Genetics of Glaucoma with Inas Aboobakar, ep 43

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Robert: There we go. Inas Aboobakar, clinician scientist from Mass Eye and Ear in Genetics, uh, welcome to the show.

Inas F. Aboobakar, MD: Thank you so much for having me

Robert: Oh, my pleasure. It was so nice meeting you, uh, last year at the Chandler Grant Society sub meeting at the AGS, and I thought you'd be an amazing guest to enlighten people on genetics. 'Cause my knowledge of genetics and glaucoma, I guess it's sort of stuck at myocilin.

Robert: Like, that's, like, the last thing I heard, uh, aside from, like, systemic diseases that, uh, like aniridia that would have glaucoma in it. So I'm assuming that a lot has come, uh, come along since then, and, uh, you'll be able to enlighten us and also, uh, how it's used for diagnosis and treating patients. So, uh- En-enlighten us.

Inas F. Aboobakar, MD: Yeah,

Robert: What,

State of Genetics

Robert: what is the state of genetics now?

Inas F. Aboobakar, MD: Yeah, so the field has come a bit of a way since then. You [00:01:00] know, with the, the diseases you mentioned, so aniridia is an early onset, causes an early onset form of glaucoma. Um, we now know, um, around 12 genes that are associated with early onset forms of genes.

Inas F. Aboobakar, MD: This includes like, um, juvenile onset open-angle glaucoma, as well as, um, developmental glaucomas associated with anterior segment dysgenesis. Um, and so, um, uh, myocillin is one of those genes that's associated with juvenile onset open-angle glaucoma, as, um, a handful of cases of pri- adult onset primary open-angle glaucoma caused by just one gene. So less than 5% of early, uh, adult onset glaucomas are caused by a single gene variant. Myocillin is one of those genes. Um, but, um, the vast majority of, uh, common forms of adult onset glaucoma, primary angle closure glaucoma, primary open angle glaucoma, pseudoexfoliation glaucoma, those are what we call complex inherited diseases.

Inas F. Aboobakar, MD: And so they're not caused by a single gene per se, but, um, the cum- cumulative effects of multiple gene variants that [00:02:00] are common in the population across many genes. And so, um, to date, there have been over hundreds of, uh, loci associated with, um, adult onset primary open-angle glaucoma. If you look at the largest genome-wide association studies for primary open-angle glaucoma specifically, that identified 127 loci.

Inas F. Aboobakar, MD: And then if you expand it to multi-trait analyses that incorporate intraocular pressure and vertical cup-to-disk ratio associated genes, and it increases to 312. And there are larger studies ongoing right now that may identify even more genes. And so we now have hundreds of genes associated with glaucoma, and so then the next question is, what do we do with all this information?

Robert: exactly. It's... So, so it's not just like, uh, like one, like one genetic mutation is Fanconi exfoliation. There'd be multiple different variations of it, so.

Inas F. Aboobakar, MD: Exactly. Well, pseudoexfoliation is a little bit of an interesting story because there, there is [00:03:00] one gene that has a stronger effect than many of the other genes. So there are, um, around, um, eight loci that are known for, um, pseudoexfoliation glaucoma, but there is one predominant genetic driver, which is, um, LOXL1.

Inas F. Aboobakar, MD: And so the effect, um, size of LOXL1 is far greater, but there are many genes associated with, um, pseudoexfoliation as well. Um, primary open-angle glaucoma, um, it's more consistent where amongst these hundreds of genes, they all have accumu- uh, a small effect size. Um, and so you need really the cumulative effect of many gene variants to really predispose you, um, to risk of developing the disease.

Inas F. Aboobakar, MD: And so what you can do is, um,

Polygenic Risk Scores

Inas F. Aboobakar, MD: take the aggregate effects of all these genes and compute what's called a polygenic risk score. And, um, and that, uh, provides important information in terms of your risk for developing the disease as well as, um, the severity of your disease as well.

Robert: So we were talking about having the patient in front of you, and

Clinical Application

Robert: how do you calculate the score, and, and how is it helpful?

Inas F. Aboobakar, MD: Yeah. So, um, you know, at this point, you know, it's still kind of one of [00:04:00] those things that I think is more of a research tool and not yet ready for primetime. I mean, some of the limitations are we just don't know enough about the, um, sort of how it changes management or how it should change management if we have this information.

