Professor Stuart MacGregor held a well-attended lecture at the 2024 RANZCO Congress where he delved into some of the revolutionary work he’s doing alongside other prominent Australian researchers to predict glaucoma with a simple testing method.
Prof MacGregor has been commercialising a project that could have significant implications for glaucoma, a disease where half of those affected don’t even realise they have it. But his work won’t stop with this disease.
With fellow Australian ophthalmic research heavyweights Professor Alex Hewitt, Professor Jamie Craig and Dr Owen Siggs, he’s been involved with new start-up Seonix Bio that has brought a polygenic risk score (PRS) test (SightScore) to market that can predict a person’s risk of primary open angle glaucoma – the most common form of this disease – using a saliva test. It’s now in use in Australian eyecare clinics and recently launched in the US.
The implications are significant beyond disease detection, also offering actionable insights into how the patient should be managed into the future, such as when they should be first monitored for glaucoma and how frequently. And there’s potential application in other eye diseases such as keratoconus and age-related macular degeneration.
“We’ve also shown that we can stratify people in terms of what age they might get glaucoma … and our PRS has also turned out to have surprising efficacy in terms of predicting functional progression, for example, or the need for treatment initiation or escalation,” Prof MacGregor, a geneticist at QIMR Berghofer in Brisbane, says.
A major domino to fall in recent years has been the ability to identify many of the genes involved in glaucoma, leveraging biobank data. Prof MacGregor has been involved in the global consortium that has now published 312 gene loci associated with the disease.
Having this visibility has paved the way for more accurate PRS tests that act as a screening tool.
The SightScore test works by scanning an individual genome for more than 2,500 genetic variants before placing them on a “genetic risk spectrum” relative to the population (think of a bell curve). The zero to 20th percentile is considered the lowest risk group, 20-70th percentile intermediate risk, 70-90th percentile higher risk and 90-100th percentile the highest risk group.
The test takes into account an individual’s genes and adds up a glaucoma risk score.
“The benefits include enabling early diagnosis or timely treatment, it offers potential efficiencies if we can identify high-risk people as well as low-risk people who might be wasting health resources. It can also help to tailor how regularly we monitor and treat people based on their genetic risk score.”
Because glaucoma is a condition with a strong genetic contribution, it’s a nice fit for a PRS. But for a screening program to be effective, Prof MacGregor says it must also have early effective treatment options, tests that can accurately diagnose the disease in question, facilities that can care for those with a positive diagnosis, and the benefits of screening must outweigh the risks. Glaucoma ticks these boxes too.
screening tool for glaucoma. Image: Seonix Bio.
To get SightScore tests into the hands of more patients, Prof MacGregor’s team have established Seonix Bio, which has commercialised their research and is working to get the tests into eyecare clinics across the country, including in optometry.
It has been developed using large-scale genome wide association studies and has been improved and validated in a range of clinical cohorts.
The test is already performing much better than PRSs for other diseases such as breast cancer, prostate cancer and type 2 diabetes, largely due to the genetic nature of glaucoma.
Prof MacGregor says by expanding sample sizes in more recent times, from ~400,000 to six million individuals, they’ve been able to deliver a test that went from testing some 2,000 markers to seven million across the genome.
“It’s still not a diagnostic test, but we’re getting dramatic risk stratification to tell who’s going to be at highest risk early on. If you translate that into how much earlier glaucoma onset would be, benchmarking this in the Blue Mountains study, you take people in the top 10% risk against the bottom 10% and you’re getting greater than 25 years earlier onset disease from using the simple saliva test.”
Other work, a retrospective study, followed patients and confirmed what the researchers hoped: that people in the top 20% of risk did actually develop glaucoma at a much higher rate than those with lower risk.
“That was very encouraging.”
Another promising disease target is keratoconus, where Prof MacGregor et al again showed good risk stratification with their test. Other recent work has shown its potential to perform better than a corneal thickness measure when predicting keratoconus risk.
This could inform decisions around corneal cross-linking and potentially identifying those at risk of corneal ectasia.
With AMD, Prof MacGregor says there are two well-known genes (Complement Factor H and ARMS2), but with many others mapped, they wanted to determine if their PRS could improve disease prediction. They were able to, even in people with three or four risk alleles for CFH and ARMS2.
The degree of risk stratification was shown to be better for later stage AMD, with “remarkable” prediction so far for AMD overall, despite the test being in its relative infancy.
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