Identifying causal relationships between 35 blood and urine biomarkers and urologic cancers: MR-meta combined with Bayesian colocalization Mendelian randomization analysis.

BACKGROUND

Blood and urine biomarkers have been associated with urologic tumors, but their causal relationship with urologic tumors is unclear.

METHODS

We performed a bidirectional Mendelian randomization (MR) analysis of the association between 35 blood and urine biomarkers and urological tumors in our discovery cohort. A Bayesian weighting approach was used to validate the positive results identified in the discovery cohort, and steiger filtering analysis was used to distinguish causality from reverse causality. Bayesian colocalization analysis was used to analyze which single nucleotide polymorphisms (SNPs) specifically co-located between the positive blood and urine biomarkers and the disease phenotypes were driven, and MR-positive results from the discovery cohort and the validation cohort were combined using the MR-meta method.

RESULTS

Several blood and urine biomarkers were found to be significantly and causally associated with urologic cancers. Notably, calcium (OR: 1.34, 95%CI 1.10-1.63, P = 0.0040) and sex hormone-binding globulin (SHBG) (OR: 0.81, 95%CI 0.70-0.95, P = 0.0092) were associated with bladder cancer; gamma glutamyl transferase (GGT) (OR: 0.91, 95%CI 0.83-0.99, P = 0.0209), lipoprotein A (Lp(a)) (OR: 1.12, 95%CI 1.01-1.24, P = 0.0399), and insulinlike growth factor 1 (IGF 1) (OR: 1.10, 95%CI 1.01-1.20, P = 0.0220) were linked to prostate cancer (PCa); non albumin protein (OR: 0.78, 95%CI 0.65-0.93, P = 0.0065) and total protein (OR: 0.80, 95%CI 0.64-0.99, P = 0.0380) were linked to renal cancer; and apolipoprotein A (Apo-A) (OR: 0.56, 95%CI 0.32-0.98, P = 0.0426) and urate (OR:1.89, 95%CI 1.03-3.47, P = 0.0399) were associated with renal pelvis cancer. These associations were validated in an independent cohort, with GGT, IGF 1, and Lp(a) being consistently linked to PCa.

CONCLUSION

This study identified significant biomarkers associated with urological cancers in blood and urine. These include GGT, IGF 1, and Lp(a), which are strong biomarkers for PCa. In addition, the findings of this study provide evidence for a handful of risk and protective factors for the development of urologic cancers.