Identification of candidate gene and miRNA linked to early- and late-stage glaucoma

Abstract

Purpose : Molecular mediators of intraocular pressure (IOP) elevation and progression to blindness in glaucoma remain ill-defined, limiting the scope of early interventions and screening. Marked variability in rates of progression and severity of glaucomatous damage to retinal ganglion cells suggests that many factors are in play. Here we have analyzed the genetic modulation of glaucoma progression in a well-established murine model (DBA/2J), to better characterize molecular factors and their time course during disease.

Methods : Gene expression profiles of retinal tissue from DBA/2J (D2; n = 13) and control DBA/2J-Gpnmb^+/+ (D2G; n = 12) mice (both sexes) were quantified and compared at different age cohorts (early stages 1–6 m and late stages 7–15 m) to identify differentially expressed genes (DEGs) between groups (DEG defined by p < 0.05 and fold-change > 1.3). Pooling was based on the well-documented timeframe for onset of glaucomatous damage in this strain. Additionally, we used previously gathered retina expression profiles of the BXD family of mice to construct a proposed microRNA (miRNA)-mediated molecular networks influencing glaucoma development using a systems genetics approach.

Results : 209 DEGs were identified with 143 in the early group (1–6 m), 66 in the late group (7–15 m) and 2 in both groups (Brp44l and Gpnmb). Early-group DEGs were primarily related to retinal structure and function, with top results comprised largely of crystallin heat shock family members. Late-group DEGs were primarily involved in innate immunity, including many members of the compliment cascade. Additionally, 3 miRNAs were identified that have significant negative correlation with Gpnmb expression, differential expression, and a fold change >1.5 (miR-125a-3p, miR-214-5p, miR-3076-5p).

Conclusions : Our results identified a number of differentially expressed genes between retinas of age-matched controls, early- and late stage glaucomatous retinas. We identified two well-known (miR-125a-3p and miR-214-5p), and one new (miR-3076-5p) miRNAs that appears to be linked to Gpnmb expression—a critical gene for glaucoma pathogenesis in this model.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.