Glaucoma: I wish I had …
Summer 2024
by Liz Hillman
Editorial Co-Director
Genetic testing for glaucoma is not quite ready for “primetime,” according to Michael Greenwood, MD, but it’s close. Dr. Greenwood and Inas F. Aboobakar, MD, provided their thoughts on the current state of glaucoma genetic testing, its potential utility for patients, and what’s on the wish list.
Current status and utility
Dr. Aboobakar, at the 2024 ASCRS Glaucoma Day, gave a comprehensive overview on the current status of genetic testing for glaucoma.
“When some people think of the genetics of glaucoma, they may think of an alphabet soup of random gene names,” she said on the podium. “Hopefully, I can convince you that it’s more than that, and it’s likely something that will play an important role in both clinical glaucoma care as well as medicine in general in the years to come. It’s therefore important to become familiar with the basics.”
Gene-based panels are already commercially available, though Dr. Aboobakar said nearly all are for early onset glaucoma. It’s important to ensure the lab performing the genetic test is CLIA certified, and referral to a genetic counselor should be considered.
Dr. Aboobakar said these tests could be used to screen first-degree relatives. If the relative also carries the gene mutation, they would warrant close surveillance, whereas if they do not have the variant, their risk is relatively similar to the general population.
Dr. Greenwood, in an interview with EyeWorld, said that he thinks genetic testing is warranted when it will impact surveillance or treatment for the patient. Where it is used now is with people who have a family history of glaucoma and when patients want to know their personal risk factors. Without genetic testing, Dr. Greenwood said those with a family history would need to be seen on a routine basis so any glaucomatous disease is detected early and treatment started. With genetic testing, if a person has a mutation or a higher risk score, it could inform closer monitoring and treatment approaches. If the patient does genetic testing and doesn’t have the gene, it saves them a lot of trips to the doctor, he said.
Unlike early onset forms of glaucoma, which are caused by a single gene mutation, in adult onset glaucomas, a single gene mutation is not sufficient for disease development in the vast majority of cases. “Instead, you have multiple genetic and environmental factors that interact to influence disease development,” Dr. Aboobakar explained. “For primary open angle glaucoma (POAG), there are a few hundred associated genes and around 10 or so for both angle closure and exfoliation glaucoma.”
With that, to test for the cumulative impact of the mutations for these diseases, a polygenic risk score (PRS) is calculated, Dr. Aboobakar said. “In very simplified terms, in order to calculate a glaucoma PRS for a given individual, you sum up all the risk alleles that they carry in all glaucoma-associated genes across the genome. Then, looking at the population distribution of these scores, you can classify an individual into high or low genetic risk groups.”
Dr. Aboobakar said studies that use large datasets with genetic and clinical information have assessed the clinical impact of PRSs for glaucoma. In one study, she said, clinical outcomes were compared for each decile of PRS. Those in the higher deciles had higher odds of glaucoma development, as well as early age of disease diagnosis, lower RNFL thickness, and greater need for incisional glaucoma surgery.
Dr. Aboobakar said that longitudinal studies that have followed cohorts of suspect and early glaucoma have also showed that PRSs are associated with faster rates of visual field progression as well as earlier initiation and escalation of treatment.
“It’s also possible to calculate pathway- based PRSs for specific glaucoma-associated genes to assess their clinical impact,” Dr. Aboobakar said, sharing information about a study in which a mitochondrial PRS was investigated. This PRS consisted of variants in two POAG-associated genes that directly influence levels of nicotinamide adenine dinucleotide phosphate in the mitochondria. Dr. Aboobakar said what’s interesting was nicotinamide, which is being investigated as a neuroprotective agent in glaucoma, also directly influences this pathway. Their group found that among glaucoma cases in the NEIGHBOR consortium dataset, those with the highest percentile of mitochondrial PRS had higher mean IOP as well as much higher prevalence of paracentral field defects. This suggests that primary open angle glaucoma that’s driven by mitochondrial genetic risk may represent a distinct disease type with specific clinical features, and it could also be more responsive to nicotinamide treatment.
Dr. Greenwood said that the overall utility of current genetic testing for glaucoma at the moment is limited. “People don’t use it on a regular basis, even if it is easily accessible. The information is a little limited,” he said.
Wish list
Dr. Greenwood said that genetic testing is “on the cusp of taking that next step where it goes from something available but not very useful to something that could be quite useful.”
“As we start to learn more about glaucoma and can identify what genes cause glaucoma and what are risk factors, it becomes more specific of a test, and it becomes a little more useful,” he said.
The goal of genetic testing, Dr. Aboobakar said, is one day to be able to collect a blood sample from a patient and run a gene panel to identify which genetic variants that they carry. For early onset forms of glaucoma, such as congenital glaucoma and juvenile open angle glaucoma, this would allow physicians to identify the causal gene mutation for their disease. With that information you can screen first-degree relatives to see if they also carry this mutation and whether they warrant close follow-up, Dr. Aboobakar continued. “One day we may be able to offer these patients targeted gene therapies,” she said.
For adult onset glaucomas, such as primary open angle glaucoma, angle closure, and exfoliation glaucoma, there are many genes associated with disease risk. To assess their cumulative impact, PRSs are calculated, which provide information on an individual’s glaucoma risk relative to the general population. It may also help identify disease subtypes based on genetic markers, and we can then use this information to provide patients with personalized disease monitoring and therapy, Dr. Aboobakar said.
Dr. Greenwood also said that once the genes and downstream effects are identified, targeted therapies that disrupt downstream effects could be developed and prescribed.
Dr. Greenwood said his hope is to have genetic testing identify risk very reliably and, if glaucoma develops, assist him in determining the best treatment regimen for the patient going forward.
“My dream is [a test that’s] easily done in the office as a point-of care test; then it allows for personalized medicine,” he said. “The only other thing I would add is a lot of times people hear genetic testing and they think it’s scary. There are a lot of unknowns. Once you get your can of worms open, what does all this mean?” Dr. Greenwood said, explaining that education and counseling will remain important.
Article Sidebar
I wish I had …
Jeff Pettey, MD, Cataract Editorial Board member, shared what he wishes he had:
For global blindness, I wish we had a glaucoma procedure as effective as trabeculectomy that was as simple to perform as cataract surgery.
About the physicians
Inas F. Aboobakar, MD
Instructor in Ophthalmology
Mass Eye and Ear
Harvard Medical School
Boston, Massachusetts
Michael Greenwood, MD
Vance Thompson Vision
Fargo, North Dakota
Relevant disclosures
Aboobakar: None
Greenwood: None
Contact
Aboobakar: Inas_Aboobakar@MEEI.HARVARD.EDU
Greenwood: michael.greenwood@vancethompsonvision.com
