Identifying a polymorphic 'switch' that influences miRNAs' regulation of a myasthenia gravis risk pathway

PLoS One. 2014 Aug 12;9(8):e104827. doi: 10.1371/journal.pone.0104827. eCollection 2014.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • Data Mining
  • Databases, Nucleic Acid
  • Genes, Switch
  • Genetic Predisposition to Disease
  • Humans
  • MicroRNAs / genetics*
  • Models, Genetic
  • Myasthenia Gravis / etiology
  • Myasthenia Gravis / genetics*
  • Polymorphism, Single Nucleotide*
  • Risk Factors
  • Signal Transduction / genetics

Substances

  • MicroRNAs

Grants and funding

This work was supported in part by the National Natural Science Foundation of China grant nos. 81171122 and 81371324, and Natural Science Foundation of Heilongjiang Province (grant nos ZD201208). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.