Inas F. Aboobakar, MD: And the second thing is, um, these scores perform differently in different ancestries, and so the best performance is in individuals of European ancestry. And then when you get to other groups like African individuals, Latino, Asian, it just does not perform as well. So we still don't fully have a, a tool that's good across populations and won't, um, exacerbate disparities. Um, but the, the essential idea is that you collect a blood sample from a patient, um, you can, um, directly assay all of these genetic variants that are associated with disease risk. Um, essentially what you do is using co- advanced computational technology, sum up the number of these variants that they have, and the weights that are assigned to each variant are kind of fine-tuned for the population of interest.

Inas F. Aboobakar, MD: Um, and, uh, but once you have this score, you compare it to scores [00:05:00] of individuals of the same ancestry, the same population, and you get what, um, what their population percentile is of risk. And that basically provides risk stratification. So you can figure out if they're low risk, um, intermediate risk, or high risk for their population.

Robert: So when you say risk, is that the risk of having glaucoma at all or the risk of progressing at a younger age or

Inas F. Aboobakar, MD: So, um, I guess it's the percentile of, um, that their score is, which a high score is associated with glaucoma risk. And so the studies show there's about 10-fold higher risk among people in the top decile of polygenic risk compared to those at the low percentile. Um, and so it gives you their risk. And then, um, there have been a few smaller studies looking at, um, risk of, um, you know, disease worsening as well as, uh, escalation of treatment, um, age at diagnosis, and so all of these factors are also associated with higher polygenic risk.

Robert: I've had over the [00:06:00] past, you know, 30 years in practice, you know, I'm here at the tail end and you're at the beginning,

Inas F. Aboobakar, MD: Hı hı

Robert: I guess. I've had three patients who have pseudoexfoliation in one eye and pigmentary in the other. Is there a genetic explanation that you've come across for this?

Inas F. Aboobakar, MD: You know, usually the two are kind of, um... I mean, I think that both diseases we don't have a full answer for, for what causes them. I think that with pseudoexfoliation, the LOXL1 association is so strong that that is likely the predominant, um, genetic driver. In terms of the genetics of pigment dispersion, you know, that is less, uh, well-studied.

Inas F. Aboobakar, MD: Um, I mean, there are genetic associations that are known, but they're kind of few and far between and don't really fully explain the genetic architecture of the disease. And to my knowledge, LOXL1 has not been associated with that, nor have any of the other genetic associations been shared among the two. Um, but I think it's an interesting observation. It would be great if we can have these [00:07:00] patients enroll in studies

Robert: Yeah.

Inas F. Aboobakar, MD: figure out what is causing them.

Robert: Yeah, I keep thinking, uh, with these patients, I should get you a blood sample and see what's going on in there. We may be onto something

Inas F. Aboobakar, MD: Yeah, I think that it would be interesting to know what is kind of, um, causing both of these things, 'cause then you can figure out, you know, mechanisms, shared me- mechanisms that could be targeted for treatment

Robert: Yes, anyone listening to this podcast, if they have patients also with pseudoxfoliation in one eye and pigmentary in the other, uh, please write in

Inas F. Aboobakar, MD: Yes.

Robert: we could identify them and see if we could find, uh, some overlapping genetic mutations. So are, are there any treatment, uh, prognosticators you get out of the genetics of glaucoma?

Inas F. Aboobakar, MD: Um, you know, there, there's evidence that, um, if you have high polygenic risk, there's earlier initiation and escalation of treatment. Um- Mm-hmm ... and so that has been reported. In terms of response to specific therapies, we don't have evidence of that in any way. Nor, nor is it clear if there is, uh, uh, [00:08:00] you know, a, a rationale for that with polygenic risk, and so

Robert: Now, do, do any of these calculations also involve, uh, clinical findings like factoring in, uh, so-called biomarkers like, uh, OCT findings?

Inas F. Aboobakar, MD: Yeah, so I guess the, there have been associations with, um, you know, um, increased RNFL thinning, um, as well as, uh, visual field progression with, um, higher polygenic risk. Um, and then, uh, in terms of need for surgery as well, there is greater need for incisional surgery in patients who have, um, higher polygenic risk. And so the association with specific clinical features has been examined as well.

Robert: Cool. So what, uh,

Current Research

Robert: what are you working on in your research these days?

