Li Shifu, Zhang Qian, Li Jian, Weng Ling
Department of Neurosurgery, Xiangya Hospital, Central South University, 87 Xiangya Street, Changsha, 410008 Hunan China.
National Clinical Research Center for Geriatric Disorders, Central South University, 87 Xiangya Street, Changsha, 410008 Hunan China.
EPMA J. 2022 Oct 12;13(4):699-723. doi: 10.1007/s13167-022-00299-w. eCollection 2022 Dec.
Although growing evidence suggests close correlations between autoimmunity and amyotrophic lateral sclerosis (ALS), no studies have reported on autoimmune-related genes (ARGs) from the perspective of the prognostic assessment of ALS. The purpose of this study was to investigate whether the circulating ARD signature could be identified as a reliable biomarker for ALS survival for predictive, preventive, and personalized medicine.
The whole blood transcriptional profiles and clinical characteristics of 454 ALS patients were downloaded from the Gene Expression Omnibus (GEO) database. A total of 4371 ARGs were obtained from GAAD and DisGeNET databases. Wilcoxon test and multivariate Cox regression were applied to identify the differentially expressed and prognostic ARGs. Then, unsupervised clustering was performed to classify patients into two distinct autoimmune-related clusters. PCA method was used to calculate the autoimmune index. LASSO and multivariate Cox regression was performed to establish risk model to predict overall survival for ALS patients. A ceRNA regulatory network was then constructed for regulating the model genes. Finally, we performed single-cell analysis to explore the expression of model genes in mutant SOD1 mice and methylation analysis in ALS patients.
Based on the expressions of 85 prognostic ARGs, two autoimmune-related clusters with various biological features, immune characteristics, and survival outcome were determined. Cluster 1 with a worsen prognosis was more active in immune-related biological pathways and immune infiltration than Cluster 2. A higher autoimmune index was associated with a better prognosis than a lower autoimmune index, and there were significant adverse correlations between the autoimmune index and immune infiltrating cells and immune responses. Nine model genes (KIF17, CD248, ENG, BTNL2, CLEC5A, ADORA3, PRDX5, AIM2, and XKR8) were selected to construct prognostic risk signature, indicating potent potential for survival prediction in ALS. Nomogram integrating risk model and clinical characteristics could predict the prognosis more accurately than other clinicopathological features. We constructed a ceRNA regulatory network for the model genes, including five lncRNAs, four miRNAs, and five mRNAs.
Expression of ARGs is correlated with immune characteristics of ALS, and seven ARG signatures may have practical application as an independent prognostic factor in patients with ALS, which may serve as target for the future prognostic assessment, targeted prevention, patient stratification, and personalization of medical services in ALS.
The online version contains supplementary material available at 10.1007/s13167-022-00299-w.
尽管越来越多的证据表明自身免疫与肌萎缩侧索硬化症（ALS）之间存在密切关联，但尚无研究从ALS预后评估的角度报道自身免疫相关基因（ARG）。本研究的目的是调查循环ARD特征是否可被确定为一种可靠的生物标志物，用于ALS生存的预测、预防和个性化医疗。
从基因表达综合数据库（GEO）下载了454例ALS患者的全血转录谱和临床特征。从GAAD和DisGeNET数据库中获得了总共4371个ARG。应用Wilcoxon检验和多变量Cox回归来识别差异表达和预后相关的ARG。然后，进行无监督聚类将患者分为两个不同的自身免疫相关簇。采用主主主成分分析（PCA）方法用于计算自身免疫指数。采用LASSO和多变量Cox回归建立风险模型，以预测ALS患者的总生存期。随后构建ceRNA调控网络来调节模型基因。最后，我们进行单细胞分析以探索模型基因在突变型SOD1小鼠中的表达以及在ALS患者中的甲基化分析。
基于85个预后相关ARG的表达，确定了两个具有不同生物学特征、免疫特征和生存结果的自身免疫相关簇。预后较差的簇1在免疫相关生物学途径和免疫浸润方面比簇2更活跃。较高的自身免疫指数比较低的自身免疫指数与更好的预后相关，并且自身免疫指数与免疫浸润细胞和免疫反应之间存在显著的负相关。选择了9个模型基因（KIF17、CD248、ENG、BTNL2、CLEC5A、ADORA3、PRDX5、AIM2和XKR8）构建预后风险特征，表明其在ALS生存预测方面具有强大的潜力。整合风险模型和临床特征的列线图比其他临床病理特征更能准确预测预后。我们为模型基因构建了一个ceRNA调控网络，包括5个lncRNA、4个miRNA和5个mRNA。
ARG的表达与ALS的免疫特征相关，7个ARG特征可能作为ALS患者独立的预后因素具有实际应用价值，这可能成为未来ALS预后评估、靶向预防、患者分层和医疗服务个性化的靶点。
在线版本包含可在10.1007/s13167-022-00299-w获取的补充材料。
