Novel Insights Into the Causal Association Between Dietary Factors and Risk of Urinary Calculus: A Multivariate and Two‐Step Mendelian Randomization Analysis

Previous observational studies preliminarily unveiled dietary habits that are associated with urinary calculus (UC). However, the causal association remained unclear. This study employed two-sample Mendelian randomization (MR) to assess the causal effects of dietary factors on UC using genome-wide association data. Multivariable MR (MVMR) was applied to identify independent dietary influences, and two-step MR explored mediation by 30 common biomarkers. Genetically predicted intake of alcohol, coffee (including decaffeinated, instant, and ground coffee), psychoactive drinks, tea, fruits (including dried fruit), and preferences for coffee without sugar, fruit, and white wine were inversely associated with calculus of the kidney and ureter (all <i>p</i> < 0.05). Additionally, preferences for fruit (including cherry and plum) and coffee with sugar were inversely associated with lower urinary tract stones (<i>p</i> < 0.05). MVMR confirmed that the protective effects of coffee (<i>p</i> = 0.0008), instant coffee (<i>p</i> = 0.0003), psychoactive drinks (<i>p</i> = 0.014), fruit (fruit consumption <i>p</i> = 4.55 × 10^-5, fruit liking <i>p</i> = 0.0007), and dried fruit (<i>p</i> = 0.003) on calculus of the kidney and ureter, as well as cherry (<i>p</i> = 0.001), fruit (<i>p</i> = 0.005), and plum liking (<i>p</i> = 0.0001) on calculus of the lower urinary tract, were independent of other dietary factors. Two-step MR further suggested calcium partially mediated the effects of fruit (4.9%), dried fruit (8.8%), and cherry liking (2.7%) on UC. These findings provide genetic evidence for the protective roles of specific dietary factors in UC development and highlight potential biological mediators, offering new insights for prevention strategies.