Investigating causal relationships of blood and urine biomarkers with urological cancer risks: a mendelian randomization study and colocalization analyses.

Background: Establishing the causal links between biomarkers and cancer enhances understanding of risk factors and facilitates the discovery of therapeutic targets. To this end, we used Mendelian randomization (MR) and colocalization analysis to explore the causal relationship of blood and urinary biomarkers (BUBs) with urological cancers (UCs). Methods: First, we used a two-sample MR study to explore the causal relationship between 33 BUBs and 4 UCs, while we performed reverse Mendelian randomization. After Bonferroni correction, for BUB and UC with significant causality we confirmed the direct causality by multivariate MR adjusting for relevant risk factors. We also applied two-step MR analysis to further explore the possible mediators between BUB and UC with significant causality, while colocalization analysis was performed for BUB, UC and possible mediators. Sensitivity analysis were performed to assess the robustness of the results. Results: A two-sample MR study found that there were 8 BUBs of CA, IGF-1, LPA, TP, CRE, BILD, TBIL and NAP with potential causality with some UCs (p<0.05), but after Bonferroni correction only IGF-1 had a significant causality with PCa (OR = 1.14, 95% CI: 1.06-1.23; p=0.0006<0.05/33). Moreover, the causal relationship between IGF-1 and PCa remained significant (P<0.05) after adjusting for relevant risk factors in the multivariate MR study. The two-step MR study found SHBG to be a mediator between IGF-1 and PCa, and the colocalization analysis found that there was a common causal variant (nearby gene TNS3) between IGF-1 and SHBG (PPH4=93.21%), which further confirmed the mediating effect of SHBG. Conclusion: Strong evidence from our study suggests that IGF-1 increases the risk of PCa by decreasing SHBG levels, and in addition some BUBs were found to have a potential causal relationship with UCs.