title: A Common Variant in MIR182 Is Associated With Primary Open-Angle Glaucoma in the NEIGHBORHOOD Consortium.
abstract: 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).
  
  
  
  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.
  
  
  
  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.
  
  
  
  Our integrative study is the first to associate rs76481776 with POAG via elevated miR-182 expression.
authors.affiliation: Department of Cellular Biology and Anatomy Augusta University, Augusta, Georgia, United States 2James & Jean Culver Vision Discovery Institute, Augusta University, Augusta, Georgia, United States 3Center for Biotechnology and Genomic Medicine, Augusta Uni.
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authors.affiliation: Department of Cellular Biology and Anatomy Augusta University, Augusta, Georgia, United States.
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authors.affiliation: Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States.
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authors.affiliation: Department of Cellular Biology and Anatomy Augusta University, Augusta, Georgia, United States.
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authors.affiliation: Department of Cellular Biology and Anatomy Augusta University, Augusta, Georgia, United States.
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authors.affiliation: Department of Ophthalmology, University of North Carolina, Chapel Hill, North Carolina, United States.
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authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States.
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authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States.
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authors.affiliation: Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States.
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authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, United States.
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authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States.
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authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States.
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authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States.
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authors.affiliation: Department of Ophthalmology, West Virginia University Eye Institute, Morgantown, West Virginia, United States.
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authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States.
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authors.affiliation: Department of Ophthalmology, UPMC Eye Center, University of Pittsburgh, Pittsburgh, Pennsylvania, United States.
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authors.affiliation: Department of Ophthalmology and Hamilton Glaucoma Center, University of California, San Diego, California, United States.
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authors.affiliation: Department of Ophthalmology and Hamilton Glaucoma Center, University of California, San Diego, California, United States.
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authors.affiliation: Department of Ophthalmology, UPMC Eye Center, University of Pittsburgh, Pittsburgh, Pennsylvania, United States.
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authors.affiliation: Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States.
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authors.affiliation: Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States.
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authors.affiliation: Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States.
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authors.affiliation: Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States.
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authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States 27Department of Ophthalmology, Mass Eye & Ear, Boston, Massachusetts, United States.
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authors.initials: LR
authors.lastname: Pasquale
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States.
authors.forename: Jonathan L
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mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001082:Aqueous Humor / Q000378:metabolism*; D055354:Exosomes / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005902:Glaucoma, Open-Angle / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007429:Intraocular Pressure / Q000502:physiology*; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics*
chemical_list: D035683:MicroRNAs; C538984:Mirn182 microRNA, human; D012313:RNA