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Signaling Pathways of Genetic Variants and Mirnas in the Pathogenesis of Myasthenia Gravis

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Signaling Pathways of Genetic Variants and Mirnas in the Pathogenesis of Myasthenia Gravis 1944 Original Article Signaling pathways of genetic variants and miRNAs in the pathogenesis of myasthenia gravis Kai Qian1,2#, Jia-Xin Xu3#, Yi Deng4#, Hao Peng2, Jun Peng2, Chun-Mei Ou5, Zu Liu3, Li-Hong Jiang2, Yong-Hang Tai6 1Faculty of Life and Biotechnology, Kunming University of Science and Technology, Kunming, China; 2Department of Thoracic Surgery, Institute of The First People’s Hospital of Yunnan Province, Kunming, China; 3Department of Cardiovascular surgery, Yan’ an Affiliated Hospital of Kunming Medical University, Kunming, China; 4Department of Oncology, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing, China; 5Department of Cardiovascular surgery, Institute of the First People’s Hospital of Yunnan Province, Kunming, China; 6School of Electronic Information in the Yunnan Normal University, Kunming, China Contributions: (I) Conception and design: K Qian, JX Xu, Y Deng; (II) Administrative support: LH Jiang, YH Tai; (III) Provision of study materials or patients: K Qian, Y Deng, J Peng; (IV)Collection and assembly of data: JX Xu, CM Ou, Z Liu, H Peng; (V) Data analysis and interpretation: K Qian, JX Xu, Y Deng; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. #These authors contributed equally to this work. Correspondence to: Li-Hong Jiang. Department of Thoracic Surgery, Institute of the First People’s Hospital of Yunnan Province, Kunming University of Science and Technology, Kunming 650032, China. Email: [email protected]; Yong-Hang Tai. School of Electronic Information in the Yunnan Normal University, Kunming, China. Email: [email protected]. Background: Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disorder causing muscle weakness and characterized by a defect in synaptic transmission at the neuromuscular junction. The pathogenesis of this disease remains unclear. We aimed to predict the key signaling pathways of genetic variants and miRNAs in the pathogenesis of MG, and identify the key genes among them. Methods: We searched published information regarding associated single nucleotide polymorphisms (SNPs) and differentially-expressed miRNAs in MG cases. We search of SNPs and miRNAs in literature databases about MG, then we used bioinformatic tools to predict target genes of miRNAs. Moreover, functional enrichment analysis for key genes was carried out utilizing the Cytoscape-plugin, known as ClueGO. These key genes were mapped to STRING database to construct a protein-protein interaction (PPI) network. Then a miRNA-target gene regulatory network was established to screen key genes. Results: Five genes containing SNPs associated with MG risk were involved in the inflammatory bowel disease (IBD) signaling pathway, and FoxP3 was the key gene. MAPK1, SMAD4, SMAD2 and BCL2 were predicted to be targeted by the 18 miRNAs and to act as the key genes in adherens, junctions, apoptosis, or cancer-related pathways respectively. These five key genes containing SNPs or targeted by miRNAs were found to be involved in negative regulation of T cell differentiation. Conclusions: We speculate that SNPs cause the genes to be defective or the miRNAs to downregulate the factors that subsequently negatively regulate regulatory T cells and trigger the onset of MG. Keywords: Myasthenia gravis (MG); polymorphism; miRNAs; signaling pathway; bioinformatics Submitted Jan 03, 2020. Accepted for publication Sep 30, 2020. doi: 10.21037/gs-20-39 View this article at: http://dx.doi.org/10.21037/gs-20-39 © Gland Surgery. All rights reserved. Gland Surg 2020;9(6):1933-1944 | http://dx.doi.org/10.21037/gs-20-39 1934 Qian et al. Signaling pathways of myasthenia gravis Introduction PubMed and Embase, up to June 1st 2019 using the MeSH terms “Myasthenia Gravis” and “Polymorphism, Single Myasthenia gravis (MG) is a chronic autoimmune Nucleotide (SNP)”, or “Genome-Wide Association Study neuromuscular disorder causing muscle weakness and (GWAS)”. We performed another search of the literature characterized by a defect in synaptic transmission at the on MG and miRNAs, using “Myasthenia Gravis” and neuromuscular junction. Currently, several autoimmune “miRNAs” as MeSH terms. The search strategies used antibodies to acetylcholine receptors (AChR), muscle- are listed in Table S1. All the identified publications were specific kinase (MuSK), and low molecular weight receptor- dealing with blood samples in MG cases and controls. We related low-density lipoprotein-4 (Lrp4) have been excluded articles without full text or not in English. Two demonstrated to attack the corresponding antigenic targets, studies collected data from these articles (KQ and YD, with leading to the