基于昼夜节律相关基因的帕金森病诊断模型。

A diagnostic model for Parkinson's disease based on circadian rhythm-related genes.

机构信息

Department of Neurology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.

Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.

出版信息

J Transl Med. 2024 Jul 8;22(1):635. doi: 10.1186/s12967-024-05424-z.

DOI:10.1186/s12967-024-05424-z

PMID:38978048

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11229228/

Abstract

BACKGROUND

Circadian rhythm (CR) disturbance is intricately associated with Parkinson's disease (PD). However, the involvement of CR-related mechanisms in the pathogenesis and progression of PD remains elusive.

METHODS

A total of 141 PD patients and 113 healthy participants completed CR-related clinical examinations in this study. To further investigate the CR-related mechanisms in PD, we obtained datasets (GSE7621, GSE20141, GSE20292) from the Gene Expression Omnibus database to identify differentially expressed genes between PD patients and healthy controls and further selected CR-related genes (CRRGs). Subsequently, the least absolute shrinkage and selection operator (LASSO) followed by logistic algorithms were employed to identify the hub genes and construct a diagnostic model. The predictive performance was evaluated by area under the curve (AUC), calibration curve, and decision curve analyses in the training set and external validation sets. Finally, RT‒qPCR and Western blotting were conducted to verify the expression of these hub genes in blood samples. In addition, Pearson correlation analysis was utilized to validate the association between expression of hub genes and circadian rhythm function.

RESULTS

Our clinical observational study revealed that even early-stage PD patients exhibited a higher likelihood of experiencing sleep disturbances, nocturnal hypertension, reverse-dipper blood pressure, and reduced heart rate variability compared to healthy controls. Furthermore, 4 CR-related hub genes (AGTR1, CALR, BRM14, and XPA) were identified and subsequently incorporated as candidate biomarkers to construct a diagnostic model. The model showed satisfactory diagnostic performance in the training set (AUC = 0.941), an external validation set GSE20295 (AUC = 0.842), and our clinical centre set (AUC = 0.805). Additionally, the up-regulation of CALR, BRM14 and the down-regulation of AGTR1, XPA were associated with circadian rhythm disruption.

CONCLUSION

CR disturbance seems to occur in the early stage of PD. The diagnostic model based on CR-related genes demonstrated robust diagnostic efficacy, offering novel insights for future clinical diagnosis of PD and providing a foundation for further exploration into the role of CR-related mechanisms in the progression of PD.

摘要

背景

昼夜节律（CR）紊乱与帕金森病（PD）密切相关。然而，CR 相关机制在 PD 的发病机制和进展中的作用仍不清楚。

方法

本研究共纳入 141 例 PD 患者和 113 例健康对照者进行 CR 相关临床检查。为进一步探讨 PD 中与 CR 相关的机制，我们从基因表达综合数据库中获取了数据集（GSE7621、GSE20141、GSE20292），以鉴定 PD 患者与健康对照者之间差异表达的基因，并进一步筛选出与 CR 相关的基因（CRRGs）。随后，采用最小绝对收缩和选择算子（LASSO）结合逻辑算法来识别关键基因，并构建诊断模型。在训练集和外部验证集中，通过曲线下面积（AUC）、校准曲线和决策曲线分析来评估预测性能。最后，通过 RT‒qPCR 和 Western blot 验证了这些关键基因在血液样本中的表达。此外，还进行了 Pearson 相关性分析以验证关键基因表达与昼夜节律功能之间的关联。

结果

我们的临床观察性研究表明，即使是早期 PD 患者，与健康对照组相比，发生睡眠障碍、夜间高血压、反杓型血压和心率变异性降低的可能性更高。此外，我们鉴定出 4 个与 CR 相关的关键基因（AGTR1、CALR、BRM14 和 XPA），并将其纳入候选生物标志物构建诊断模型。该模型在训练集（AUC=0.941）、外部验证集 GSE20295（AUC=0.842）和我们的临床中心集（AUC=0.805）中均表现出良好的诊断性能。此外，CALR、BRM14 的上调和 AGTR1、XPA 的下调与昼夜节律紊乱有关。