Wang Dawei, Shi Donghui, Si Shuxin, Xu Rao, Luo Fangxiu, Zhou Zijian
Department of Urology, Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai China.
Department of Urology Suzhou Wu Zhong People's Hospital Suzhou China.
Food Sci Nutr. 2025 Aug 19;13(8):e70800. doi: 10.1002/fsn3.70800. eCollection 2025 Aug.
Urolithiasis is a common and recurrent condition with significant health burdens; however, the causal relationships between dietary factors, plasma metabolites, and the urolithiasis risk remain poorly understood. To address this, we aimed to identify the causal associations between food habits and the risk of urolithiasis, and quantify the mediating role of plasma metabolites, employing two-sample Mendelian randomization (MR) and experimental approaches. This MR analysis was based on summary statistics for calculus of kidney and ureter from published genome-wide association studies (GWAS), including 10,556 cases and 400,681 controls of European ancestry. Furthermore, we used a two-step MR to quantify the proportion of the effect of 1400 plasma metabolites-mediated food habits on urolithiasis. Our MR analysis identified eight food intake factors and 15 food liking factors associated with urolithiasis. Metabolomic-wide MR analysis identified 50 plasma metabolites associated with urolithiasis. Seven pairs of stone-associated food factors and their metabolites were identified. Consistent with the MR results, widely targeted metabolomics analysis revealed that Mannose (fold change, FC = 0.54, = 0.001) and Threonate (FC = 0.64, = 0.0269) levels were significantly decreased in calcium oxalate (CaOx) kidney stone rat models compared with the control group. Integration of GWAS and eQTL data revealed 21 metabolite-related genes using a summary-data-based MR (SMR) test. Analysis of GSE73680 revealed that LAMA2 (logFC = -1.31, = 0.003) and CSNK1G3 (logFC = -0.76, = 0.042) were downregulated in the CaOx group. Both genes (LAMA2: OR = 0.74, 95% CI = 0.56-0.98, = 0.04; CSNK1G3: OR = 0.74, 95% CI = 0.58-0.94, = 0.01) were associated with a reduced risk of CaOx stones. RNA-Seq and RT-qPCR assays validated that the expression of LAMA2 and CSNK1G3 was decreased in oxalate-induced HK-2 and NRK-52E cells. Our study identified a causal relationship between food habits and the risk of urolithiasis with the effect mediated by plasma metabolites.
尿石症是一种常见且易复发的疾病，会带来重大的健康负担；然而，饮食因素、血浆代谢物与尿石症风险之间的因果关系仍知之甚少。为了解决这个问题，我们旨在通过双样本孟德尔随机化（MR）和实验方法，确定饮食习惯与尿石症风险之间的因果关联，并量化血浆代谢物的中介作用。这项MR分析基于已发表的全基因组关联研究（GWAS）中肾结石和输尿管结石的汇总统计数据，包括10,556例病例和400,681例欧洲血统对照。此外，我们使用两步MR来量化1400种血浆代谢物介导的饮食习惯对尿石症影响的比例。我们的MR分析确定了与尿石症相关的8种食物摄入因素和15种食物喜好因素。全代谢组MR分析确定了50种与尿石症相关的血浆代谢物。确定了7对与结石相关的食物因素及其代谢物。与MR结果一致，广泛靶向代谢组学分析显示，与对照组相比，草酸钙（CaOx）肾结石大鼠模型中甘露糖（倍数变化，FC = 0.54，P = 0.001）和苏糖酸（FC = 0.64，P = 0.0269）水平显著降低。整合GWAS和eQTL数据，使用基于汇总数据的MR（SMR）检验揭示了21个代谢物相关基因。对GSE73680的分析显示，CaOx组中LAMA2（logFC = -1.31，P = 0.003）和CSNK1G3（logFC = -0.76，P = 0.042）下调。这两个基因（LAMA2：OR = 0.74，95%CI = 0.56 - 0.98，P = 0.04；CSNK1G3：OR = 0.74，95%CI = 0.58 - 0.94，P = 0.01）均与CaOx结石风险降低相关。RNA测序和RT-qPCR分析验证了草酸诱导的HK-2和NRK-52E细胞中LAMA2和CSNK1G3的表达降低。我们的研究确定了饮食习惯与尿石症风险之间的因果关系，其作用由血浆代谢物介导。
