Abstract
ObjectiveThis study aimed to explore the shared mechanism and candidate drugs of multiple sclerosis (MS) and Sjögren’s syndrome (SS).MethodsMS- and SS-related susceptibility genes and differentially expressed genes (DEGs) were identified by bioinformatics analysis based on genome-wide association studies (GWAS) and transcriptome data from GWAS catalog and Gene Expression Omnibus (GEO) database. Pathway enrichment, Gene Ontology (GO) analysis, and protein–protein interaction analysis for susceptibility genes and DEGs were performed. The drugs targeting common pathways/genes were obtained through Comparative Toxicogenomics Database (CTD), DrugBank database, and Drug–Gene Interaction (DGI) Database. The target genes of approved/investigational drugs for MS and SS were obtained through DrugBank and compared with the common susceptibility genes.ResultsBased on GWAS data, we found 14 hub common susceptibility genes (HLA-DRB1, HLA-DRA, STAT3, JAK1, HLA-B, HLA-DQA1, HLA-DQA2, HLA-DQB1, HLA-DRB5, HLA-DPA1, HLA-DPB1, TYK2, IL2RA, and MAPK1), with 8 drugs targeting two or more than two genes, and 28 common susceptibility pathways, with 15 drugs targeting three or more than three pathways. Based on transcriptome data, we found 3 hub common DEGs (STAT1, GATA3, PIK3CA) with 3 drugs and 10 common risk pathways with 435 drugs. “JAK-STAT signaling pathway” was included in common susceptibility pathways and common risk pathways at the same time. There were 133 overlaps including JAK-STAT inhibitors between agents from GWAS and transcriptome data. Besides, we found that IL2RA and HLA-DRB1, identified as hub common susceptibility genes, were the targets of daclizumab and glatiramer that were used for MS, indicating that daclizumab and glatiramer may be therapeutic for SS.ConclusionWe observed the shared mechanism of MS and SS, in which JAK-STAT signaling pathway played a vital role, which may be the genetic and molecular bases of comorbidity of MS with SS. Moreover, JAK-STAT inhibitors were potential therapies for MS and SS, especially for their comorbidity.
Highlights
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) [1]
3.1.1 Identification of Susceptibility Genes and Enrichment Analysis A total of 385 single-nucleotide polymorphism (SNP) of MS and 19 SNPs of s syndrome (SS) were obtained from genome-wide association studies (GWAS) data, as well as 260 and 22 susceptibility genes, respectively (Supplementary Tables S1, S2 and Supplementary Figures S1, S2)
Through comparing hub common susceptibility genes and target genes of available drugs, we found that IL2RA and human leukocyte antigen (HLA)-DRB1 that were
Summary
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) [1]. The etiology and pathogenesis of MS are complex, in which autoimmune responses based on genetic susceptibility and environmental risk factors have a vital role. The initiation of autoimmune responses is not fully explained, which may be related to Epstein–Barr virus (EBV) antigen mimicking or epitope expansion in genetically susceptible individuals [2]. Comorbidity of MS with many other autoimmune diseases is found in our clinical work, including Sjögren’s syndrome (SS). Epidemiological studies show that the prevalence of SS in MS patients is about 1% up to 16.7% in primary progressive MS patients, with the incidence of sicca syndrome (typical symptoms but not meeting the diagnostic criteria of SS) up to 10%, while the prevalence of SS in the general population is only 0.06%, indicating that the prevalence of SS in MS patients is higher than that in the general population [3]. SS involves CNS with a 5.8%–38% probability, and 52%–80% of these conditions occur before SS diagnosis [3]
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