Genetically predicted 91 circulating inflammatory proteins in relation to risk of urological malignancies: a Mendelian randomization study

Abstract

Background: Urological malignancies, including kidney, bladder, and prostate cancer, are major health concerns worldwide. Inflammation has been implicated in the pathogenesis of these cancers, and circulating inflammatory proteins may play a role in their development. However, the causal relationship between specific plasma proteins and urological malignancies remains unclear.

Methods: We performed a two-sample Mendelian randomization (MR) analysis using summary statistics from genome-wide association studies (GWAS). Instrumental variables representing genetic variants associated with circulating inflammatory proteins were used to infer causality on the risk of kidney, bladder, and prostate cancer. Four MR methods were utilized to provide robust effect estimates.

Results: Our analysis identified several plasma proteins associated with a lower risk of kidney and bladder cancer, including Eukaryotic translation initiation factor 4E-binding protein 1, Caspase 8, Natural killer cell receptor 2B4, and Tumor necrosis factor ligand superfamily member 12. However, after adjusting for multiple testing, these associations did not remain statistically significant. For prostate cancer, CUB domain-containing protein 1 and Interleukin-10 receptor subunit beta were found to be protective, while Glial cell line-derived neurotrophic factor and SIR2-like protein 2 were identified as risk factors. After FDR adjustment, none of the inflammatory proteins were found to be significantly associated with a lower risk of prostate cancer.

Conclusion: Our findings suggest that certain plasma proteins may be involved in the development of urological malignancies. Mendelian randomization provides a useful framework for investigating causal relationships between inflammatory proteins and urological cancers, offering potential insights into their underlying biology and therapeutic targets.

Keywords: Mendelian randomization; bladder cancer; inflammatory proteins; kidney cancer; prostate cancer; urological malignancies.

Figure 1

Assumptions of the Mendelian randomization (MR) analysis for circulating inflammatory proteins and PCa. The MR study assumes that genetic variants are associated with only circulating inflammatory proteins and not with confounders or alternative causal pathways, that is, the IVs affect the PCa only directly through immune cell signatures. Abbreviation: IVs; instrument variables.

Figure 2

Associations of genetically predicted circulating inflammatory proteins and the risk of kidney cancer. Abbreviations: SNPs: single nucleotide polymorphisms; IVW: inverse variance weighted.

Figure 3

Associations of genetically predicted circulating inflammatory proteins and the risk of bladder cancer. Abbreviations: SNPs: single nucleotide polymorphisms; IVW: inverse variance weighted.

Figure 4

Associations of genetically predicted circulating inflammatory proteins and the risk of prostate cancer. Abbreviations: SNPs: single nucleotide polymorphisms; IVW: inverse variance weighted.