN, HL: Refinement of the study design;

MH, DN: Writing of the initial manuscript draft and advising on the statistical plan and data analysis;

JP, HL: Critical revision of the manuscript;

TT, QT, YG, FC, YW: Study administration and data collection;

All authors: Review and approval of the final draft of the manuscript.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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