Identifying therapeutic targets for kidney stone disease through proteome-wide Mendelian randomization and colocalization analysis.

IF 2 2区医学 Q2 UROLOGY & NEPHROLOGY

Urolithiasis Pub Date : 2024-11-25 DOI:10.1007/s00240-024-01669-x

Zilong Liang, Conglei Hu, Haofeng Pang, Yi Sha, Liping Yao, Fei Liu

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Abstract

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.

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通过全蛋白质组孟德尔随机化和共定位分析确定肾结石病的治疗靶点。

肾结石病（KSD）在全球的发病率和复发率不断上升。孟德尔随机化有助于药物的再利用和治疗靶点的发现。这项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。一项蛋白质组范围的 MR 研究评估了血浆蛋白质与 KSD 风险的因果关系。该研究分析了英国生物库蛋白质组学分析项目（2940个蛋白质）和KSD芬兰基因R10（10556个病例，400681个对照）的数据。共定位分析确定了共同的因果变异。此外，一项全基因组关联研究（Phenome-wide association study，PheWAS）利用 FinnGen 探索了药物蛋白的不良反应。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

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来源期刊

Urolithiasis UROLOGY & NEPHROLOGY-

CiteScore

4.50

自引率

6.50%

发文量

期刊介绍： Official Journal of the International Urolithiasis Society The journal aims to publish original articles in the fields of clinical and experimental investigation only within the sphere of urolithiasis and its related areas of research. The journal covers all aspects of urolithiasis research including the diagnosis, epidemiology, pathogenesis, genetics, clinical biochemistry, open and non-invasive surgical intervention, nephrological investigation, chemistry and prophylaxis of the disorder. The Editor welcomes contributions on topics of interest to urologists, nephrologists, radiologists, clinical biochemists, epidemiologists, nutritionists, basic scientists and nurses working in that field. Contributions may be submitted as full-length articles or as rapid communications in the form of Letters to the Editor. Articles should be original and should contain important new findings from carefully conducted studies designed to produce statistically significant data. Please note that we no longer publish articles classified as Case Reports. Editorials and review articles may be published by invitation from the Editorial Board. All submissions are peer-reviewed. Through an electronic system for the submission and review of manuscripts, the Editor and Associate Editors aim to make publication accessible as quickly as possible to a large number of readers throughout the world.