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

Liu, Yutao; Bailey, Jessica N. 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 E.; Gaasterland, Terry; Gordon, Mae O.; Igo, Robert P.; Kang, Jae H.; Kass, Michael A.; Kraft, Peter; Lee, Richard K.; Lichter, Paul R.; 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 N.; Medeiros, Felipe A.; Wollstein, Gadi; Zack, Donald J.; Zhang, Kang; Pericak‐Vance, Margaret A.; González, Pedro; Stamer, W. Daniel; Kuchtey, John; Kuchtey, Rachel W.; Allingham, R. Rand; Hauser, Michael A.; Pasquale, Louis R.; Haines, Jonathan L.; Wiggs, Janey L.

doi:10.1167/iovs.16-19688

Cited by 49 publications

(43 citation statements)

References 48 publications

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“…19,20 In addition, polymorphisms located in miRNA-binding sites within the 3′UTR of target genes are expected to affect miRNA-mediated gene regulation. 20,21 Previous studies 19,21–23 have shown that such miRNA-related variants contribute to complex disease risk; a candidate variant association study 24 has also recently reported the association between genetic variation in miR-182 and POAG. In this study, we applied an in silico study on the existing GWAS of IOP and optic disc parameters 5 and performed in vitro experiments to identify miRNAs and target genes that may play a role in POAG.…”

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confidence: 99%

A Genome-Wide Scan for MicroRNA-Related Genetic Variants Associated With Primary Open-Angle Glaucoma

Ghanbari

Iglesias

Springelkamp

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PurposeTo identify microRNAs (miRNAs) involved in primary open-angle glaucoma (POAG), using genetic data. MiRNAs are small noncoding RNAs that posttranscriptionally regulate gene expression. Genetic variants in miRNAs or miRNA-binding sites within gene 3′-untranslated regions (3′UTRs) are expected to affect miRNA function and contribute to disease risk.MethodsData from the recent genome-wide association studies on intraocular pressure, vertical cup-to-disc ratio (VCDR), cupa area and disc area were used to investigate the association of miRNAs with POAG endophenotypes. Putative targets of the associated miRNAs were studied according to their association with POAG and tested in cell line by transfection experiments for regulation by the miRNAs.ResultsOf 411 miRNA variants, rs12803915:A/G in the terminal loop of pre–miR-612 and rs2273626:A/C in the seed sequence of miR-4707 were significantly associated with VCDR and cup area (P values < 1.2 × 10−4). The first variant is demonstrated to increase the miR-612 expression. We showed that the second variant does not affect the miR-4707 biogenesis, but reduces the binding of miR-4707-3p to CARD10, a gene known to be involved in glaucoma. Moreover, of 72,052 miRNA-binding-site variants, 47 were significantly associated with four POAG endophenotypes (P value < 6.9 × 10−6). Of these, we highlighted 10 variants that are more likely to affect miRNA-mediated gene regulation in POAG. These include rs3217992 and rs1063192, which have been shown experimentally to affect miR-138-3p– and miR-323b-5p–mediated regulation of CDKN2B.ConclusionsWe identified a number of miRNAs that are associated with POAG endophenotypes. The identified miRNAs and their target genes are candidates for future studies on miRNA-related therapies for POAG.

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confidence: 99%

A Genome-Wide Scan for MicroRNA-Related Genetic Variants Associated With Primary Open-Angle Glaucoma

Ghanbari

Iglesias

Springelkamp

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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“…RNA isolation was performed using the miRCURY RNA Isolation Kit–Cell & Plant (catalog # 300110) (Exiqon, Woburn, MA) following the manufacturer’s instructions, as previously described [49, 50]. The selection of this kit was based on the recommendation of several publications and our own experience with different kits [51, 52].…”

Section: Methodsmentioning

confidence: 99%

“…The ddPCR experiments were performed using our previously published protocol [50, 53]. We selected two miRNAs, hsa-miR-16 and hsa-miR-451, which have been previously reported as being abundantly expressed in isolated serum exosomes [39, 54, 55].…”

