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