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

Abstract

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.

Objectives, design and main findings until 2020 from the Rotterdam Study

“…We found no evidence for a common genetic background between POAG and myopia [286]. We did find an association with microRNAs [287]. We also focused on imaging, and found associations between a thinner retinal nerve fiber layer thickness and age, IOP, visual impairment, and history of systemic hypertension and stroke.…”

<p>Differential miRNA Expression: Signature for Glaucoma in Pseudoexfoliation</p>

“…miRNAs are small circulatory RNA sequences which regulate several cell processes and tissue functions. 8,[10][11][12][13][14][15] We found several novel miRNA, notably, hsa-miR-122-5p, controlling TGF and ECM related cell processes differentially expressed in PXF stages which has not been reported in ocular disorders like glaucoma earlier. These miRNA like hsa-miR-122-5p may act like switches that trigger differential downstream processes despite elevated TGF levels by post-transcriptional gene modifications in the tissues like TM marking the onset of glaucoma or disease progression.…”

microRNA Profiling in Glaucoma Eyes With Varying Degrees of Optic Neuropathy by Using Next-Generation Sequencing

“…Ghanbari et al 65 used data from the recent genome-wide association studies to investigate the association of miRNAs with POAG endophenotypes. They found variants in the miR-612 precursor and in the miR-4707 seed region that are significantly associated with vertical cup-to-disc ratio and cup area.…”