Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, 150081, Heilongjiang, China.
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China.
Sci Rep. 2021 Dec 14;11(1):23920. doi: 10.1038/s41598-021-03357-x.
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.
重症肌无力（MG）是一种复杂的神经自身免疫性疾病，其发病机制尚未阐明。新出现的证据表明，基因、非编码 RNA 和遗传变异在 MG 的发病机制中起重要作用。然而，位于长非编码 RNA（lncRNA）上的单核苷酸多态性（SNP）的分子机制可能会干扰 lncRNA 介导的 ceRNA 调控功能，这在 MG 中尚不清楚。在本研究中，我们整理了 276 个经实验证实的 MG 风险基因和 192 个 MG 风险 miRNA。然后，我们基于多步计算策略构建了一个基于 lncRNA 的 ceRNA 网络用于 MG。接下来，我们系统地整合了风险途径，并基于公共数据库中的数据确定了 lncRNA 中与 MG 相关的候选 SNPs。此外，我们构建了一个基于途径的 lncRNA-SNP 介导网络（LSPN），其中包含 128 个针对 8 个 MG 风险途径的 lncRNA。通过分析网络，我们提出了一个潜在的机制，解释“lncRNA-SNP-mRNA-途径”轴如何影响 MG 的发病机制。此外，从“lncRNA-SNP-mRNA-途径”轴中提取了 25 个 lncRNA 和 51 个 lncRNA 上的 SNP。最后，功能分析表明，与 MG 相关的 lncRNA-SNP 介导的 ceRNA 调控对与 MAPK 信号通路有关。总之，本研究基于途径构建了 MG 特异性的 lncRNA-SNP 介导的 ceRNA 调控网络，有助于阐明 lncRNA-SNP 在 MG 发病机制中的作用，并为 lncRNA-SNP 作为 MG 潜在遗传风险生物标志物的机制提供新的见解。
