Purine and citrate metabolism in urolithiasis and bladder cancer: An integrated genetic, gene-expression, and targeted metabolite analysis

BACKGROUND: Metabolic reprogramming is a hallmark of bladder cancer (BC), but the contribution of inherited variation in purine and citrate metabolism remains incompletely understood. Because urolithiasis shares selected metabolic and epidemiological features with BC, we compared both disorders to identify shared and disease-specific molecular patterns. METHODS: H NMR in a Polish case-control cohort. Genetic associations were assessed using multivariable models adjusted for age, sex, smoking, and BMI, with BH-FDR correction. Genotype-expression, genotype-metabolite, and expression-metabolite relationships were evaluated, and peripheral findings were compared with GSE13507 and TCGA-BLCA bladder-tissue data. RESULTS: ACLY rs2304497 was associated with both diseases, whereas PNP rs1713420 showed a BC-specific association after multivariable adjustment and BH-FDR correction. XDH rs2295475 associations did not remain significant after multiple-testing correction, and formal interaction analyses provided no BH-FDR-significant evidence of effect modification. Peripheral ACLY and GART transcript abundance was lower in both disease groups, while PNP was additionally lower in urolithiasis. Urinary citrate and hypoxanthine were reduced only in urolithiasis. No cross-layer associations remained significant after adjustment and BH-FDR correction. In external bladder tissue, GART was increased in both datasets, while ACLY and HPRT1 were increased in paired TCGA-BLCA tumours. CONCLUSIONS: The findings indicate shared and disease-specific molecular patterns but do not support a simple linear relationship between inherited variation, peripheral transcript abundance, and urinary metabolites. Direct functional and tissue-specific validation is required.