Dysregulation of the urea cycle (UC) has been detected in colorectal cancer (CRC). However, the impact of the UC's end product, urea, on CRC development remains unclear. We investigated the association between serum urea and CRC risk based on the data of 348 872 participants cancer-free at recruitment from the UK Biobank. Multivariable Cox proportional hazards models were fitted to conduct risk estimates. Stratification analyses based on sex, diet pattern, metabolic factors (including body mass index [BMI], the estimated glomerular filtration rate [eGFR] and type 2 diabetes [T2D]) and genetic profiles (the polygenic risk score [PRS] of CRC) were conducted to find potential modifiers. During an average of 9.0 years of follow-up, we identified 3408 (1.0%) CRC incident cases. Serum urea showed a nonlinear relationship with CRC risk (P-nonlinear: .035). Lower serum urea levels were associated with a higher CRC risk, with a fully-adjusted hazard ratio (HR) of 1.26 (95% confidence interval [CI]: 1.13-1.41) in the first quartile (Q1) of urea, compared to the Q4. This association was largely consistent across subgroups of sex, protein diet, BMI, eGFR and CRC-PRSs (P-interaction >.05); however, it was stronger in the T2D, with an interaction between urea and T2D on both additive (synergy index: 3.32, [95% CI: 1.24-8.88]) and multiplicative scales (P-interaction: .019). Lower serum urea concentrations were associated with an increased risk of CRC, with a more pronounced effect observed in individuals with T2D. Maintaining stable levels of serum urea has important implications for CRC prevention, particularly in individuals with T2D.
Keywords: colorectal cancer; polygenic risk scores; serum urea; type 2 diabetes.
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