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A Common Variant in MIR182 Is Associated With Primary Open-Angle Glaucoma in the NEIGHBORHOOD Consortium.

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

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