背景:慢性肾脏疾病(CKD)是一种没有有效治愈方法的进行性疾病。我们旨在通过整合血浆蛋白质组和转录组确定CKD和肾功能的潜在药物靶标。
方法:我们设计了一个全面的分析管道,涉及两个样本孟德尔随机化(MR)(用于蛋白质),基于摘要的MR(SMR)(用于mRNA),和共定位(用于编码基因),以确定CKD的潜在多组学生物标志物,并结合蛋白质-蛋白质相互作用,基因本体论(GO),和单细胞注释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)。
结果:利用来自3种大规模GWAS的3032种蛋白质的pQTL以及相应的血液和组织特异性eQTL,我们鉴定了32种与CKD相关的蛋白质,在不同的CKD数据集中进行了验证,肾功能指标,和临床类型。值得注意的是,具有先前MR支持的12种蛋白质,包括成纤维细胞生长因子5(FGF5),异戊烯基-二磷酸δ-异构酶2(IDI2),抑制素βC链(INHBC),亲丁素亚家族3成员A2(BTN3A2),BTN3A3,尿调蛋白(UMOD),补体成分4A(C4a),C4b,170kDa的中心体蛋白(CEP170),血清学定义的结肠癌抗原8(SDCCAG8),MHCI类多肽相关序列B(MICB),和肝脏表达的抗菌肽2(LEAP2),得到确认。据我们所知,以前没有报道过20种新的致病蛋白。五种新型蛋白质,即,GCKR(OR1.17,95%CI1.10-1.24),IGFBP-5(OR0.43,95%CI0.29-0.62),SRAGE(OR1.14,95%CI1.07-1.22),GNPTG(OR0.90,95%CI0.86-0.95),和YOD1(OR1.39,95%CI1.18-1.64,)通过了MR,SMR,和共定位分析。其他15种蛋白质也是候选靶标(GATM,AIF1L,DQA2,PFKFB2,NFATC1,活化素AC,ApoA-IV,MFAP4,DJC10,C2CD2L,TCEA2HLA-E,PLD3、AIF1和GMPR1)。这些蛋白质相互作用,它们的编码基因主要富集在免疫相关途径中或在组织中呈现特异性,肾脏相关的组织细胞,和肾单细胞。
结论:我们对血浆蛋白质组和转录组数据的综合分析确定了CKD的32个潜在治疗靶点,肾功能,和特定的CKD临床类型,为开发新的免疫疗法提供潜在的目标,联合疗法,或有针对性的干预措施。
BACKGROUND: 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.
METHODS: 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).
RESULTS: 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.
CONCLUSIONS: 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.