Competitive endogenous RNA network and pathway-based analysis of LncRNA single-nucleotide polymorphism in myasthenia gravis

Tianfeng Wang,Jianjian Wang,Shuang Li,Lihua Wang,Hongyu Gao,Shangwei Ning,Si Xu,Xiaotong Kong,Huixue Zhang,Xu Wang,Li Liu,Xiaoyu Lu

doi:10.1038/s41598-021-03357-x

Abstract

Myasthenia gravis (MG) is a complex neurological autoimmune disease with a pathogenetic mechanism that has yet to be elucidated. Emerging evidence has revealed that genes, non-coding RNAs and genetic variants play significant roles in the pathogenesis of MG. However, the molecular mechanisms of single nucleotide polymorphisms (SNPs) located on lncRNAs could disturb lncRNA-mediated ceRNA regulatory functions still unclear in MG. In this study, we collated 276 experimentally confirmed MG risk genes and 192 MG risk miRNAs. We then constructed a lncRNA-mediated ceRNA network for MG based on multi-step computational strategies. Next, we systematically integrated risk pathways and identified candidate SNPs in lncRNAs for MG based on data acquired from public databases. In addition, we constructed a pathway-based lncRNA-SNP mediated network (LSPN) that contained 128 lncRNAs targeting 8 MG risk pathways. By analyzing network, we propose a latent mechanism for how the “lncRNA-SNP-mRNA-pathway” axis affects the pathogenesis of MG. Moreover, 25 lncRNAs and 51 SNPs on lncRNAs were extracted from the “lncRNA-SNP-mRNA-pathway” axis. Finally, functional analyses demonstrated lncRNA-SNPs mediated ceRNA regulation pairs associated with MG participated in the MAPK signaling pathway. In summary, we constructed MG-specific lncRNA-SNPs mediated ceRNA regulatory networks based on pathway in the present study, which was helpful to elucidate the roles of lncRNA-SNPs in the pathogenesis of MG and provide novel insights into mechanism of lncRNA-SNPs as potential genetic risk biomarkers of MG.

Highlights

Myasthenia gravis (MG) is an autoimmune disease that is mediated by acetylcholine receptor antibodies which attack the postsynaptic membrane at the neuromuscular junction, resulting in muscle weakness and fatigue[1]
These findings revealed the fundamental characteristics of co-expressed Long non-coding RNA (lncRNA) that are involved in the pathogenesis of MG
The identification of single nucleotide polymorphisms (SNPs) in lncRNAmediated competing endogenous RNA (ceRNA) regulation pairs in MG by considering relevant risk pathways could help us to illustrate the potential roles of lncRNA-SNPs in the progression of MG

Summary

Introduction

Myasthenia gravis (MG) is an autoimmune disease that is mediated by acetylcholine receptor antibodies which attack the postsynaptic membrane at the neuromuscular junction, resulting in muscle weakness and fatigue[1]. It is conceivable that lncRNA-associated SNPs could affect the regulation of lncRNAs. the presence of risk-associated SNPs on lncRNAs may lead to alterations on the miRNA binding sites and result in the gain or loss of ceRNA interactions[19]. The functional rs664589 polymorphism in lncRNA MALAT1 is known to alter the miR-194-5p binding site and result in increased levels of MALAT1 expression, reducing the risk of colorectal c ancer[22]. The rs710886 SNP in lncRNA PCAT1 is known to lead to the loss of miRNA-145 binding sites, resulting in increased levels of PCAT1 expression and the inhibition of tumor cell invasion and proliferation[23]. We identified and characterized the effects of lncRNAs that feature SNPs and affect ceRNA regulation pairs in MG; these may represent new biomarkers and therapeutic targets for patients with MG

Methods

Results

Conclusion