A recent study published in Acta Ophthalmologica assessed the link between localized vascular and retinal nerve fiber layer (RNFL) loss and genetic risk for glaucoma and cardiovascular disease via polygenic risk scores (PRS).
Give me some background first.
Per the Centers for Disease Control (CDC), PRS factor in the different versions of many genes that an individual has related to a specific disease to measure their risk for developing the condition.
A previous study from the same Australian research team determined that wedge-shaped vascular defects have approximately a 16% prevalence in suspect and early primary open-angle glaucoma (POAG) eyes, with strong agreement with localized RNFL wedge defects.
Vascular wedge defects are characterized by focal microvasculature loss extending outward from the optic nerve in an arcuate, wedge shape, and can be visualized by optical coherence tomography angiography (OCT-A).
Anything else?
The vascular theory for glaucoma suggests that microvascular dysfunction and insufficient blood flow causes glaucomatous loss.
Large cohort population studies have identified cardiovascular risk factors with increased risk of glaucoma—supporting this hypothesis and motivating the authors of this study to investigate the potential genetic link between glaucoma risk factors and cardiovascular disease.
Now, talk about the study.
In total, 858 eyes were included from 455 participants (94% Caucasian) enrolled in the Progression Risk of Glaucoma: Relevant Single Nucleotide Polymorphisms (SNPS) of Significant Association (PROGRESSA) study with suspect and early manifest open-angle glaucoma.
Eyes were included if they had valid genetic data and either localized vascular and/or RNFL wedge-shaped defects that were identifiable by OCT-A and OCT imaging, respectively.
Go on…
Analyses focused on the associations with pre-established PRS for genetic risk of glaucoma and cardiovascular disease using glaucoma risk factors and systemic vascular disease outcomes.
Findings?
Of note, higher genetic risk for glaucoma was linked with both vascular wedge defects (p<0.001) and RNFL defects (p=0.020).
Further, a higher glaucoma PRS was associated with the presence of multiple vascular wedges per eye (p=0.005).
What about the risk of glaucoma progression?
Glaucoma progression based on global RNFL loss was associated with both vascular and RNFL wedge defects (p<0.001 and p=0.008, respectively).
Researchers reported that 162 eyes had both types of wedges in similar distribution, though some participants had vascular change without RNFL defects (21 eyes) and vice versa (126 eyes).
Tell me more about wedge defects and glaucoma risk factors.
Both vascular wedges and RNFL wedge defects were more associated with:
- Older age
- Lower IOP
- Higher vertical cup to disc ratio (VCDR)
- Lower central corneal thickness (CCT)
- Lower visual acuity
- Worse mean deviation
- Likelihood of receiving glaucoma treatment
While these relationships could indicate that vascular wedge defects are a feature of progressed glaucoma, they appeared in suspect and early manifest glaucoma eyes, frequently prior to any major functional damage.
Meaning…
Localized RNFL wedge defects are commonly linked with normal-tension glaucoma (NTG), potentially clarifying why both vascular and RNFL wedge defects were associated with lower IOP.
Possibly, this could also be explained because participants with defects received more aggressive IOP-lowering treatments.
And cardiovascular/glaucoma PRS?
The glaucoma PRS was significantly associated with vascular wedge defects (p=0.007), but not RNFL defects (p=0.070) after controlling for disc hemorrhage.
No relationship was found between vascular wedge defects and cardiovascular PRS.
Expert opinion?
According to the study authors, “The lack of association with systemic cardiovascular PRS suggests that the vascular dropout could be a locally driven process.”
“It could still be that vascular dropout is secondary to RNFL loss, but these findings may support the existence of a vascular glaucoma phenotype in some cases, while others manifest RNFL loss with no change in vasculature,” they added.
Take home.
People with a higher genetic risk of glaucoma—based on their PRS—were more likely to have retinal vascular wedge defects and structural glaucomatous loss; however this did not relate to systemic cardiovascular risk.
This could suggest a local pathophysiology for the vascular defects in some cases, which could have clinical relevance in the early stages of glaucoma and in individuals at high genetic risk.
Next steps?
Identifying patients with a predisposition for glaucoma using PRS could impact treatment and clinical decisions, and indicates a potential advantage of incorporating OCT-A monitoring into clinical practice.