Dietary Influence on Urolithiasis Risk Mediated by Plasma Metabolites: A Mendelian Randomization and Experimental Study Linking Genes, Metabolites, and Clinical Outcomes

ABSTRACT 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, p = 0.001) and Threonate (FC = 0.64, p = 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, p = 0.003) and CSNK1G3 (logFC = −0.76, p = 0.042) were downregulated in the CaOx group. Both genes (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) 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.