Scientists have revealed why not all individuals with a high inherited risk of glaucoma may ultimately develop the disease.
Glaucoma is an eye condition that damages the optic nerve, which can lead to blindness. Image credit: Akshit Dhasmana via Unsplash
This collaborative study from researchers in the UK, US, and Japan is published today as a Reviewed Preprint in eLife, and presents valuable findings on the importance of the plasma metabolome in glaucoma risk prediction, according to the editors. They add that the evidence is solid and the research offers valuable insights for the design of protective therapeutic strategies for glaucoma.
Glaucoma is a leading cause of irreversible sight loss that usually has no symptoms until eye damage has already occurred. Around 50–70% of people with glaucoma remain undiagnosed, and there is no cure available. To detect the disease early, researchers have developed genetic risk scores to identify people who might be most at risk of developing glaucoma. Although glaucoma has a genetic component, it is also significantly influenced by environmental and lifestyle factors – not everyone who has a high genetic risk of glaucoma goes on to develop the disease.
“Although it’s possible that current genetic tests don’t capture all of the inherited risk of glaucoma, it is also possible that other factors make some people more resilient to developing the disease,” says co-first author Keva Li, a medical student in the Department of Ophthalmology at Icahn School of Medicine at Mount Sinai, New York, US. “Previous studies have indicated a potential role for blood metabolites in evaluating glaucoma risk. We set out to see if adding information about metabolites to genetic risk scores could increase their predictive accuracy for glaucoma.”
Metabolites – the intermediate and end products of cell processes – can provide a holistic measure of the physiological status of cells and tissues. Recent advances in metabolomics – the study of all the metabolites in a sample – have opened up avenues to explore metabolites as markers of diseases such as glaucoma.
The researchers analyzed genetic and metabolomic data for 117,698 participants in the UK Biobank, 4,658 of whom had glaucoma and 113,040 controls without glaucoma. In addition to genetics and metabolomics data, they also used clinical data such as the pressure within the eye and the thickness of optical nerves, along with lifestyle data including smoking status and alcohol consumption, and information about long-term conditions such as diabetes and high cholesterol.
They then tested four different combinations of these data in risk models to determine their respective utility for predicting glaucoma. Overall, they found that adding metabolomics data improved the prediction accuracy in all the models, but only modestly compared with models based on genetic, clinical, and demographic data alone.
“Given this modest improvement, we hypothesised that metabolites might be better for distinguishing patients within risk groups, such as those with a high genetic risk who do not go on to develop glaucoma,” says Keva.
To test this, they grouped participants by their genetic risk and then tested whether metabolomics data could predict who within the highest and lowest risk groups would go on to develop glaucoma. Their analysis revealed that higher levels of three metabolites – lactate, pyruvate, and citrate – were associated with a 29% reduced risk of glaucoma in people at the highest genetic risk. Moreover, these metabolites had no link with glaucoma in the lower risk group of people, suggesting that, in people at the highest genetic risk, these metabolites could serve as resilience factors.
To explore this theory, the team tested whether treatment with pyruvate protects mice with glaucoma. As hypothesised, they found that supplementing the mice with pyruvate prevented the increases in intraocular pressure and degeneration of the optic nerve typically seen in glaucoma. Pyruvate and lactate are already known to be important energy sources and neuroprotectants for retina cells, and these results provide evidence that these metabolites may also protect the eyes in other ways. “The administration of resilience metabolites to protect against glaucoma is a growing focus of our research and holds exciting promise,” says co-first author Nicholas Tolman, Postdoctoral Research Scientist in co-senior author Simon John’s Lab, Department of Ophthalmology at Columbia University Medical Center, New York, US.
Although these results come from a predominantly European group of participants and the predictive accuracy for glaucoma might not hold true in more diverse populations, the findings open new avenues for the development of metabolite-based therapeutics that could mitigate a high inherited risk of glaucoma.
“This is the first study to incorporate metabolite data with genetic risk scores into glaucoma prediction algorithms and to identify biomarkers associated with resilience to the disease. Future work is needed to understand how non-genetic factors known to impact glaucoma risk, such as air pollution, stress, physical activity, and diet, could change the metabolomic risk score and alter glaucoma genetic predisposition,” concludes Louis Pasquale, Professor of Ophthalmology at the Icahn School of Medicine at Mount Sinai. Pasquale is a co-senior author of the study alongside Jae Hee Kang, from the Channing Division of Network Medicine at Harvard Medical School and Brigham and Women's Hospital, Massachusetts, US, and Simon John from the Department of Ophthalmology at the Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center.
To find out more about the UK Biobank, visit https://www.ukbiobank.ac.uk.
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