Polygenic Risk Scores Can Identify Patients Who Should Receive IOP-Lowering Treatment

An intraocular pressure (IOP) polygenic risk score (PRS) could identify which patients would benefit the most from intensive treatment to lower IOP and manage their risk of glaucoma, according to a study published in JAMA Ophthalmology.¹ Vertical cup-disc ratio (VCDR) PRS can also be used to determine the risk of glaucoma, even in patients with normal IOP.

Glaucoma is an eye condition that can lead to vision loss and blindness, with the most prevalent form of glaucoma being primary open-angle glaucoma (POAG)² at 2.4% global prevalence. IOP and VCDR are 2 of the risk factors for POAG and are necessary in attempting to diagnose the condition early to prevent the worst outcomes in patients. Due to the heritability of IOP and VCDR, a PRS could be beneficial in identifying individuals who are most at risk. This study aimed to assess how PRS can help to identify patients who are at highest risk based ont heir OP and VCDR scores.

This study used multiple cohorts from previous studies, including the Canadian Longitudinal Study on Aging (CLSA), the Busselton Healthy Aging Study (BHAS) and the UK Biobank. The CLSA contained data from Canadians aged between 45 and 85 years collected between 2010 and 2015. IOP measurements that compensated for the cornea were calculated for baseline and follow-up in this dataset. Any participant who did not have IOP measurements was excluded.

A PRS may be able to predict the incidence of glaucoma in individuals, allowing for more targeted treatment for these patients | Image credit: Alessandro Grandini - stock.adobe.com

The BHAS included participants from Busselton, Western Australia, with data collected from individuals aged 46 to 64 years between 2010 and 2015. There were 4839 individuals for IOP PRS validation and 1588 individuals who had VCDR PRS validation. The UK Biobank was also used for this study and collected data on individuals aged 40 to 69 years from 2006 to 2010 who lived in the UK. Patients with African, East Asian, and South Asian ancestry were included.

There were 5890 samples from the CLSA used to assess the association between VCDR and IOP and PRS. The researchers found that the baseline model accounted for 3.8% (95% CI, 2.9-4.8) of the variance in unadjusted VCDR and 2.5% (95% CI, 1.8-3.4) in adjusted VCDR. The new PRS was able to explain 22.0% (95% CI, 20.1-23.9) of the variance in phenotypes within the adjusted VCDR and 21.9% (95% CI, 20.1-23.8) in the unadjusted VCDR, both in the CLSA dataset. Variance in phenotypes for IOP was also able to be explained at a rate of 12.9% (95% CI, 11.3-14.6). A total of 3.1% (95% CI, 2.3-4.0) of the variance in phenotypes was accounted for in the baseline model.

There were 1588 samples in the BHAS dataset that were used to perform a PRS validation. The variance was explained in 0.98% (95% CI, 0.3-2.2) of the adjusted VCDR and 0.79% (95% CI, 0.2-1.9) of the unadjusted VCDR. The PRS was able to explain 19.7% of the variance and 18.3% of the variance in adjusted and unadjusted VCDR respectively. The IOP PRS was able to explain 9.6% of the variance in phenotype.

Using the UK Biobank, the VCDR PRS variance explained in 5.2%, 12.1%, and 14.3% for African, East Asian, and South Asian populations, respectively; IOP PRS variance explained 2.3%, 3.2%, and 7.5% in those same populations.

There were some limitations to this study. The PRS was drawn from samples of individuals with European ancestry and was less predictive in people without European ancestry because of this. Future studies for African individuals may be needed in this field to account for differences in IOP in this subgroup. These results have also not affected clinically relevant outcomes for glaucoma.

The researchers concluded that a new PRS based on the latest genome-wide association studies, which was able to predict VCDR or IOP more accurately compared with previous data. This can be used to help predict glaucoma in these patients.

References

1. He W, Lee SSY, Diaz Torres S, et al. Predictive power of polygenic risk scores for intraocular pressure or vertical cup-disc ratio. JAMA Ophthalmol. Published online November 21, 2024. doi:10.1001/jamaophthalmol.2024.4856
2. Glaucoma. National Eye Institute. Updated November 15, 2023. Accessed November 21, 2024. https://www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/glaucoma