Inas F. Aboobakar, MD: that's a good question. So I'm interested in kind of taking these scores and, um, trying to make them even better. I mean, we know that they are a great risk stratification tool, but they're not [00:09:00] perfect. And one of the things is, uh, these scores kind of, um, take all this genetic variation across the genome and kind of, um, you know, break it down into one-- or, uh, sum it up into one score. And the score is probably different, um, for different people based on which specific genes are, um, driving their score. And so if, if certain people have gene variants that are in a certain biological pathway, for example, they may have a different disease trajectory than people who have the same, um, cumulative genetic risk score, but their disease is driven by variants in different pathways.

Inas F. Aboobakar, MD: And so we're interested in understanding the specific biological drivers of disease in any given individual in hopes of making treatment as well as diagnosis and monitoring decisions more tailored and personalized for an individual patient. And so that's the goal of my work. Um, the other thing that I'm interested in is looking at the association of these polygenic risk scores, um, and integrating other factors that, um, are associated with disease such as social determinants of health.

Inas F. Aboobakar, MD: And so we've been doing work to [00:10:00] integrate the two, and we found that actually if you integrate both, um, factors, there's a strong gene-environment interaction between the two that actually amplifies your risk far more than each-- either factor alone. Um, and so I think it's important to take into factor some of these other, um, risk factors that are, um, conventionally looked at in isolation

Robert: What do you mean by that?

Inas F. Aboobakar, MD: So, um, an individual

Inas F. Aboobakar, MD: So we looked at, um, the association of polygenic risk- or sorry, the interaction of polygenic risk scores as well as the CDC Social Vulnerability Index. Um, and this was done in a diverse cohort from the All of Us Research Program, and included a large number of individuals of both European and African ancestry.

Inas F. Aboobakar, MD: And we derived polygenic risk scores for these individuals, as well as a Social Vulnerability Index, which was computed using, um, three digits residential zip code data that was provided as well. Um, and when we tested, um, the two in a model and included the interaction of the two, what we found was that individuals who have high [00:11:00] polygenic risk but have low social vulnerability were at much lower risk of disease than individuals who had high polygenic risk plus high social vulnerability.

Inas F. Aboobakar, MD: So you're keeping the genetic risk constant, and you're, um, altering how much social vulnerability you have. That, um, has about a tenfold, um, effect on disease risk in individuals of African ancestry. In individuals of European ancestry, there was also a fourfold difference. And so that means that your genetic susceptibility, I mean, it's not always expressed, and, um, it can be context-dependent based on your individual life circumstances

Robert: So that basically mean, uh, those people with better access to care are... will more likely have better outcome with the same Polygenic

Inas F. Aboobakar, MD: I think

Robert: score

Inas F. Aboobakar, MD: Exactly. It computes various factors including socioeconomic status, education levels, housing, transportation, all of these variables. And so people who have better scores, um, are less likely to develop glaucoma compared to those who don't.[00:12:00]

Robert: So still the key is detecting as early as possible for glaucoma is what we always try to do, and, and, uh, that way we could treat because it just gets harder to treat the more advanced the damage is. And you're

Inas F. Aboobakar, MD: Exactly

Robert: doing the, uh, the calculations behind that to help prove that, so awesome. Any other things you'd like to add?

Inas F. Aboobakar, MD: Um, I think that, you know, um,

Family Screening Advice

Inas F. Aboobakar, MD: the biggest thing right now that we can do in terms of patients, you know, um, you know, when they come in with a, a family history of glaucoma, we don't necessarily need a polygenic risk score at this moment in time to know that their relatives are at high risk. We do know that from population-based studies that there's tenfold higher risk in first-degree relatives. So I always tell all my patients, even right now, you know, like, make sure that your family members are kind of, uh, screened for disease as well. And, um, there's another great program through, um, AGS Family Matters where, you know, that is, um, kind of a goal of that is to increase, um, screening among first-degree relatives.

Inas F. Aboobakar, MD: And so I think that is always something to emphasize [00:13:00] to patients, that we do know that your first-degree relative, it's a strongly hereditary disease. There's lots of genetic factors and, um, you can always have your family members screened as well so that their disease is caught at an earlier scan, uh, time point and, uh, something can be done to prevent vision

Closing Remarks

Robert: Great. Great advice. Well, Inas Aboobakar from, uh, Mass Eye and Ear, thanks so much for being on the show

Inas F. Aboobakar, MD: Thank you so much. Appreciate it

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