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ARVO 2024: The incoming prevalence of polygenic risk scores


Nazlee Zebardast, MD, MSc, overviews her 2 presentations from ARVO 2024 that utilized polygenic risk scores to identify patients' genetic risk of developing low risk for different glaucoma subtypes.

Polygenic risk scores (PRS) may very well be on their way to eye care providers' practices, according to Nazlee Zebardast. In her overview of 2 posters presented during this year's Association for Research in Vision and Ophthalmology (ARVO) annual meeting, she details the significant data garnered from studies that utilized PRS to determine genetic risk of primary open-angle glaucoma (POAG) in study participants, among other glaucoma subtypes.

Video Transcript

Editor’s note - The following transcript has been lightly edited for clarity.

Emily Kaiser Maharjan:

Hi everyone, I'm here with Dr. Nazlee Zebardast who presented posters at ARVO regarding open-angle glaucoma and is here to share some of that data with us. So thank you so much for taking the time to talk today Dr. Zebardast.

Nazlee: Zebardast, MD, MSc:

Glad to be here. Thanks for having me.

Kaiser Maharjan:

Of course. So first, can you tell me a little bit about your poster on primary open-angle glaucoma polygenic risk score as an identifier for patients at low risk of disease onset?


Yes, so just a little bit first about what polygenic risk scores (PRS) are. So glaucoma is a very genetic disease. It's a highly heritable disease, including primary open-angle glaucoma (POAG). And it's not genetic in the sense that you get it for sure if a parent has that or you know, a family member has it, but it's what we call it a polygenic disease or a complex disease. So there are a lot of different variants or mutations that in combination lead to increased risk of the disease, combined with your lifestyle and environmental factors. So we can develop something called a polygenic risk score using the genetic information, so your DNA variants, and we can combine them using advanced statistical methods and develop a score that can summarize someone's overall genetic risk for disease. And so these sorts of scores have been developed in the past and for the most part, they have focused on identifying individuals that are at high risk for disease. And we do know that we have a large number of glaucoma suspects, so people that come to our clinics that may never get visual field loss or may never develop any problems. But we don't know for sure who they are, we just follow them once a year or a couple of times a year.

So we thought what might be interesting is to see whether our polygenic risk score can identify those that might be at lower risk of disease. And the eye care hypertension treatment study (OHTS) was a perfect sample size and perfect study to do this because it's a 20 year longitudinal study of individuals that didn't have disease to begin with and were followed over time. And so we constructed a polygenic risk score, divided it to develop a threshold for low versus high. And we're able to show that if you were under our cut-off, the likelihood of developing glaucoma was much, much lower than people that were above the cut-off. And interestingly, even when you look at the high risk group, so clinically, the OHTS developed a 5 factor model that can identify people that are at higher risk. Our analysis shows that even if you're in that higher risk clinical group but are below the PRS thresholds, you may not really need early treatment because there may not be much benefit to it.

Kaiser Maharjan:

That's fascinating. So I'm gonna kind of switch gears a little bit and jump into your other poster about genetic risk for open-angle glaucoma subtypes and the association with visual field defect glasses. Can you tell me a little bit about that?


Yes. So, the genome-wide association studies that have been done today and have differentiated between normal tension and high tension glaucoma. So, we have GWAS for primary open angle glaucoma but we also know that there are certain variants or genetic markers for having high tension versus normal tension glaucoma. So we developed a polygenic risk score and a genetic risk score for these 3 different subtypes. Specifically, POAG, high tension glaucoma, and [normal tension glaucoma, or] NTG. And we did use the machine learning model to partition visual fields into different patterns and glaucoma presents with different visual field components or visual field patterns. And we were able to show that our normal tension glaucoma PRS seems to be more associated with a paracentral visual field defect, which is what we see clinically, and that high tension PRS is more associated with a severe diffuse loss, which is also what we observe clinically, because these patients tend to have more severe glaucoma. And that primary open angle glaucoma PRS was somewhere in between. So I think this is really interesting proof of concept because we're able to show that our polygenic risk scores correlate with what we see clinically from a visual field perspective and potentially can be used to kind of forecast what kind of defect someone may be able to develop.

Kaiser Maharjan:

Yeah, absolutely. That's so fascinating. Were there any findings that surprised you in either of these studies?


I think we were surprised. So for the first study we were surprised that even people who were in the high clinical risk group treatment didn't seem to make much difference and so I think that really points to the fact that early treatment seems to be the most beneficial for people that are both clinically and genetically at high risk. Because if you're not at high genetic risk, it's possible that there are other mechanisms or other lifestyle and environmental factors that are at play, that lowering IOP may not have as much of an impact.

And then I'll just add 1 other thing was when we looked at the OHTS dataset, glaucoma was determined based on structural features, but also based on visual field loss. And so when we looked at the endpoint based on structural features, which generally indicates milder disease, we weren't able to see much benefit of our polygenic risk score. But when we looked at visual field defects as in functional vision loss, we were able to see a big impact of polygenic risk score, which seems to suggest that higher genetic risk is associated with more severe and clinically important disease.

Kaiser Maharjan:

That's very interesting. What are some key takeaways from these posters that you really want to drive home to eye care providers?


So I think the important thing I want people to become familiar with is polygenic risk scores because these scores are going to enter our clinical practice. They're being used and developed for a number of diseases, not just glaucoma, for diabetes, for cardiovascular diseases, and cancer risk, etc. So, I think what we will see as we go forward is that people, more and more people will get genotyped, and they will get their risk scores given to them. And clinicians have to understand what to do with that and what that means. And we have to develop better ways to integrate that into our clinical practice for more personalized care of our patients. So I think polygenic risk scores are coming and I think that it's important to become familiar with how to use them as a clinician.

Kaiser Maharjan:

Thank you so much for taking the time to tell me about these ARVO posters on open angle glaucoma and risk and all of that great stuff. The science is absolutely fascinating, and I really appreciate you filling in some of the details. So thank you.


Of course, I'm happy to do it. Thanks for having me.

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