West China Hospital, Sichuan University, Chengdu, People's Republic of China.
Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
Cancer Med. 2023 Feb;12(3):3610-3622. doi: 10.1002/cam4.5204. Epub 2022 Sep 7.
Many observational epidemiology studies discovered that kidney cancer and impaired kidney function have a bidirectional relationship. However, it remains unclear whether these two kinds of traits are causally linked. In this study, we aimed to investigate the bidirectional causal relation between kidney cancer and kidney function biomarkers (creatinine-based estimated glomerular filtration rate (eGFRcrea), cystatin C-based estimated glomerular filtration rate (eGFRcys), blood urea nitrogen (BUN), serum urate, and urinary albumin-to-creatinine ratio (UACR)).
For both directions, single-nucleotide polymorphisms (SNPs), as genetic instruments, for the five kidney function traits were selected from up to 1,004,040 individuals, and SNPs for kidney cancer were from 408,786 participants(1338 cases). In the main analysis, we applied two state-of-the-art MR methods, namely, contamination mixture and Robust Adjusted Profile Score to downweight the effect of weak instrument bias, pleiotropy, and extreme outliers. We additionally conducted traditional MR analyses as sensitivity analyses. Summary-level data of European ancestry were extracted from UK Biobank, Chronic Kidney Disease Genetics Consortium, and Kaiser Permanente.
Based on 99 SNPs, we found that the eGFRcrea had a significant negative causal effect on the risk of kidney cancer (OR = 0.007, 95% CI:2.6 × 10 -0.569, p = 0.041). After adjusting for body composition or diabetes, urate had a significant negative causal effect on kidney cancer (OR <1, p < 0.05). For UACR, it showed a strong causal effect on kidney cancer, after adjusting for body composition (OR = 14.503, 95% CI: 2.546-96.001, p = 0.032). Due to lacking significant signals and effect power for the reverse MR, further investigations are warranted.
Our study suggested a potential causal effect of damaged kidney function on kidney cancer. EGFRcrea and UACR might be causally associated with kidney cancer, especially when patients were comorbid with obesity or diabetes. We called for larger sample-size studies to further unravel the underlying causal relationship and the exact mechanism.
许多观察性流行病学研究发现，肾癌和肾功能受损之间存在双向关系。然而，目前尚不清楚这两种特征是否存在因果关系。在这项研究中，我们旨在研究肾癌和肾功能生物标志物（基于肌酐的估算肾小球滤过率（eGFRcrea）、基于半胱氨酸蛋白酶抑制剂 C 的估算肾小球滤过率（eGFRcys）、血尿素氮（BUN）、血清尿酸和尿白蛋白与肌酐比值（UACR））之间的双向因果关系。
对于两个方向，我们从多达 1004040 个人中选择了单核苷酸多态性（SNP）作为五种肾功能特征的遗传工具，而肾癌的 SNP 则来自 408786 名参与者（1338 例）。在主要分析中，我们应用了两种最先进的 MR 方法，即污染混合物和稳健调整的轮廓评分，以减轻弱工具偏倚、多效性和极端异常值的影响。我们还进行了传统的 MR 分析作为敏感性分析。欧洲血统的汇总数据是从英国生物库、慢性肾脏病遗传学联合会和 Kaiser Permanente 中提取的。
基于 99 个 SNP，我们发现 eGFRcrea 对肾癌风险有显著的负向因果影响（OR=0.007，95%CI：2.6×10 -0.569，p=0.041）。在调整身体成分或糖尿病后，尿酸对肾癌有显著的负向因果影响（OR<1，p<0.05）。对于 UACR，在调整身体成分后，它对肾癌表现出强烈的因果影响（OR=14.503，95%CI：2.546-96.001，p=0.032）。由于反向 MR 缺乏显著信号和效应力，需要进一步的研究。
我们的研究表明，肾功能受损可能对肾癌有潜在的因果影响。eGFRcrea 和 UACR 可能与肾癌有因果关系，尤其是当患者合并肥胖或糖尿病时。我们呼吁进行更大样本量的研究，以进一步揭示潜在的因果关系和确切机制。
