Department of Urology, Xijing Hospital, Air Force Medical University, Xi'an, 710032, China.
Graduate Department, Xi'an Medical University, Xi'an, 710021, China.
Urolithiasis. 2024 Nov 25;52(1):167. doi: 10.1007/s00240-024-01669-x.
Kidney stone disease (KSD) is facing rising global prevalence and recurrence rates. Mendelian randomization aids in drug repurposing and the discovery of therapeutic targets. This study utilized Mendelian randomization (MR) to identify protein targets for KSD treatment and assess potential adverse drug reactions. A proteome-wide MR study assessed plasma proteins' causal relationship with KSD risk. Data from UK Biobank Proteomics Profiling Project (2940 proteins) and FinnGen R10 for KSD (10,556 cases, 400,681 controls) were analyzed. Colocalization analysis identified shared causal variants. Additionally, a Phenome-wide association study (PheWAS) used the FinnGen to explore adverse reactions of druggable proteins. MR study found ITIH4, F12, FKBPL positively correlated with KSD risk, while DAG1, ITIH1, LTB, CACYBP negatively correlated (Pfdr < 0.05). Colocalization analysis and PheWAS identified CACYBP as the most promising druggable protein for the prevention or treatment of nephrolithiasis recurrence. This study identified genetic protein biomarkers for KSD risk and explored potential drug side effects, offering new insights and targets for prevention and treatment.
肾结石病（KSD）的全球患病率和复发率呈上升趋势。孟德尔随机化有助于药物再利用和治疗靶点的发现。本研究利用孟德尔随机化（MR）来确定治疗 KSD 的蛋白质靶点，并评估潜在的药物不良反应。一项全蛋白质组 MR 研究评估了血浆蛋白与 KSD 风险的因果关系。分析了来自英国生物库蛋白质组学分析项目（2940 种蛋白质）和 FinnGen R10 的 KSD 数据（10556 例病例，400681 例对照）。共定位分析确定了共享的因果变异。此外，使用 FinnGen 的表型全基因组关联研究（PheWAS）探索了可用药蛋白的不良反应。MR 研究发现 ITIH4、F12、FKBPL 与 KSD 风险呈正相关，而 DAG1、ITIH1、LTB、CACYBP 呈负相关（Pfdr<0.05）。共定位分析和 PheWAS 确定 CACYBP 是预防或治疗肾结石复发最有前途的可用药蛋白。本研究确定了 KSD 风险的遗传蛋白质生物标志物，并探索了潜在的药物副作用，为预防和治疗提供了新的见解和靶点。
