Jiang Qinhong, Su Xiaozhe, Liao Wenbiao, He Ziqi, Wang Yunhan, Jiang Rong, Dong Caitao, Yang Sixing
Department of Urology, Renmin Hospital of Wuhan University, No. 099, Zhang zhidong Road, Wuhan, Hubei Province 430060, People's Republic of China.
Hum Mol Genet. 2025 Jan 23;34(1):47-63. doi: 10.1093/hmg/ddae159.
Given the high recurrence rate of kidney stones, surgical lithotripsy and stone removal are not the ultimate treatments for kidney stones. There's an urgent need to explore the genetic mechanisms behind the susceptibility to kidney stones and to identify potential targets for prevention, to reduce the renal damage caused by recurrent stone formation. In this study, we screened 4548 circulating proteins using proteome-wide Mendelian Randomization (MR) to find proteins with a causal relationship to kidney stone risk. Additionally, proteome-wide association study (PWAS) and colocalization analysis were used to validate and prioritize candidate proteins. Moreover, downstream analyses including single-cell analysis, enrichment analysis, protein-protein interaction (PPI), and druggability analysis were conducted on the proteins causally related to kidney stones, to further explore the genetic mechanisms of susceptibility and the potential of proteins as drug targets. Ultimately, 22 target proteins associated with the risk of kidney stones were identified. Six plasma proteins (COLGALT1, CLMP, LECT1, ITIH1, CDHR3, CPLX2) were negatively correlated with kidney stone risk, while the genetic overexpression of 16 target proteins (GJA1, STOM, IRF9, F9, TMPRSS11D, ADH1B, SPINK13, CRYBB2, TNS2, DOCK9, OXSM, MST1, IL2, LMAN2, ITIH3, KLRF1) increased the risk of kidney stones. Based on the PWAS and colocalization analysis results, the 22 target proteins were classified into 3 tiers: IL2, CPLX2, and LMAN2 as tier 1 proteins with the most compelling evidence, MST1, ITIH1, and ITIH3 as tier 2 proteins, and the rest as tier 3 proteins. Enrichment analysis and PPI showed that target proteins mainly affect the occurrence of kidney stones through leukocyte activation and cell junction assembly. Druggability analysis suggested that IL2, MST1, and ITIH1 have potential as drug targets, and potential drugs were evaluated through molecular docking. In summary, this study employed multiple analytical methods to screen plasma proteins related to susceptibility to kidney stones, providing new insights into the genetic mechanisms of kidney stones and potential targets for treatment and prevention.
鉴于肾结石的高复发率，手术碎石和取石并非肾结石的最终治疗方法。迫切需要探索肾结石易感性背后的遗传机制，并确定潜在的预防靶点，以减少复发性结石形成所导致的肾脏损害。在本研究中，我们使用全蛋白质组孟德尔随机化（MR）筛选了4548种循环蛋白，以寻找与肾结石风险存在因果关系的蛋白。此外，还使用了全蛋白质组关联研究（PWAS）和共定位分析来验证候选蛋白并对其进行优先级排序。此外，对与肾结石有因果关系的蛋白进行了包括单细胞分析、富集分析、蛋白质-蛋白质相互作用（PPI）和药物可及性分析在内的下游分析，以进一步探索易感性的遗传机制以及蛋白作为药物靶点的潜力。最终，确定了22种与肾结石风险相关的靶蛋白。六种血浆蛋白（COLGALT1、CLMP、LECT1、ITIH1、CDHR3、CPLX2）与肾结石风险呈负相关，而16种靶蛋白（GJA1、STOM、IRF9、F9、TMPRSS11D、ADH1B、SPINK13、CRYBB2、TNS2、DOCK9、OXSM、MST1、IL2、LMAN2、ITIH3、KLRF1）的基因过表达增加了肾结石的风险。根据PWAS和共定位分析结果，将这22种靶蛋白分为3个层级：IL2、CPLX2和LMAN2为证据最确凿的1级蛋白，MST1、ITIH1和ITIH3为2级蛋白，其余为3级蛋白。富集分析和PPI表明，靶蛋白主要通过白细胞激活和细胞连接组装影响肾结石的发生。药物可及性分析表明，IL2、MST1和ITIH1具有作为药物靶点的潜力，并通过分子对接对潜在药物进行了评估。总之，本研究采用多种分析方法筛选了与肾结石易感性相关的血浆蛋白，为肾结石的遗传机制以及治疗和预防的潜在靶点提供了新的见解。
