Identifying a Polymorphic ‘Switch’ That Influences miRNAs' Regulation of a Myasthenia Gravis Risk Pathway

The significant roles of genetic variants in myasthenia gravis (MG) pathogenesis have been demonstrated in many studies, and recently it has been revealed that aberrant level/regulation of microRNAs (miRNAs) might contribute to the initiation and progression of MG. However, the dysfunction of miRNA associated with single nucleotide polymorphisms (miRSNPs) has not been well investigated in MG. In this study, we created a contemporary catalog of 89 MG risk genes via manual literature-mining. Based on this risk gene catalog, we obtained 18 MG risk pathways. Furthermore, we identified 93 miRNAs that target MG risk pathways and revealed the miRSNPs ‘switches’ in miRNA regulation in the MG risk pathways by integrating the database information of miRSNPs. We also constructed a miRNA-mediated SNP switching pathway network (MSSPN) to intuitively analyze miRNA regulation of MG risk pathways and the relationship of the polymorphism ‘switch’ with these changes in regulation. Moreover, we carried out in-depth dissection on the correlation between hsa05200 (pathway in cancer) and MG development, and elaborated the significance of 4 high-risk genes. By network analysis and literature mining, we proposed a potential mechanism of miRSNPs→gene→pathway effects on MG pathogenesis, especially for rs28457673 (miR-15/16/195/424/497 family)→IGF1R→hsa05200 (pathway in cancer). Therefore, our studies have revealed a functional role for genetic modulators in MG pathogenesis at a systemic level, which could be informative for further miRNA and miRSNPs studies in MG.