A Genome-Wide Scan for MicroRNA-Related Genetic Variants Associated With Primary Open-Angle Glaucoma.
Ghanbari Mohsen, Iglesias Adriana I, Springelkamp Henriët, van Duijn Cornelia M, Ikram M Arfan, Dehghan Abbas, Erkeland Stefan J, Klaver Caroline C W, Meester-Smoor Magda A
AI Summary
This study found specific genetic variants in microRNAs and their binding sites are linked to glaucoma traits, suggesting these miRNAs and their target genes are potential therapeutic targets for POAG.
Abstract
Purpose
To 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.
Methods
Data 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.
Results
Of 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.
Conclusions
We 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.
MeSH Terms
Shields Classification
Key Concepts6
The genetic variant rs12803915:A/G in the terminal loop of pre-miR-612 was significantly associated with vertical cup-to-disc ratio (VCDR) and cup area (P values < 1.2 × 10-4) in a genome-wide scan using data from recent genome-wide association studies on intraocular pressure, VCDR, cup area, and disc area.
The genetic variant rs2273626:A/C in the seed sequence of miR-4707 was significantly associated with vertical cup-to-disc ratio (VCDR) and cup area (P values < 1.2 × 10-4) in a genome-wide scan using data from recent genome-wide association studies on intraocular pressure, VCDR, cup area, and disc area.
The genetic variant rs12803915:A/G in the terminal loop of pre-miR-612 is demonstrated to increase miR-612 expression.
The genetic variant rs2273626:A/C in the seed sequence of miR-4707 does not affect miR-4707 biogenesis but reduces the binding of miR-4707-3p to CARD10, a gene known to be involved in glaucoma.
Of 72,052 miRNA-binding-site variants, 47 were significantly associated with four primary open-angle glaucoma (POAG) endophenotypes (P value < 6.9 × 10-6) in a genome-wide scan using data from recent genome-wide association studies.
The miRNA-binding-site variants rs3217992 and rs1063192 have been shown experimentally to affect miR-138-3p- and miR-323b-5p-mediated regulation of CDKN2B, a gene implicated in primary open-angle glaucoma (POAG).
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