全蛋白质组孟德尔随机化确定了肾炎的治疗靶点。

IF 2 2区 医学 Q2 UROLOGY & NEPHROLOGY
Li Wang, Kun-Peng Li, Si-Yu Chen, Shun Wan, Xiao-Ran Li, Li Yang
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引用次数: 0

摘要

肾结石病(KSD)是一种由环境和遗传因素共同作用导致的多发性疾病,具有发病率高、复发率高的特点。我们的目标是阐明潜在的致病蛋白,并确定 KSD 的潜在药理靶点。这项研究利用了来自英国生物库医药蛋白质组学项目(UKBPPP)和芬兰基因数据库 R10 版的无与伦比的血浆蛋白和 KSD 全基因组关联研究(GWAS)数据。通过孟德尔随机分析,确定了对 KSD 有因果影响的蛋白质。随后的共定位分析证实了这些发现的稳定性,而富集分析则评估了这些蛋白质的药理干预潜力。最后,我们进行了一项全表型关联研究(PheWAS),涵盖了FinnGen数据库R10版收录的所有表型(2408种表型)。我们的磁共振分析发现,基于遗传预测因子,血浆中蛋白质 FKBPL、ITIH3 和 SERPINC1 水平升高与 KSD 风险增加之间存在明显关联。相反,蛋白质 CACYBP、DAG1、ITIH1 和 SEMA6C 对 KSD 有保护作用,具有统计学意义(PFDR 0.8)。富集分析揭示了关键通路,包括透明质酸代谢、富含胶原的细胞外基质和丝氨酸型内肽酶抑制。此外,我们的 PheWAS 将相关蛋白与 356 种不同的疾病联系起来(PFDR
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Proteome-wide mendelian randomization identifies therapeutic targets for nephrolithiasis.

Proteome-wide mendelian randomization identifies therapeutic targets for nephrolithiasis.

Kidney Stone Disease (KSD) constitutes a multifaceted disorder, emerging from a confluence of environmental and genetic determinants, and is characterized by a high frequency of occurrence and recurrence. Our objective is to elucidate potential causative proteins and identify prospective pharmacological targets within the context of KSD. This investigation harnessed the unparalleled breadth of plasma protein and KSD pooled genome-wide association study (GWAS) data, sourced from the United Kingdom Biobank Pharma Proteomics Project (UKBPPP) and the FinnGen database version R10. Through Mendelian randomization analysis, proteins exhibiting a causal influence on KSD were pinpointed. Subsequent co-localization analyses affirmed the stability of these findings, while enrichment analyses evaluated their potential for pharmacological intervention. Culminating the study, a phenome-wide association study (PheWAS) was executed, encompassing all phenotypes (2408 phenotypes) catalogued in the FinnGen database version R10. Our MR analysis identified a significant association between elevated plasma levels of proteins FKBPL, ITIH3, and SERPINC1 and increased risk of KSD based on genetic predictors. Conversely, proteins CACYBP, DAG1, ITIH1, and SEMA6C showed a protective effect against KSD, documented with statistical significance (PFDR<0.05). Co-localization analysis confirmed these seven proteins share genetic variants with KSD, signaling a shared genetic basis (PPH3 + PPH4 > 0.8). Enrichment analysis revealed key pathways including hyaluronan metabolism, collagen-rich extracellular matrix, and serine-type endopeptidase inhibition. Additionally, our PheWAS connected the associated proteins with 356 distinct diseases (PFDR<0.05), highlighting intricate disease interrelations. In conclusion, our research elucidated a causal nexus between seven plasma proteins and KSD, enriching our grasp of prospective therapeutic targets.

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来源期刊
Urolithiasis
Urolithiasis UROLOGY & NEPHROLOGY-
CiteScore
4.50
自引率
6.50%
发文量
74
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.
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