Cracking the (Genetic) Code
Is genotyping the answer to improving glaucoma management?
Anthony Khawaja | | 7 min read | Discussion
Although glaucoma can cause irreversible, irreparable damage to vision, treatment can slow or halt disease progression, so early detection is important. Unfortunately, our current screening tests – if applied to a general population – don’t work well enough; as a result, population screening for glaucoma is not currently recommended in some countries, including the UK and the US.
Using people’s genetic codes to identify a subset of the population that will benefit from screening may be the solution to this problem. In the last decade, there has been huge progress in discovering many of the genetic variants that contribute to glaucoma risk. It was back in 2018 when we first realized that the great number of risk variants we had discovered could be considered collectively to predict – with surprising accuracy – whether someone would end up developing glaucoma. This approach of combining thousands of risk variants into a single number, a polygenic risk score, has become popular across many common diseases, including glaucoma.
Instead of having to screen whole populations, genotyping enables targeted screening for those at a higher risk for glaucoma. Our current screening tests will perform much better when applied to a subset of the population with a higher prevalence of undetected glaucoma. In other words, there will be far fewer false positive referrals to secondary care if our current screening tests are applied to this enriched subset of the population.
A separate challenge in glaucoma care comes after diagnosis. At present, we cannot accurately predict which of our patients are at the highest risk of progressing and losing vision. If we could better predict this, we could ensure our limited healthcare resources are used optimally, focusing on the highest risk patients, but also saving costs, unnecessary treatment, and follow-up for those at lower risk.
It remains unclear whether the genetic variants which increase the risk of developing glaucoma also increase the risk of vision loss among patients with glaucoma. Instead of comparing people with glaucoma to people without glaucoma in the general population, we need more longitudinal genetic studies amongst cohorts of glaucoma patients, identifying the genetic variants that lead to worse disease.
A step in the right direction
This need was the motivation behind the Moorfields Glaucoma Bioresource – a project that involves recruiting glaucoma patients at Moorfields Eye Hospital, in collaboration with the NIHR BioResource (1). We can then combine our patients’ genetic information with their clinical outcome data over time.
The other way the Bioresource can help is by assessing how patients respond to different common treatments to enable tailoring of treatment options accordingly. There are multiple treatment options for glaucoma and it remains unclear which treatment would work best for individual patients.
There have been some really important randomized control trials, such as the LiGHT trial, that supports laser as an initial treatment for patients with ocular hypertension or primary open-angle glaucoma, and the TAGS study, which supports trabeculectomy as a reasonable first option for people with advanced glaucoma (2,3). However, these landmark studies only offer guidance on what may be best on average, rather than what would be optimal for individual patients.
We believe that the genetic code contains the answer to these challenges. For example, our genetic studies have suggested a substantial cause of higher intraocular pressure results from variation in pathways influencing Schlemm’s canal and collector channels, and not, as one might expect, the trabecular meshwork. This finding, which challenges previous dogma, is striking as some of our treatment options only target the trabecular meshwork (for example, trabecular stents and selective laser trabeculoplasty). It may be that we can identify, using the genetic code, which glaucoma patients primarily have a problem in Schlemm’s canal and collector channels and therefore might not do so well with trabecular meshwork treatment and ensure that they move onto a different type of treatment.
In addition to the Moorfields Glaucoma Bioresource – another major study we are looking at is the UK Biobank study, which includes the genetic testing of half a million people in the UK (4). We know who has got glaucoma just by self report at the moment, but we are in the process of linking the UK Biobank to eye care electronic medical record (EMR) data from 15 centers around the country that use the Medisoft – a specialist ophthalmology EMR that efficiently documents disease progression and response to treatments. These 15 centers serve 15 of the 22 UK Biobank recruitment center regions and we therefore have estimates that we should get linked clinical data with UK Biobank data for over 10,000 patients with glaucoma. That would be another great source to help complete the research we need to enable more personalized glaucoma care.
Work in motion
When will it be feasible for the genetic testing detailed above to be available for our patients and communities? Many experts believe that it is “when” and not “if.” A future where whole populations have genetic data available is increasingly looking like it will happen sooner rather than later. For example, the consumer company “23andMe” charges less than £150 for testing of markers across the whole genetic code (5). And now, they have started to report the polygenic risk score for glaucoma to their customers. Already, members of the public and some of our patients will know their polygenic risk score for glaucoma, and we need to be able to advise them accordingly.
Most exciting is the current “Our Future Health” study that has commenced in the UK (6). They are recruiting and carrying out genetic testing for five million adults – over 10 percent of the adults in the country. This effort will establish the processes of storing and leveraging genetic data for users of the NHS, and pave the way for ultimately genotyping all NHS users in the future. I see a future where the NHS would hold the genetic information of all people centrally, allowing doctors to use small subsets of this information to inform personalized care; glaucoma specialists would leverage the information to inform targeted population screening and risk stratification in the clinic; cardiologists would use the data to help them decide which patients to treat with different blood pressure medications or statins; oncologists would decide at what age should you start breast cancer screening or prostate cancer screening.
The genetic testing in Our Future Health costs around $25 per person, and it will be the best value medical test there has ever been because it will help improve care across all specialties.
So, what should we advise members of the public who are identified to have a high polygenic risk score for glaucoma (for example, from a 23andMe test)? The key message is to ensure that they have their eyes checked every one to two years at a local optometrist. There are also lifestyle modifications that can mitigate a high genetic risk. Indeed, in the last few years, we have identified that limiting caffeine or alcohol intake can reduce a higher genetic risk of glaucoma. Though these studies cannot prove cause and effect, this information is of interest to the public – especially those who have been identified as being at a high risk of glaucoma before they have developed any disease.
Will this future form of personalized glaucoma care be limited to specialist centers with genetic expertise? I don’t believe that ophthalmologists will need to be genetics experts to understand this information. All information can be summarized into one polygenic risk score number. It will simply be a case of understanding whether that number is low, medium, high, or very high to help doctors guide their risk stratification and which treatment option would be best.
- Fight for Sight, “Establishing the Moorfields Glaucoma BioResource to predict glaucoma development and personalize care” (2021). Available at: bit.ly/3MkXt2r.
- Moorfields Eye Charity, “The LiGHT trial - improving treatments for glaucoma.” Available at: bit.ly/3TV4zfC.
- A J King, “Primary trabeculectomy for advanced glaucoma: pragmatic multicentre randomized controlled trial (TAGS),” BMJ, 12, 373 (2021). PMID: 33980505.
- UK Biobank (2023). Available at: bit.ly/3zfMmjt.
- 23andMe (2023). Available at: https://bit.ly/3ZqGE96.
- Our Future Health (2023). Available at: bit.ly/3lToBdY.