Abstract
BACKGROUND: Kidney stones are increasingly common globally, and drug-induced kidney stones are often under-recognized. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used, and their potential link to kidney stones is an area of concern. The aim of this study is to explore the potential relationship between NSAIDs and kidney stones using Mendelian randomization (MR). METHODS: NSAIDs target genes were identified, and expression quantitative trait locus data were used to find genetic instruments. We conducted a summary data-based MR analysis to verify associations between genetic instruments and inflammatory factors and then assessed the causal relationship between target gene expressions and kidney stones. Sensitivity analyses, including colocalization analysis, horizontal pleiotropy assessment, investigation of weak instrumental variable impact, use of multiple data sources and methods, and testing of associations between inflammatory factors and kidney stone risk, were performed. RESULTS: Twelve target genes were identified. After comprehensive analysis, only NEU1 showed a significant genetically proxied association with kidney stone risk. A decrease in genetically proxied NEU1 expression was associated with an increased risk of kidney stones (odds ratio = 0.6, 95% CI 0.47-0.77). Sensitivity analyses supported the reliability of this association. No significant association was observed between tumour necrosis factor-alpha (TNF-α) and kidney stones, suggesting that the NEU1-kidney stone association may be independent of TNF-α. CONCLUSIONS: Genetically proxied lower NEU1 expression was associated with higher kidney stone risk. This association appeared independent of TNF-α levels. These findings warrant further mechanistic studies to investigate NEU1-related pathways in nephrolithiasis.