Institute of Neurology, General Hospital of Northern Theater Command, Shenyang, Liaoning 110016, China.
Institute of Neurology, General Hospital of Northern Theater Command, Shenyang, Liaoning 110016, China.
J Proteomics. 2024 Jul 15;303:105216. doi: 10.1016/j.jprot.2024.105216. Epub 2024 Jun 5.
The aim of this study was to investigate the plasma proteome in individuals with intracranial aneurysms (IAs) and identify biomarkers associated with the formation and rupture of IAs. Proteomic profiles (N = 1069 proteins) were assayed in plasma (N = 120) collected from patients with ruptured and unruptured intracranial aneurysms (RIA and UIA), traumatic subarachnoid hemorrhage (tSAH), and healthy controls (HC) using tandem mass tag (TMT) labeling quantitative proteomics analysis. Gene ontology (GO) and pathway analysis revealed that these relevant proteins were involved in immune response and extracellular matrix organization pathways. Seven candidate biomarkers were verified by ELISA in a completely separate cohort for validation (N = 90). Among them, FN1, PON1, and SERPINA1 can be utilized as diagnosis biomarkers of IA, with a combined area under the ROC curve of 0.891. The sensitivity was 93.33%, specificity was 75.86%, and accuracy was 87.64%. PFN1, ApoA-1, and SERPINA1 can serve as independent risk factors for predicting aneurysm rupture. The combined prediction of aneurysm rupture yielded an area under the ROC curve of 0.954 with a sensitivity of 96.15%, specificity of 81.48%, and accuracy of 88.68%. This prediction model was more effective than PHASES score. In conclusion, high-throughput proteomics analysis with population validation was performed to assess blood-based protein expression characteristics. This revealed the potential mechanism of IA formation and rupture, facilitating the discovery of biomarkers. SIGNIFICANCE: Although the annual rupture rate of small unruptured aneurysms is believed to be minimal, studies have indicated that ruptured aneurysms typically have an average size of 6.28 mm, with 71.8% of them being <7 mm in diameter. Hence, evaluating the possibility of rupture in UIA and making a choice between aggressive treatment and conservative observation emerges as a significant challenge in the management of UIA. No biomarker or scoring system has been able to satisfactorily address this issue to date. It would be significant to develop biomarkers that could be used for early diagnosis of IA as well as for prediction of IA rupture. After TMT proteomics analysis and ELISA validation in independent populations, we found that FN1, PON1, and SERPINA1 can be utilized as diagnostic biomarkers for IA, and PFN1, ApoA-1, and SERPINA1 can serve as independent risk factors for predicting aneurysm rupture. Especially, when combined with ApoA-1, SERPINA1, and PFN1 for predicting IA rupture, the area under the curve (AUC) was 0.954 with a sensitivity of 96.15%, specificity of 81.48%, and accuracy of 88.68%. This prediction model was more effective than PHASES score.
本研究旨在探讨颅内动脉瘤（IA）患者的血浆蛋白质组学，并鉴定与 IA 形成和破裂相关的生物标志物。使用串联质量标签（TMT）标记定量蛋白质组学分析，对收集自破裂颅内动脉瘤（RIA）和未破裂颅内动脉瘤（UIA）、创伤性蛛网膜下腔出血（tSAH）和健康对照（HC）患者的血浆（N=120）中的蛋白质组学图谱（N=1069 种蛋白质）进行检测。基因本体（GO）和途径分析表明，这些相关蛋白参与免疫反应和细胞外基质组织途径。在一个完全独立的队列中，通过 ELISA 验证了 7 个候选生物标志物进行验证（N=90）。其中，FN1、PON1 和 SERPINA1 可用作 IA 的诊断生物标志物，ROC 曲线下面积为 0.891。灵敏度为 93.33%，特异性为 75.86%，准确性为 87.64%。PFN1、ApoA-1 和 SERPINA1 可作为预测动脉瘤破裂的独立危险因素。对动脉瘤破裂的联合预测得出 ROC 曲线下面积为 0.954，灵敏度为 96.15%，特异性为 81.48%，准确性为 88.68%。该预测模型比 PHASES 评分更有效。总之，进行了高通量蛋白质组学分析和人群验证，以评估基于血液的蛋白质表达特征。这揭示了 IA 形成和破裂的潜在机制，有助于发现生物标志物。意义：尽管人们认为小未破裂动脉瘤的年破裂率很小，但研究表明，破裂的动脉瘤通常平均直径为 6.28mm，其中 71.8%的直径<7mm。因此，评估 UIA 的破裂可能性并在积极治疗和保守观察之间做出选择，是 UIA 管理中的一个重大挑战。到目前为止，还没有一种生物标志物或评分系统能够令人满意地解决这个问题。开发能够用于 IA 的早期诊断以及预测 IA 破裂的生物标志物将具有重要意义。在独立人群中进行 TMT 蛋白质组学分析和 ELISA 验证后，我们发现 FN1、PON1 和 SERPINA1 可用作 IA 的诊断生物标志物，PFN1、ApoA-1 和 SERPINA1 可用作预测动脉瘤破裂的独立危险因素。特别是，当用于预测 IA 破裂时，结合 ApoA-1、SERPINA1 和 PFN1 的曲线下面积（AUC）为 0.954，灵敏度为 96.15%，特异性为 81.48%，准确性为 88.68%。该预测模型比 PHASES 评分更有效。
