Increased Risk of POAG Associated With Polygenic Risk Score

Patients with ocular hypertension had an increased risk of primary open angle glaucoma (POAG) if they had a higher polygenic risk score (PRS), according to a study published in JAMA Ophthalmology. Prediction of POAG was also found to improve with the inclusion of PRS.

POAG accounts for about 69% of incidences of glaucoma, one of the leading causes of blindness. Intraocular pressure (IOP) has been the only risk factor for the development and progression of POAG that can be altered. POAG is also a heritable disease, which can be evaluated with the PRS using an aggregate of overall genetic burden. This study aimed to use data from the Ocular Hypertension Treatment Study (OHTS) to create a PRS and if POAG risk was linked to underlying genetic risk outside of demographic and ocular factors.

Close-up of eyes | Image credit: Alessandro Grandini - stock.adobe.com

OHTS was a randomized clinical trial that assessed the efficacy of topical therapy that lowered IOP. There were 1636 participants with ocular hypertension (OHTN) from 22 sites in the United States who were included in the study and randomization began in 1994 and ended in June 2002 for phase 1; phase 2 began in June 2002 and last until March 2009 and phase 3 began in July 2015 and ended in June 2020. A total of 1077 participants also participated in the ancillary genetics study. Most of the participants had European or African ancestry.

The POAG PRS was created using summary statistics from a cross-ancestry POAG genome-wide association study meta-analysis. A total of 8,813,496 genomic variants from 449,186 cross-ancestry participants in the UK Biobank were used to train the PRS. A baseline regression analysis was used for predicting the time from conversion of OHTN to POAG.

Overall, there were 1009 participants included for this study, of which 55.7% were female and the mean (SD) age was 55.9 (9.3) years. There were 287 eyes in 212 participants who developed POAG.

Participants who contracted POAG has a significantly higher mean (SD) PRS score (0.24 [0.95]) compared with participants who didn’t develop POAG (–0.12 [1.00]). Mean PRS was higher in participants of European ancestry who contracted POAG (0.29 [0.95]) compared with the participants of European ancestry who did not contract POAG (–0.13 [0.99]). This trend was not found in those of African ancestry, as those who contracted POAG did not have a significantly higher PRS compared with those who did not contract POAG (0.13 [0.93] vs –0.10 [1.04]).

Those in the lowest and highest baseline risk tertiles did not have a significant difference in mean PRS overall as well as those specifically of European and African ancestry. However, a significantly increased risk of POAG onset was found in the highest tertile of PRS compared with those in the lowest at the end of phase 1 (3.01-fold, 5.93% absolute increase), phase 2 (2.30-fold, 9.96% absolute increase), and phase 3 (2.00-fold, 9.93% absolute increase). This extended to those of European and African ancestry.

A decile higher PRS score was associated with a greater risk of POAG conversion per eye equivalent to 2.46% (95% CI, 2.10-2.81). A linear regression found an increase from 14.85% (95% CI, 11.73%-17.98%) conversion in 20 years in the lowest decile to 36.99% (95% CI, 33.86%-40.11%) conversion in the highest. Each decile was associated with a greater conversion risk for POAG equivalent to 1.36% (95% CI, 1.08%-1.64%).

There were some limitations to this study. POAG could have been classified incorrectly in the UK Biobank, which could result in poor training of the PRS. The sample size was relatively small and had a low proportion of participants who had POAG. Participants were also lost to follow-up over the course of 15 years. Generalizability of the study would be improved from validation of the PRS in external study populations.

The researchers concluded that a high PRS score for POAG was associated with an increased risk for the eye condition in patients with OHTN.

Reference

Singh RK, Zhao Y, Elze T, et al. Polygenic risk scores for glaucoma onset in the ocular hypertension treatment study. JAMA Ophthalmol. Published online March 14, 2024. doi:10.1001/jamaophthalmol.2024.0151