Liu Junfa, Dong Kaiyi, Qin Gang, Ye Chunyan, Wu Jinghan, Wang E, Dong Zhitao
Department of Urology, The Second Xiangya Hospital, Central South University, No. 139 Renmin Road, Changsha, 410011, Hunan, China.
Department of Cardiac Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China.
Inflammopharmacology. 2025 Aug;33(8):4615-4627. doi: 10.1007/s10787-025-01866-z. Epub 2025 Jul 29.
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).
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.
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.
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.
肾结石在全球范围内日益普遍，而药物性肾结石往往未得到充分认识。非甾体抗炎药（NSAIDs）被广泛使用，其与肾结石的潜在联系是一个令人关注的领域。本研究的目的是利用孟德尔随机化（MR）探索NSAIDs与肾结石之间的潜在关系。
确定NSAIDs的靶基因，并使用表达定量性状位点数据来寻找遗传工具。我们进行了基于汇总数据的MR分析，以验证遗传工具与炎症因子之间的关联，然后评估靶基因表达与肾结石之间的因果关系。进行了敏感性分析，包括共定位分析、水平多效性评估、弱工具变量影响调查、使用多个数据源和方法，以及炎症因子与肾结石风险之间关联的测试。
确定了12个靶基因。综合分析后，只有NEU1显示出与肾结石风险有显著的遗传代理关联。遗传代理的NEU1表达降低与肾结石风险增加相关（优势比=0.6，95%可信区间0.47-0.77）。敏感性分析支持了这种关联的可靠性。未观察到肿瘤坏死因子-α（TNF-α）与肾结石之间有显著关联，这表明NEU1与肾结石的关联可能独立于TNF-α。
遗传代理的较低NEU1表达与较高的肾结石风险相关。这种关联似乎独立于TNF-α水平。这些发现值得进一步进行机制研究，以探讨肾结石病中与NEU1相关的途径。
