Department of Urology, The First Affiliated Hospital of Zhengzhou University, No.1 East Jianshe Road, District of Erqi, Zhengzhou, 450052, Henan, People's Republic of China.
Sci Rep. 2024 Sep 27;14(1):22114. doi: 10.1038/s41598-024-72970-3.
There is an urgent need to pinpoint novel targets for drug discovery in the context of chronic kidney disease (CKD), and the proteome represents a significant pool of potential therapeutic targets. To address this, we performed proteome-wide analyses using Mendelian randomization (MR) and colocalization techniques to uncover potential targets for CKD. We extracted summary-level data from the ARIC study, focusing on 7213 European American (EA) individuals and 4657 plasma proteins. To broaden our analysis, we incorporated genetic association data from Icelandic cohorts, thereby enhancing our investigation into the correlations with chronic kidney disease (CKD), creatinine-based estimated glomerular filtration rate (eGFRcrea), and estimated glomerular filtration rate (eGFR). We utilized genetic association data from the GWAS Catalog, including CKD (765,348, 625,219 European ancestry and 140,129 non-European ancestry), eGFRcrea (1,004,040, European ancestry), and eGFR (567,460, European ancestry). Employing MR analysis, we estimated the associations between proteins and CKD risk. Additionally, we conducted colocalization analysis to evaluate the existence of shared causal variants between the identified proteins and CKD. We detected notable correlations between levels predicted based on genetics of three circulating proteins and CKD, eGFRcrea, and eGFR. Notably, our colocalization analysis provided robust evidence supporting these associations. Specifically, genetically predicted levels of Transcription elongation factor A protein 2 (TCEA2) and Neuregulin-4 (NRG4) exhibited an inverse relationship with CKD risk, while Glucokinase regulatory protein (GCKR) showed an increased risk of CKD. Furthermore, our colocalization analysis also supported the associations of TCEA2, NRG4, and GCKR with the risk of eGFRcrea and eGFR.
在慢性肾脏病 (CKD) 的背景下，迫切需要确定新的药物发现靶点，而蛋白质组代表了大量潜在的治疗靶点。为了解决这个问题，我们使用孟德尔随机化 (MR) 和共定位技术进行了蛋白质组全谱分析，以揭示 CKD 的潜在靶点。我们从 ARIC 研究中提取了汇总水平数据，重点关注 7213 名欧洲裔美国人 (EA) 个体和 4657 种血浆蛋白。为了扩大我们的分析范围，我们整合了冰岛队列的遗传关联数据，从而加强了我们对与慢性肾脏病 (CKD)、基于肌酐的估计肾小球滤过率 (eGFRcrea) 和估计肾小球滤过率 (eGFR) 的相关性的研究。我们利用来自 GWAS 目录的遗传关联数据，包括 CKD（765348、625219 名欧洲血统和 140129 名非欧洲血统）、eGFRcrea（1004040 名欧洲血统）和 eGFR（567460 名欧洲血统）。我们使用 MR 分析估计了蛋白质与 CKD 风险之间的关联。此外，我们还进行了共定位分析，以评估已识别蛋白质与 CKD 之间是否存在共同的因果变异。我们检测到三种循环蛋白的遗传预测水平与 CKD、eGFRcrea 和 eGFR 之间存在显著相关性。值得注意的是，我们的共定位分析为这些关联提供了强有力的证据支持。具体来说，基于遗传预测的转录伸长因子 A 蛋白 2 (TCEA2) 和神经调节蛋白 4 (NRG4) 的水平与 CKD 风险呈负相关，而葡萄糖激酶调节蛋白 (GCKR) 则显示出 CKD 的风险增加。此外，我们的共定位分析还支持 TCEA2、NRG4 和 GCKR 与 eGFRcrea 和 eGFR 风险的关联。
