A common variant in MIR182 is associated with primary open-angle glaucoma in the NEIGHBORHOOD consortium

Yutao Liu, Jessica Cooke Bailey, Inas Helwa, W. Michael Dismuke, Jingwen Cai, Michelle Drewry, Murray H. Brilliant, Donald L. Budenz, William G. Christen, Daniel I. Chasman, John H. Fingert, Douglas Gaasterland, Terry Gaasterland, Mae O. Gordon, Robert P. Igo, Jae H. Kang, Michael A. Kass, Peter Kraft, Richard K. Lee, Paul LichterSayoko E. Moroi, Anthony Realini, Julia E. Richards, Robert Ritch, Joel S. Schuman, William K. Scott, Kuldev Singh, Arthur J. Sit, Yeunjoo E. Song, Douglas Vollrath, Robert Weinreb, Felipe Medeiros, Gadi Wollstein, Donald J. Zack, Kang Zhang, Margaret A. Pericak-Vance, Pedro Gonzalez, W. Daniel Stamer, John Kuchtey, Rachel W. Kuchtey, R. Rand Allingham, Michael A. Hauser, Louis R. Pasquale, Jonathan L. Haines, Janey L. Wiggs

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

PURPOSE. Noncoding microRNAs (miRNAs) have been implicated in the pathogenesis of glaucoma. We aimed to identify common variants in miRNA coding genes (MIR) associated with primary open-angle glaucoma (POAG). METHODS. Using the NEIGHBORHOOD data set (3853 cases/33,480 controls with European ancestry), we first assessed the relation between 85 variants in 76 MIR genes and overall POAG. Subtype-specific analyses were performed in high-tension glaucoma (HTG) and normal-tension glaucoma subsets. Second, we examined the expression of miR-182, which was associated with POAG, in postmortem human ocular tissues (ciliary body, cornea, retina, and trabecular meshwork [TM]), using miRNA sequencing (miRNA-Seq) and droplet digital PCR (ddPCR). Third, miR-182 expression was also examined in human aqueous humor (AH) by using miRNA-Seq. Fourth, exosomes secreted from primary human TM cells were examined for miR-182 expression by using miRNA-Seq. Fifth, using ddPCR we compared miR-182 expression in AH between five HTG cases and five controls. RESULTS. Only rs76481776 in MIR182 gene was associated with POAG after adjustment for multiple comparisons (odds ratio [OR] = 1.23, 95% confidence interval [CI]: 1.11-1.42, P = 0.0002). Subtype analysis indicated that the association was primarily in the HTG subset (OR = 1.26, 95% CI: 1.08-1.47, P = 0.004). The risk allele T has been associated with elevated miR-182 expression in vitro. Data from ddPCR and miRNA-Seq confirmed miR-182 expression in all examined ocular tissues and TM-derived exosomes. Interestingly, miR-182 expression in AH was 2-fold higher in HTG patients than nonglaucoma controls (P = 0.03) without controlling for medication treatment. CONCLUSIONS. Our integrative study is the first to associate rs76481776 with POAG via elevated miR-182 expression.

Original languageEnglish (US)
Pages (from-to)4528-4535
Number of pages8
JournalInvestigative Ophthalmology and Visual Science
Volume57
Issue number10
DOIs
StatePublished - Aug 1 2016

Keywords

  • Exosome
  • Genetic association
  • NEIGHBORHOOD
  • POAG
  • miR-182

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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    Liu, Y., Bailey, J. C., Helwa, I., Dismuke, W. M., Cai, J., Drewry, M., Brilliant, M. H., Budenz, D. L., Christen, W. G., Chasman, D. I., Fingert, J. H., Gaasterland, D., Gaasterland, T., Gordon, M. O., Igo, R. P., Kang, J. H., Kass, M. A., Kraft, P., Lee, R. K., ... Wiggs, J. L. (2016). A common variant in MIR182 is associated with primary open-angle glaucoma in the NEIGHBORHOOD consortium. Investigative Ophthalmology and Visual Science, 57(10), 4528-4535. https://doi.org/10.1167/IOVS.16-19688