Wang Xin, Wang Yifei, Zhang Xuemei, Hong Xiangxiang, Rang Xinming, Yang Dan, Huang Shan, Xu Chaohan, Fu Jin
Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, Heilongjiang Province, China.
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang Province, China.
Mult Scler Relat Disord. 2023 Oct;78:104903. doi: 10.1016/j.msard.2023.104903. Epub 2023 Jul 17.
Clinical observation has revealed that multiple sclerosis (MS) and autoimmune thyroid disease (AITD) are strongly correlated. The aim of this study was to explore the shared molecular causes of MS and AITD, and to conduct drug rearrangement on this basis, search for comorbidity drugs and feasible drugs for mutual reference between the two diseases.
Based on genome-wide association study (GWAS) data and transcriptome data, susceptibility genes and differentially expressed genes related to MS and AITD were identified by bioinformatics analysis. Pathway enrichment, gene ontology (GO), protein-protein interaction analysis, and gene-pathway network analysis of the above genes were performed to identify a common target pool, including common genes, common hub genes, and common pathways, and to explore the specific pathogenesis of the two diseases, respectively. Drugs that target the common pathways/genes were identified through the Comparative Toxicogenomics Database (CTD), DrugBank database, and Drug-Gene Interaction (DGI) Database. Common hub genes were compared with the target genes of drugs approved for treating MS/AITD and drugs under investigation identified by DrugBank and ClinicalTrials, respectively.
We identified a pool of shared targets containing genes and pathways, including 46 common genetic susceptibility pathways and 9 common differentially expressed pathways, including JAK-STAT signaling pathway, Th17 cell differentiation, Th1 and Th2 cell differentiation, PD-L1 expression and PD-1 checkpoint pathway in cancer, etc. In addition, a total of 29 hub genes, including TYK2, JAK1, STAT3, IL2RA, HLA-DRB1, and TLR3, were identified. Drugs approved for treating MS or AITD, such as methylprednisolone, cyclophosphamide, glatiramer, natalizumab, and methimazole, can target the shared genes and pathways, among which methylprednisolone and cyclophosphamide have been shown to be beneficial for the treatment of the two diseases, indicating that these drugs have the potential to become a priority in the treatment of comorbidities. Moreover, drugs targeting multiple common genes and pathways, including tacrolimus, deucravacitinib, and nivolumab, were identified as potential drugs for the treatment of MS, AITD, and their comorbidities.
We observed that T-cell activation-related genes and pathways play a major role in the pathogenesis of both MS and AITD, which may be the molecular basis of the comorbidity. Moreover, we identified a variety of drugs which may be used as priority or potential treatments for comorbidities.
临床观察显示，多发性硬化症（MS）与自身免疫性甲状腺疾病（AITD）密切相关。本研究旨在探索MS和AITD共同的分子病因，并在此基础上进行药物重排，寻找两种疾病相互参照的合并用药及可行药物。
基于全基因组关联研究（GWAS）数据和转录组数据，通过生物信息学分析鉴定与MS和AITD相关的易感基因和差异表达基因。对上述基因进行通路富集、基因本体（GO）、蛋白质-蛋白质相互作用分析以及基因-通路网络分析，以确定一个共同的靶点库，包括共同基因、共同枢纽基因和共同通路，并分别探索两种疾病的具体发病机制。通过比较毒理基因组学数据库（CTD）、药物银行数据库和药物-基因相互作用（DGI）数据库，确定靶向共同通路/基因的药物。将共同枢纽基因分别与已批准用于治疗MS/AITD的药物以及药物银行和临床试验中确定的在研药物的靶点基因进行比较。
我们确定了一个包含基因和通路的共同靶点库，其中包括46条共同的遗传易感通路和9条共同的差异表达通路，如JAK-STAT信号通路、Th17细胞分化、Th1和Th2细胞分化、癌症中的PD-L1表达和PD-1检查点通路等。此外，共鉴定出29个枢纽基因，包括TYK2、JAK1、STAT3、IL2RA、HLA-DRB1和TLR3。已批准用于治疗MS或AITD的药物，如甲基泼尼松龙、环磷酰胺、格拉替雷、那他珠单抗和甲巯咪唑，可靶向共同基因和通路，其中甲基泼尼松龙和环磷酰胺已被证明对两种疾病的治疗有益，表明这些药物有可能成为合并症治疗的首选。此外，靶向多个共同基因和通路的药物，包括他克莫司、德卡伐替尼和纳武单抗，被确定为治疗MS、AITD及其合并症的潜在药物。
我们观察到与T细胞活化相关的基因和通路在MS和AITD的发病机制中起主要作用，这可能是合并症的分子基础。此外，我们鉴定出多种可能用作合并症优先或潜在治疗药物的药物。
