Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing, 100191, China.
Peking University Health Science Center, Beijing, 100191, China.
Genome Med. 2024 Jun 19;16(1):84. doi: 10.1186/s13073-024-01356-x.
Chronic kidney disease (CKD) is a progressive disease for which there is no effective cure. We aimed to identify potential drug targets for CKD and kidney function by integrating plasma proteome and transcriptome.
We designed a comprehensive analysis pipeline involving two-sample Mendelian randomization (MR) (for proteins), summary-based MR (SMR) (for mRNA), and colocalization (for coding genes) to identify potential multi-omics biomarkers for CKD and combined the protein-protein interaction, Gene Ontology (GO), and single-cell annotation to explore the potential biological roles. The outcomes included CKD, extensive kidney function phenotypes, and different CKD clinical types (IgA nephropathy, chronic glomerulonephritis, chronic tubulointerstitial nephritis, membranous nephropathy, nephrotic syndrome, and diabetic nephropathy).
Leveraging pQTLs of 3032 proteins from 3 large-scale GWASs and corresponding blood- and tissue-specific eQTLs, we identified 32 proteins associated with CKD, which were validated across diverse CKD datasets, kidney function indicators, and clinical types. Notably, 12 proteins with prior MR support, including fibroblast growth factor 5 (FGF5), isopentenyl-diphosphate delta-isomerase 2 (IDI2), inhibin beta C chain (INHBC), butyrophilin subfamily 3 member A2 (BTN3A2), BTN3A3, uromodulin (UMOD), complement component 4A (C4a), C4b, centrosomal protein of 170 kDa (CEP170), serologically defined colon cancer antigen 8 (SDCCAG8), MHC class I polypeptide-related sequence B (MICB), and liver-expressed antimicrobial peptide 2 (LEAP2), were confirmed. To our knowledge, 20 novel causal proteins have not been previously reported. Five novel proteins, namely, GCKR (OR 1.17, 95% CI 1.10-1.24), IGFBP-5 (OR 0.43, 95% CI 0.29-0.62), sRAGE (OR 1.14, 95% CI 1.07-1.22), GNPTG (OR 0.90, 95% CI 0.86-0.95), and YOD1 (OR 1.39, 95% CI 1.18-1.64,) passed the MR, SMR, and colocalization analysis. The other 15 proteins were also candidate targets (GATM, AIF1L, DQA2, PFKFB2, NFATC1, activin AC, Apo A-IV, MFAP4, DJC10, C2CD2L, TCEA2, HLA-E, PLD3, AIF1, and GMPR1). These proteins interact with each other, and their coding genes were mainly enrichment in immunity-related pathways or presented specificity across tissues, kidney-related tissue cells, and kidney single cells.
Our integrated analysis of plasma proteome and transcriptome data identifies 32 potential therapeutic targets for CKD, kidney function, and specific CKD clinical types, offering potential targets for the development of novel immunotherapies, combination therapies, or targeted interventions.
慢性肾脏病（CKD）是一种无法治愈的进行性疾病。我们旨在通过整合血浆蛋白质组和转录组来鉴定 CKD 和肾功能的潜在药物靶点。
我们设计了一个综合分析管道，包括两样本孟德尔随机化（MR）（用于蛋白质）、基于汇总的 MR（SMR）（用于 mRNA）和共定位（用于编码基因），以鉴定 CKD 和联合蛋白质-蛋白质相互作用、基因本体论（GO）和单细胞注释的潜在多组学生物标志物，以探索潜在的生物学作用。结果包括 CKD、广泛的肾功能表型和不同的 CKD 临床类型（IgA 肾病、慢性肾小球肾炎、慢性肾小管间质性肾炎、膜性肾病、肾病综合征和糖尿病肾病）。
利用来自 3 个大型全基因组关联研究的 3032 种蛋白质的 pQTLs 及其相应的血液和组织特异性 eQTLs，我们鉴定了 32 种与 CKD 相关的蛋白质，这些蛋白质在不同的 CKD 数据集、肾功能指标和临床类型中得到了验证。值得注意的是，有 12 种蛋白质具有先前的 MR 支持，包括成纤维细胞生长因子 5（FGF5）、异戊烯二磷酸 delta-异构酶 2（IDI2）、抑制素 beta C 链（INHBC）、butyrophilin 亚家族 3 成员 A2（BTN3A2）、BTN3A3、尿调蛋白（UMOD）、补体成分 4A（C4a）、C4b、中心体蛋白 170 kDa（CEP170）、血清定义的结肠癌抗原 8（SDCCAG8）、MHC Ⅰ类多肽相关序列 B（MICB）和肝表达抗菌肽 2（LEAP2），得到了证实。据我们所知，有 20 种新的因果蛋白质以前没有报道过。有 5 种新的蛋白质，即葡萄糖激酶调节蛋白（GCKR）（OR 1.17，95%CI 1.10-1.24）、胰岛素样生长因子结合蛋白 5（IGFBP-5）（OR 0.43，95%CI 0.29-0.62）、可溶性晚期糖基化终产物受体（sRAGE）（OR 1.14，95%CI 1.07-1.22）、GNPTG（OR 0.90，95%CI 0.86-0.95）和 YOD1（OR 1.39，95%CI 1.18-1.64）通过了 MR、SMR 和共定位分析。其他 15 种蛋白质也是候选靶点（GATM、AIF1L、DQA2、PFKFB2、NFATC1、激活素 AC、Apo A-IV、MFAP4、DJC10、C2CD2L、TCEA2、HLA-E、PLD3、AIF1 和 GMPR1）。这些蛋白质相互作用，其编码基因主要富集在免疫相关途径中，或在组织、肾脏相关组织细胞和肾脏单细胞中表现出特异性。
我们对血浆蛋白质组和转录组数据的综合分析鉴定了 32 个潜在的 CKD、肾功能和特定 CKD 临床类型的治疗靶点，为新型免疫疗法、联合疗法或靶向干预的开发提供了潜在的靶点。
