在结直肠癌（CRC）中检测到尿素循环（UC）的失调。然而，UC最终产物尿素对CRC发展的影响尚不清楚。我们基于来自英国生物库的348 872名招募时无癌症的参与者的数据，研究了血清尿素与CRC风险的关联。使用多变量Cox比例风险模型进行风险估计。根据性别、饮食模式、代谢因素（包括体重指数[BMI]、估算肾小球滤过率[eGFR]和2型糖尿病[T2D]）以及遗传特征（结直肠癌的多基因风险评分[PRS]）进行分层分析，以寻找潜在的修饰因子。在平均随访期为9.0年的过程中，我们发现3408例（1.0%）CRC新发病例。血清尿素与CRC风险呈非线性关系（非线性P值为0.035）。较低的血清尿素水平与较高的CRC风险相关，与Q4相比，尿素第一四分位数（Q1）的全面调整风险比（HR）为1.26（95%可信区间[CI]：1.13-1.41）。该关联在性别、蛋白质饮食、BMI、eGFR和CRC-PRS的亚组中基本一致（P交互作用>.05）；然而，在T2D中的效应更强，尿素与T2D在加法（协同指数：3.32，[95%CI：1.24-8.88]）和乘法尺度上交互作用（交互作用P值：.019）。较低的血清尿素浓度与CRC风险增加有关，T2D患者中观察到更明显的效应。保持血清尿素稳定的水平对于CRC预防尤其重要，特别是在T2D患者中。© 2023 UICC.

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.© 2023 UICC.