High genetic risk associated with rapid visual field worsening in glaucoma
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Individuals with a high polygenic risk were more likely to experience rapid structural and functional progression in early-stage glaucoma, despite receiving intensive treatment, researchers reported in JAMA Ophthalmology.
“Polygenic risk scores (PRSs) are a probabilistic summary of an individual’s genetic risk of a disease or trait and are increasingly recognized as a tool in disease risk prediction and phenotyping,” Owen M. Siggs, MD, DPhil, of the department of ophthalmology at Flinders University in Australia, and colleagues wrote. “In the context of glaucoma, PRSs have been shown to effectively stratify risk of glaucoma, age at diagnosis and the rate of OCT thinning in early manifest glaucoma cases.”
To examine the association of polygenic risk with visual field progression in early-stage glaucoma, researchers collected data from 1,103 people with primary open-angle glaucoma (POAG) in the Progression Risk of Glaucoma: Relevant SNPs With Significant Association (PROGRESSA) study.
They included 1,777 eyes from 896 individuals for structural progression analyses and 1,563 eyes from 808 individuals for functional progression analyses. Participants, most of whom were of European ancestry, had a mean age of 62.1 years, and 44% were men. They were matched with 17,642 individuals for PRS reference.
According to results, individuals in the top 5% PRS risk group were at greater risk for visual field progression compared with the bottom 95% PRS group after 5 years (HR = 1.5; P = .005) and had a faster rate of peripapillary retinal nerve fiber layer (pRNFL) thinning (mean = –1.64 vs. –1.36; P = .01), after adjusting for age, sex and OCT device.
Even with higher treatment intensity, participants in the top 5% PRS group were more likely to experience fast pRNFL progression compared with the bottom 95% PRS group (OR = 1.5; P = .02).
Conversely, individuals in the bottom 20% PRS risk group were at lower risk for visual field progression compared with an intermediate 75% risk group over 3 years (HR = 0.52; P = .04), and had a slower rate of pRNFL progression by 0.27 m per year (P = .04).
“Both structural and functional glaucoma progression outcomes were influenced by glaucoma genetic risk, with individuals in the top 5% of the PRS distribution progressing earlier than those in the bottom 95%, corresponding with a higher treatment intensity in the former,” Siggs and colleagues wrote.
“Since treatment is initiated or escalated in response to glaucoma worsening and is highly effective at slowing progression, we would expect the true association of PRS with glaucoma progression to be even greater and would also anticipate a similar association between PRS and time to treatment initiation or escalation.”
Perspective
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The integration of genetic testing in glaucoma care has been a long-awaited development. With this longitudinal cohort study, Siggs and colleagues show promising results by demonstrating the relationship of a genetic-based scoring metric in differentiating rates of progression, as determined by perimetry and retinal nerve fiber layer measurements.
The potential benefits of a validated genetic-based metric are far-reaching. Consider its use in a patient diagnosed with early glaucoma: a high or low score, as used in this study, would provide a predictive value for that patient’s risk of progression. Such models would increase confidence in clinical decisions made during that patient's care, and those with higher scores may further benefit from more aggressive interventions.
Additional research is needed to determine how this genetic scoring metric would apply to diverse populations; this system was developed in a cohort composed exclusively of people with European ancestry. As well, improvements in access to genetic testing will be necessary before it can be widely adopted in clinical care. Despite these limitations, this study provides compelling evidence for the efficacy of genetic testing in glaucoma care. Further research of this and other genetic-based metrics may yet prove instrumental in our management of this complex condition.
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