High glaucoma polygenic risk is strongly associated with development of glaucoma in patients with pseudoexfoliation syndrome

Abstract

Purpose : Existing healthcare models utilise a “one size fits all” approach to glaucoma surveillance, with few tools available to accurately identify true high-risk individuals. This retrospective cohort study investigated whether a glaucoma polygenic risk score (GPRS) can provide additional risk stratification in pseudoexfoliation syndrome (PEX) cohorts.

Methods : All 648 participants in the Australian and New Zealand Registry of Advanced Glaucoma with PEX and a GPRS were included. Glaucoma status was graded by ophthalmologist (n=394 participants with pseudoexfoliative glaucoma, n=101 pseudoexfoliation with ocular hypertension [OHT], and n=153 pseudoexfoliation syndrome without OHT or glaucoma). GPRS was calculated with published methods and expressed as a centile of a normative reference population. Multivariable logistic and linear regression, and cox proportional hazard models of GPRS quintile predicting clinically-important glaucoma outcomes were performed. Results were replicated within the separate Blue Mountains Eyes Study (BMES).

Results : Within the discovery cohort, PEX cases with glaucoma had a higher mean GPRS than those with PEX alone (60 +/- 1.36 SEM versus 45 +/- 2.3 SEM, p<0.001). PEX cases in the top quintile were at 3.7 times (95% CI 2.00 - 6.98, p<0.001) greater odds of developing glaucoma than those in the bottom quintile, with a mean age of glaucoma diagnosis 4 years younger (95% CI 0.69-7.05, p=0.018), greater odds of bilateral central field loss (p=0.001), and escalation to surgical intervention (p=0.01). In the replication cohort, PEX cases with glaucoma had a mean GPRS higher than PEX cases without glaucoma (p<0.001). In both cohorts, patients with pseudoexfoliation who had not developed glaucoma had a GPRS lower than population average (p=0.035). Participants with pseudoexfoliative glaucoma had a GPRS lower than primary open-angle glaucoma counterparts across the glaucoma severity spectrum (p<0.001).

Conclusions : A GPRS can be used to identify patients at risk of developing glaucoma secondary to pseudoexfoliation, and poorer disease outcomes. Pseudoexfoliation and polygenic risk could act as additive risk factors to glaucoma development. Patients with pseudoexfoliation without glaucoma have a lower genetic risk than the average person. Use of this GPRS could influence glaucoma surveillance models in individuals with pseudoexfoliation syndrome.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.