Yuan Weichen, Li Jun, Gao Shang, Sun Wei, Zhao Fangkun
Department of Ophthalmology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China.
Key Lens Research Laboratory of Liaoning Province, Shenyang, China.
Front Pharmacol. 2024 Aug 16;15:1428472. doi: 10.3389/fphar.2024.1428472. eCollection 2024.
This study aimed to identify novel therapeutic targets for primary open-angle glaucoma (POAG).
The summary-data-based Mendelian randomization (SMR) method was used to evaluate the genetic association between plasma proteins and POAG. Two sets of plasma protein quantitative trait loci (pQTLs) data considered exposures were obtained from the Icelandic Decoding Genetics Study and UK Biobank Pharma Proteomics Project. The summary-level genome-wide association studies data for POAG were extracted from the latest Round 10 release of the FinnGen consortium (8,530 cases and 391,275 controls) and the UK Biobank (4,737 cases and 458,196 controls). Colocalization analysis was used to screen out pQTLs that share the same variant with POAG as drug targets identified. The two-sample Mendelian randomization, reverse causality testing and phenotype scanning were performed to further validate the main findings. Protein-protein interaction, pathway enrichment analysis and druggability assessment were conducted to determine whether the identified plasma proteins have potential as drug targets.
After systematic analysis, this study identified eight circulating proteins as potential therapeutic targets for POAG. Three causal proteins with strong evidence of colocalization, ROBO1 (OR = 1.38, = 1.48 × 10, PPH4 = 0.865), FOXO3 (OR = 0.35, = 4.34 × 10, PPH4 = 0.796), ITIH3 (OR = 0.89, = 2.76 × 10, PPH4 = 0.767), were considered tier one targets. Five proteins with medium support evidence of colocalization, NCR1 (OR = 1.25, = 4.18 × 10, PPH4 = 0.682), NID1 (OR = 1.38, = 1.54 × 10, PPH4 = 0.664), TIMP3 (OR = 0.91, = 4.01 × 10, PPH4 = 0.659), SERPINF1 (OR = 0.81, = 2.77 × 10, PPH4 = 0.59), OXT (OR = 1.17, = 9.51 × 10, PPH4 = 0.526), were classified as tier two targets. Additional sensitivity analyses further validated the robustness and directionality of these findings. According to druggability assessment, Pimagedine, Resveratrol, Syringaresinol and Clozapine may potentially be important in the development of new anti-glaucoma agents.
Our integrated study identified eight potential associated proteins for POAG. These proteins play important roles in neuroprotection, extracellular matrix regulation and oxidative stress. Therefore, they have promising potential as therapeutic targets to combat POAG.
本研究旨在确定原发性开角型青光眼（POAG）的新型治疗靶点。
基于汇总数据的孟德尔随机化（SMR）方法用于评估血浆蛋白与POAG之间的遗传关联。两组被视为暴露因素的血浆蛋白定量性状位点（pQTLs）数据分别来自冰岛解码遗传学研究和英国生物银行药物蛋白质组学项目。POAG的全基因组关联研究汇总数据从芬兰基因联盟的最新第10轮发布（8530例病例和391275例对照）以及英国生物银行（4737例病例和458196例对照）中提取。共定位分析用于筛选出与POAG共享相同变异体的pQTLs作为已确定的药物靶点。进行两样本孟德尔随机化、反向因果关系检验和表型扫描以进一步验证主要发现。进行蛋白质-蛋白质相互作用、通路富集分析和药物可及性评估以确定所鉴定的血浆蛋白是否具有作为药物靶点的潜力。
经过系统分析，本研究确定了八种循环蛋白作为POAG的潜在治疗靶点。三种具有强共定位证据的因果蛋白，即ROBO1（OR = 1.38，= 1.48×10，PPH4 = 0.865）、FOXO3（OR = 0.35，= 4.34×10，PPH4 = 0.796）、ITIH3（OR = 0.89，= 2.76×10，PPH4 = 0.767），被视为一级靶点。五种具有中等共定位支持证据的蛋白，即NCR1（OR = 1.25，= 4.18×10，PPH4 = 0.682）、NID1（OR = 1.38，= 1.54×10，PPH4 = 0.664）、TIMP3（OR = 0.91，= 4.01×10，PPH4 = 0.659）、SERPINF1（OR = 0.81，= 2.77×10，PPH4 = 0.59）、OXT（OR = 1.17，= 9.51×10，PPH4 = 0.526），被归类为二级靶点。额外的敏感性分析进一步验证了这些发现的稳健性和方向性。根据药物可及性评估，匹马吉定、白藜芦醇、丁香树脂醇和氯氮平可能在新型抗青光眼药物的开发中具有重要意义。
我们的综合研究确定了八种与POAG潜在相关的蛋白。这些蛋白在神经保护、细胞外基质调节和氧化应激中发挥重要作用。因此，它们作为对抗POAG的治疗靶点具有广阔的潜力。
