A Common Variant in MIR182 Is Associated With Primary Open-Angle Glaucoma in the NEIGHBORHOOD Consortium.
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.
Liu, Y; Bailey, JC; Helwa, I; Dismuke, WM; Cai, J; Drewry, M; Brilliant, MH; Budenz, DL; Christen, WG; Chasman, DI; Fingert, JH; Gaasterland, D; Gaasterland, T; Gordon, MO; Igo, RP; Kang, JH; Kass, MA; Kraft, P; Lee, RK; Lichter, P; Moroi, SE; Realini, A; Richards, JE; Ritch, R; Schuman, JS; Scott, WK; Singh, K; Sit, AJ; Song, YE; Vollrath, D; Weinreb, R; Medeiros, F; Wollstein, G; Zack, DJ; Zhang, K; Pericak-Vance, MA; Gonzalez, P; Stamer, WD; Kuchtey, J; Kuchtey, RW; Allingham, RR; Hauser, MA; Pasquale, LR; Haines, JL; Wiggs, JL
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