A new study published in eLife from researchers in the U.K., U.S., and Japan suggests that blood metabolites may provide a key to refining glaucoma disease risk predictions. The investigators reported development of a model that integrates genetic data with metabolomics, revealing that metabolites in the blood can help identify individuals who are more resilient to developing glaucoma despite having a high genetic risk.
“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,” said co-first author Keva Li, a medical student at the Icahn School of Medicine at Mount Sinai. The study aimed to better understand why some individuals with a high genetic predisposition to glaucoma do not develop the disease, despite current genetic risk models.
Glaucoma is a leading cause of irreversible blindness and is known to be influenced by both genetic and environmental factors. The disease usually remains undiagnosed until significant damage has occurred to the eye, and current genetic risk scores do not fully capture the complexity of glaucoma’s development. In this study, the researchers sought to integrate blood metabolite data into existing genetic models to see if it could improve the accuracy of risk prediction.
The study involved an analysis of data from 117,698 participants in the UK Biobank, including 4,658 individuals diagnosed with glaucoma and 113,040 controls. The data encompassed genetic data; clinical data such as the pressure within the eye and the thickness of optical nerves; metabolomic data; and lifestyle factors such as smoking and alcohol consumption. The researchers used these data to test the predictive capabilities of four different risk models.
The findings showed that the incorporation of metabolomics data into the risk models provided only a modest increase in prediction accuracy.
“Given this modest improvement, we hypothesized 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,” said Keva.
To determine if this was the case, the investigators next grouped those in the study based on genetic risk and then tested whether metabolomic data had the ability to predict which of the groups had the highest and lowest risk of developing glaucoma. This grouping of participants revealed that higher levels of three specific metabolites—lactate, pyruvate, and citrate—were associated with a 29% reduced risk of glaucoma among individuals with the highest genetic risk scores.
To further explore this, the team tested whether treatment with pyruvate protected mouse models of glaucoma from developing the disease. As the investigators expected, the research showed that treating the mouse models 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,” said co-first author Nicholas Tolman, PhD, a postdoctoral research scientist in the lab of Simon John, PhD, in the department of ophthalmology at Columbia University Medical Center.
While the results are promising, the study’s authors noted that the data is based on a predominantly European cohort, and future research will need to explore how these findings apply to more diverse populations.