Section: Methodsmentioning

confidence: 99%

A Comparative Study of Serum Exosome Isolation Using Differential Ultracentrifugation and Three Commercial Reagents

et al. 2017

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Exosomes play a role in cell-to-cell signaling and serve as possible biomarkers. Isolating exosomes with reliable quality and substantial concentration is a major challenge. Our purpose is to compare the exosomes extracted by three different exosome isolation kits (miRCURY, ExoQuick, and Invitrogen Total Exosome Isolation Reagent) and differential ultracentrifugation (UC) using six different volumes of a non-cancerous human serum (5 ml, 1 ml, 500 μl, 250 μl, 100 μl, and 50 μl) and three different volumes (1 ml, 500 μl and 100 μl) of six individual commercial serum samples collected from human donors. The smaller starting volumes (100 μl and 50 μl) are used to mimic conditions of limited availability of heterogeneous biological samples. The isolated exosomes were characterized based upon size, quantity, zeta potential, CD63 and CD9 protein expression, and exosomal RNA (exRNA) quality and quantity using several complementary methods: nanoparticle tracking analysis (NTA) with ZetaView, western blot, transmission electron microscopy (TEM), the Agilent Bioanalyzer system, and droplet digital PCR (ddPCR). Our NTA results showed that all isolation techniques produced exosomes within the expected size range (40–150 nm). The three kits, though, produced a significantly higher yield (80–300 fold) of exosomes as compared to UC for all serum volumes, except 5 mL. We also found that exosomes isolated by the different techniques and serum volumes had similar zeta potentials to previous studies. Western blot analysis and TEM immunogold labelling confirmed the expression of two common exosomal protein markers, CD63 and CD9, in samples isolated by all techniques. All exosome isolations yielded high quality exRNA, containing mostly small RNA with a peak between 25 and 200 nucleotides in size. ddPCR results indicated that exosomes isolated from similar serum volumes but different isolation techniques rendered similar concentrations of two selected exRNA: hsa-miR-16 and hsa-miR-451. In summary, the three commercial exosome isolation kits are viable alternatives to UC, even when limited amounts of biological samples are available.

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“…MYOC may enter the aqueous humor in MYOC-containing exosomes, which may help regulate aqueous outflow in the TM (Dismuke et al, 2015; Hardy et al, 2005; Hoffman et al, 2009; Liu et al, 2016; Perkumas et al, 2007; Stamer et al, 2011). It has been proposed that glaucoma-associated MYOC protein interferes with protein trafficking, receptor-mediated endocytosis, programmed cell death, myelination of the optic nerve, and stress to the endoplasmic reticulum (ER) (Koch et al, 2014; Kwon et al, 2013; Kwon et al, 2014; McKay et al, 2013; Zode et al, 2011).…”

Section: Genetic Linkage Analyses Of Poagmentioning

confidence: 99%

“…Variants in PMM2 and CDC-TGFBR3 are associated with POAG while variants in C12ORF23 have been associated with NTG (Bailey et al, 2016; Chen et al, 2014; Li et al, 2015). A variant in the MIR182 gene has been associated with POAG, especially in those with elevated IOP (Drewry et al, 2016; Liu et al, 2016). Interestingly, elevated expression of miR-182 has been reported to contribute to stress-induced premature senescence in human TM cells (Li et al, 2009).…”

Section: Association Studies In Poagmentioning

confidence: 99%

Major review: Molecular genetics of primary open-angle glaucoma

Liu

Allingham

2017

Experimental Eye Research

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Glaucoma is a leading cause of irreversible blindness worldwide. Primary open-angle glaucoma (POAG), the most common type, is a complex inherited disorder that is characterized by progressive retinal ganglion cell death, optic nerve head excavation, and visual field loss. The discovery of a large, and growing, number of genetic and chromosomal loci has been shown to contribute to POAG risk, which carry implications for disease pathogenesis. Differential gene expression analyses in glaucoma-affected tissues as well as animal models of POAG are enhancing our mechanistic understanding in this common, blinding disorder. In this review we summarize recent developments in POAG genetics and molecular genetics research.

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

Cited by 49 publications

References 48 publications

A Genome-Wide Scan for MicroRNA-Related Genetic Variants Associated With Primary Open-Angle Glaucoma

A Genome-Wide Scan for MicroRNA-Related Genetic Variants Associated With Primary Open-Angle Glaucoma

A Comparative Study of Serum Exosome Isolation Using Differential Ultracentrifugation and Three Commercial Reagents

Major review: Molecular genetics of primary open-angle glaucoma

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