Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, 730030, People's Republic of China.
Gansu Province Clinical Research Center for Urology, Lanzhou, China.
Urolithiasis. 2024 Sep 6;52(1):126. doi: 10.1007/s00240-024-01627-7.
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 (P<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 (P<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.
肾结石病（KSD）是一种多方面的疾病，由环境和遗传因素共同作用引起，其发病率和复发率都很高。我们的目标是在 KSD 的背景下，阐明潜在的致病蛋白，并确定有前途的药物靶点。本研究利用了英国生物库制药蛋白质组学项目（UKBPPP）和 FinnGen 数据库版本 R10 中无与伦比的血浆蛋白和 KSD 全基因组关联研究（GWAS）数据的广度。通过孟德尔随机化分析，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，而富集分析评估了它们用于药物干预的潜力。研究的最后，进行了表型全基因组关联研究（PheWAS），涵盖了 FinnGen 数据库版本 R10 中所有的表型（2408 个表型）。我们的 MR 分析发现，血浆中 FKBPL、ITIH3 和 SERPINC1 等蛋白水平升高与 KSD 风险增加之间存在显著关联，这是基于遗传预测得出的。相反，CACYBP、DAG1、ITIH1 和 SEMA6C 等蛋白对 KSD 具有保护作用，这具有统计学意义（P<0.05）。共定位分析证实这七种蛋白与 KSD 共享遗传变异，表明存在共同的遗传基础（PPH3+PPH4>0.8）。富集分析揭示了关键途径，包括透明质酸代谢、富含胶原蛋白的细胞外基质和丝氨酸内肽酶抑制。此外，我们的 PheWAS 将相关蛋白与 356 种不同的疾病联系起来（P<0.05），突出了复杂的疾病相互关系。总之，我们的研究阐明了七种血浆蛋白与 KSD 之间的因果关系，丰富了我们对潜在治疗靶点的理解。
