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

Authors

• Yutao Liu, Augusta University
• Jessica Cooke Bailey, Case Western Reserve University
• Inas Helwa, Augusta University
• W. Michael Dismuke, Duke University
• Jingwen Cai, Augusta University
• Michelle Drewry, Augusta University
• Murray H. Brilliant, Marshfield Clinic Research Foundation
• Donald L. Budenz, University of North Carolina at Chapel Hill
• William G. Christen, Brigham and Womens Hospital
• Daniel I. Chasman, Brigham and Women’s Hospital
• John H. Fingert, University of Iowa
• Douglas Gaasterland, The Emmes Corporation
• Terry Gaasterland, University of California at San Diego
• Mae O. Gordon, Washington University School of Medicine
• Robert P. Igo Jr., Case Western Reserve University
• Jae H. Kang, Brigham and Women’s Hospital
• Michael A. Kass, Washington University School of Medicine
• Peter Kraft, Harvard University
• Richard K. Lee, University of Miami
• Paul Lichter, The University Of Michigan
• Sayoko E. Moroi, The University Of Michigan
• Anthony Realini, West Virginia University
• Julia E. Richard, The University Of Michigan
• Robert Ritch, New York Eye and Ear Infirmary of Mount Sinai
• Joel S. Schuman, University of Pittsburgh
• William K. Scott, University of Miami
• Kuldev Singh, Stanford University
• Arthur J. Sit, Mayo Clinic
• Yeunjoo E. Song, Case Western Reserve University
• Douglas Vollrath, Stanford University
• Robert Weinreb, University of California - San Diego
• Felipe Medeiros, University of California - San Diego
• Gadi Wollstein, University of Pittsburgh
• Donald J. Zack, Johns Hopkins University Hospital
• Kang Zhang, University of California - San Diego
• Margaret A. Pericak-Vance, University of Miami
• Pedro Gonzalez, Duke University
• W. Daniel Stamer, Duke University
• John Kuchtey, Vanderbilt University Medical Center
• Rachel W. Kuchtey, Vanderbilt University Medical Center
• R. Rand Allingham, Duke University Medical Center
• Michael A. Hauser, Duke University Medical Center
• Louis R. Pasquale, Mass Eye & Ear
• Jonathan L. Haines, Case Western Reserve University
• Janey L. Wiggs, Mass Eye & Ear

Document Type

Article

Publication Date

2016

College/Unit

School of Medicine

Department/Program/Center

Ophthalmology

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 miR182 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] ¼ 1.23, 95% confidence interval [CI]: 1.11–1.42, P ¼ 0.0002). Subtype analysis indicated that the association was primarily in the HTG subset (OR ¼ 1.26, 95% CI: 1.08–1.47, P ¼ 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 ¼ 0.03) without controlling for medication treatment.

CONCLUSIONS. Our integrative study is the first to associate rs76481776 with POAG via elevated miR-182 expression.

Digital Commons Citation

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. Jr.; Kang, Jae H.; Kass, Michael A.; Kraft, Peter; Lee, Richard K.; Lichter, Paul; Moroi, Sayoko E.; Realini, Anthony; Richard, 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.; and Wiggs, Janey L., "A Common Variant in MIR182 Is Associated With Primary Open-Angle Glaucoma in the NEIGHBORHOOD Consortium" (2016). Faculty & Staff Scholarship. 1976.
https://researchrepository.wvu.edu/faculty_publications/1976

Source Citation

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., Jr, 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 Opthalmology & Visual Science, 57(10), 4528. https://doi.org/10.1167/iovs.16-19688

Comments

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