Affiliation:
1. Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences; National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Beijing, China
2. Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
Abstract
Background
Juvenile dermatomyositis (JDM) is an immune-mediated disease characterized by chronic organ inflammation. The pathogenic mechanisms remain ill-defined.
Methods
Raw microarray data of JDM were obtained from the gene expression omnibus (GEO) database. Based on the GSE3307 dataset with 39 samples, weighted correlation network analysis (WGCNA) was performed to identify key modules associated with pathological state. Functional enrichment analyses were conducted to identify potential mechanisms. Based on the criteria of high connectivity and module membership, candidate hub genes were selected. A protein-protein interaction network was constructed to identify hub genes. Another dataset (GSE11971) was used for the validation of real hub genes. Finally, the real hub genes were used to screen out small-molecule compounds via the Connectivity map database.
Results
Three modules were considered as key modules for the pathological state of JDM. Functional enrichment analysis indicated that responses to interferon and metabolism were dysregulated. A total of 45 candidate hub genes were selected according to the pre-established criteria, and 20 genes could differentiate JDM from normal controls by validation of another external dataset (GSE11971). These real hub genes suggested the pivotal role of mitochondrial dysfunction and interferon signature in JDM. Furthermore, drug repositioning highlighted the importance of acacetin, helveticoside, lanatoside C, deferoxamine, LY-294002, tanespimycin and L01AD from downregulated genes with the potential to perturb the development of JDM, while betonicine, felodipine, valproic acid, trichostatin A and sirolimus from upregulated genes provided potentially therapeutic goals for JDM.
Conclusions
There are 20 real hub genes associated with the pathological state of JDM, suggesting the pivotal role of mitochondrial dysfunction and interferon signature in JDM. This analysis predicted several kinds of small-molecule compounds to treat JDM.
Funder
Chinese National Key Technology R&D Program of Ministry of Science and Technology
National Science and Technology Major Project of the Ministry of Science and Technology of China
Chinese Academy of Medical Sciences
National Natural Science Foundation of China
Subject
General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience
Cited by
7 articles.
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