Tang Yizhen, Pan Yiqiong, Chen Yuhong, Kong Xiangmei, Chen Junyi, Zhang Hengli, Tang Guangxian, Wu Jihong, Sun Xinghuai
Department of Ophthalmology and Visual Science, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
NHC Key Laboratory of Myopia, Chinese Academy of Medical Sciences, and Shanghai Key Laboratory of Visual Impairment and Restoration (Fudan University), Shanghai, China.
Front Pharmacol. 2021 Apr 14;12:621146. doi: 10.3389/fphar.2021.621146. eCollection 2021.
Glaucoma is the second leading cause of blindness globally characterized by progressive loss of retinal ganglion cells (RGCs) and irreversible visual deficiency. As the most common type of glaucoma, primary open angle glaucoma (POAG) is currently an unmet medical need with limited therapy by lowering intraocular pressure (IOP). However, some patients continue to progress even though their IOP are controlled. Although early diagnosis and prompt treatment are crucial in preventing irreversible visual impairment, there are currently no biomarkers for screening POAG. Metabolomics has the advantages of illustrating the final downstream products of the genome and establishing the closest link to the phenotype. So far, there is no study investigating the metabolomic profiles in both aqueous humor and plasma of POAG patients. Therefore, to explore diagnostic biomarkers, unveil underlying pathophysiology and potential therapeutic strategies, a widely targeted metabolomic approach was applied using ultrahigh-resolution mass spectrometry with C18 liquid chromatography to characterize the metabolomic profiles in both aqueous humor and plasma of 28 POAG patients and 25 controls in our study. Partial least squares-discriminant analysis (PLS-DA) was performed to determine differentially expressed metabolites (DEMs) between POAG and age-matched controls. The area under the receiver operating characteristic curve (AUC) was calculated to assess the prediction accuracy of the DEMs. The correlation of DEMs with the clinical parameters was determined by Pearson correlation, and the metabolic pathways were analyzed using MetaboAnalyst 4.0. PLS-DA significantly separated POAG from controls with 22 DEMs in the aqueous humor and 11 DEMs in the plasma. Additionally, univariate ROC analysis and correlation analysis with clinical parameters revealed cyclic AMP (AUC = 0.87), 2-methylbenzoic acid (AUC = 0.75), 3'-sialyllactose (AUC = 0.73) in the aqueous humor and N-lac-phe (AUC = 0.76) in the plasma as potential biomarkers for POAG. Moreover, the metabolic profiles pointed towards the alteration in the purine metabolism pathway. In conclusion, the study identified potential and novel biomarkers for POAG by crosslinking the metabolomic profiles in aqueous humor and plasma and correlating with the clinical parameters. These findings have important clinical implications given that no biomarkers are currently available for glaucoma in the clinic, and the study provided new insights in exploring diagnostic biomarkers and potential therapeutic strategies of POAG by targeting metabolic pathways.
青光眼是全球第二大致盲原因，其特征为视网膜神经节细胞（RGCs）进行性丧失和不可逆的视力缺陷。作为最常见的青光眼类型，原发性开角型青光眼（POAG）目前是一种未得到满足的医疗需求，通过降低眼压（IOP）进行治疗的方法有限。然而，一些患者即使眼压得到控制仍会病情进展。尽管早期诊断和及时治疗对于预防不可逆视力损害至关重要，但目前尚无用于筛查POAG的生物标志物。代谢组学具有阐明基因组最终下游产物并建立与表型最紧密联系的优势。到目前为止，尚无研究调查POAG患者房水和血浆中的代谢组学特征。因此，为了探索诊断生物标志物、揭示潜在的病理生理学和潜在治疗策略，在我们的研究中采用了一种广泛靶向代谢组学方法，使用超高效液相色谱-超高分辨率质谱对28例POAG患者和25例对照的房水和血浆中的代谢组学特征进行表征。进行偏最小二乘判别分析（PLS-DA）以确定POAG与年龄匹配对照之间的差异表达代谢物（DEMs）。计算受试者工作特征曲线下面积（AUC）以评估DEMs的预测准确性。通过Pearson相关性确定DEMs与临床参数的相关性，并使用MetaboAnalyst 4.0分析代谢途径。PLS-DA显著区分了POAG与对照，房水中有22种DEMs，血浆中有11种DEMs。此外，单变量ROC分析以及与临床参数的相关性分析显示，房水中的环磷酸腺苷（AUC = 0.87）、2-甲基苯甲酸（AUC = 0.75）、3'-唾液酸乳糖（AUC = 0.73）以及血浆中的N-乳糖-苯丙氨酸（AUC = 0.76）作为POAG的潜在生物标志物。此外，代谢谱指向嘌呤代谢途径的改变。总之，该研究通过交联房水和血浆中的代谢组学特征并与临床参数相关联，确定了POAG潜在的新型生物标志物。鉴于目前临床上尚无青光眼的生物标志物，这些发现具有重要的临床意义，并且该研究为通过靶向代谢途径探索POAG的诊断生物标志物和潜在治疗策略提供了新的见解。
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