Genomics of ocular hypertension: a unifying hypothesis

The National Eye Institute awarded Tufts Medical Center Parent, Inc. $490,875 on August 1, 2026, under the Vision Research program (CFDA 93.867) to conduct genome-wide association studies on steroid-induced ocular hypertension and related glaucomas, with focus on the COL11A1 genetic locus and its role in trabecular meshwork and juxtacanalicular tissue fibrosis that impedes aqueous humor outflow.

The research project examines how genomic variants in COL11A1, which encodes the alpha1 chain of type XI collagen essential for collagen fibril organization, converge functionally across steroid-induced ocular hypertension, primary open-angle glaucoma, pseudoexfoliation glaucoma, and primary angle-closure glaucoma. The team identified overlapping risk loci across these phenotypes through one of the largest steroid-induced ocular hypertension GWAS conducted to date, with COL11A1 variants predicted to disrupt protein production through effects on expression and splicing. The research investigates how COL11A1 protein loss leads to disorganized collagen fibers and elevated outflow resistance, using insights from tendon-specific knockout mice to understand aqueous outflow regulation through the ciliary muscle-scleral spur biomechanical unit.

Work is performed in Boston, Massachusetts. The award period runs from August 1, 2026, through July 31, 2028. The assistance type is a Project Grant, a competitive research funding mechanism supporting time-limited investigations of specific hypotheses or innovative approaches.

Abstract

Elevated intraocular pressure (IOP) is the primary risk factor for both the onset and progression of glaucoma. IOP is determined by the balance of aqueous humor production, resistance to its outflow and episcleral venous pressure. However, all forms of elevated IOP are due to increased outflow resistance localized to the trabecular meshwork (TM) and juxtacanalicular tissue (JCT) of the outflow pathways. In primary angle-closure glaucoma (pacg) the iris obstructs outflow. In pseudoexfoliation glaucoma (pexg), fibrillar deposits clog the TM. In both high-tension primary open-angle glaucoma (poag) and steroid-induced ocular hypertension (sioh), fibrosis and cytoskeletal remodeling in the TM and JCT leads to increased tissue stiffness, causing diminished outflow. All glaucomas are highly heritable and genome-wide association studies (gwass) have identified risk-associated genomic variants. In contrast, little has been done for sioh. To address this knowledge GAP, the project team conducted one of the first, as well as the largest sioh gwas to date. Not surprisingly, a striking degree of overlap was observed with risk loci implicated in poag, but unexpectedly also the other high-tension glaucomas. Risk locus COL11A1 stood out because of overlap with all the phenotypes. Effect alleles were observed to be different for the different phenotypes, however they converged functionally, all CO-localizing with expression or splicing quantitative trait loci predicted to disrupt COL11A1 protein production. COL11A1 encodes the ALPHA1 chain of type XI collagen, essential for collagen fibril organization. In tendon-specific knockout (KO) mice, COL11A1 protein loss results in disorganized, hypoplastic collagen fibers in the limb tendons. Interestingly, the rate of aqueous outflow is regulated via a tendon - one emanating from the CM that inserts into the scleral spur, forming a biomechanical unit that can modulate TM tension. Significantly, transcriptomic data revealed strong COL11A1 expression in the TM, JCT, and CM of humans and mice. Based on this, the project team proposes a unifying hypothesis to explain functional convergence on COL11A1 for the different high tension ocular phenotypes. They hypothesize that COL11A1 deficiency disrupts tendon architecture at the TM-CM interface, leading to biomechanical uncoupling of the TM and CM, thereby reducing the capacity to dynamically regulate IOP. To investigate this innovative idea, the project team will use the KO mouse model in which COL11A1 expression is disrupted specifically in tendons. First, COL11A1 expression, localization and organization will be evaluated in the aqueous outflow pathways, applying a series of cutting- edge biochemical and imaging techniques. Second, outflow facility will be measured over time and compared to IOP, also measured over time. The planned study is potentially of very high impact, promising to define a novel mechanism whereby genomic variants disrupt the capacity to regulate IOP, that can be used to develop innovative treatment strategies.