onset of MG (1). However, the involved 7 years and 12 years of experience in MG, respectively. genetic and molecular mechanisms leading to the induction YD has two years of statistical work experience. Both are and production of these antibodies remain unclear. familiar with English). A variety of genetic variants, e.g., −3279 and IVS9+459 in Foxp3, have been shown to be strongly associated with MG risk (2). Mutations in different genes encoding molecules Prediction of miRNA target genes important in the neuromuscular junction cause major Target genes of these miRNAs were predicted using the changes in function (3). Nevertheless, several miRNAs, bioinformatics prediction tool “miRWalk” (http://www. e.g., miR-122 and miR-185 (4) have been reported to be umm.uni-heidelberg.de/apps/zmf/mirwalk/) (6) and differentially expressed in the serum or peripheral blood validated by all the other tools provided on the miRWalk mononuclear cells (PBMC) of MG patients, showing website including miRanda, miRDB, RNA22, and the close connections between these miRNAs and the Targetscan. pathophysiology of MG (5). Aberrant microRNA (miRNA) expression suggests that epigenetic modification influences MG risk (4). Pathway enrichment analyses Genes are the core of genetics and epigenetics. The In order to identify pathways involving the genes targeted overwhelming majority of associated genes are involved in by SNPs or miRNAs, we performed enrichment analysis the immune system. Therefore, we presumed that some using online functional annotation tools, i.e., DAVID key genes targeted by these genetic variants or miRNAs, (http://david.abcc.ncifcrf.gov/, updated in May 2018) (7) i.e., at the DNA or RNA level, are involved in some and STRING (http://string-db. org/, version 10.0) (8) The critical pathways to trigger the onset of MG. By using top most significant pathways were confirmed by gene bioinformatics tools, we aimed to predict these key genes counts ≥5, and both satisfied the Bonferroni-corrected and signaling pathways. We present the following article in cutoff (Bonferroni P value <0.05). accordance with the MDAR reporting checklist (available at http://dx.doi.org/10.21037/gs-20-39). Analysis of protein-protein interaction networks Methods Protein-protein interaction networks (PPIs) and clusters of these proteins were verified by STRING (confidence scores A summary of the following steps is shown in Figure 1. The ≥0.4). The key genes were defined as those with higher study was conducted in accordance with the Declaration of degrees of connectivity in PPIs. Cytoscape was utilized Helsinki (as revised in 2013). to construct the protein interaction network, which was used to calculate the score of gene nodes by using three centrality methods [i.e., Degree Centrality, Betweenness Global search of SNPs and miRNAs in literature databases Centrality, and Closeness Centrality (9-11)]. The key genes To identify publications on MG and genetic variants, a were defined as those with higher degrees of connectivity in comprehensive, systematic search of existing literature PPIs, which were identified by a network topology analysis was first conducted. We searched the databases Medline, (11,12). © Gland Surgery. All rights reserved. Gland Surg 2020;9(6):1933-1944 | http://dx.doi.org/10.21037/gs-20-39 Gland Surgery, Vol 9, No 6 December 2020 1935 Global search of published SNPs and miRNAs related to onset of MG 13 published articles on miRNAs and MG 71 published articles on SNPs and MG Significantly differentially expressed miRNA in MG cases compared to healthy controls 10 miRNAs in PBMC (5 up-regulated and 5 down-regulated) 20 miRNAs in serum (11 up-regulated and 9 down-regulated) 86 candidate SNPs in 44 genes with close association to the risk of MG Predicted gene-miRNA interaction search by using miRwalk 24,179 genes in PBMC and 37,127 genes in serum related to miRNAs of MG patients Pathway enrichment analysis DAVID STRING Identification of MicroRNAs and SNPs target signaling pathway Figure 1 Flow chart of the strategy of the global search in PUBMED, target-gene prediction, KEGG pathway enrichment and protein– protein interaction (PPI) analysis. Statistical analysis Five genes containing the reported SNPs associated with MG risk were involved in the inflammatory bowel disease Statistical analysis was carried out by using the MedCalc (IBD) signaling pathway, and FoxP3 was the key gene Statistical Software version v19.0.3 (MedCalc Software bvba, Ostend, Belgium). The key genes were defined We used DAVID and STRING to identify signaling as those with higher degrees of connectivity in PPIs, pathways of the 44 genes containing candidate SNPs which were identified by a network topology analysis. (Table S1), and found these genes were involved in 15 The PathExNet tool was also used to isolate the genes signaling pathways (Table 1).
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