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. 2024 Nov 7;142(12):1132-1139.
doi: 10.1001/jamaophthalmol.2024.4376. Online ahead of print.

Primary Open-Angle Glaucoma Polygenic Risk Score and Risk of Disease Onset: A Post Hoc Analysis of a Randomized Clinical Trial

Sayuri Sekimitsu  1   2 , Nabil Ghazal  1 , Kanza Aziz  2 , Yan Zhao  2 , Rishabh K Singh  3 , John H Fingert  4 , Mae O Gordon  5 , Michael A Kass  5 , Todd Scheetz  4 , Ayellet V Segrè  2   6 , Louis R Pasquale  7 , Janey L Wiggs  2   6 , James D Brandt  8 , Nazlee Zebardast  2
Affiliations

Primary Open-Angle Glaucoma Polygenic Risk Score and Risk of Disease Onset: A Post Hoc Analysis of a Randomized Clinical Trial

Sayuri Sekimitsu et al. JAMA Ophthalmol. .

Abstract

Importance: Primary open-angle glaucoma (POAG) is a heritable disease. A polygenic risk score (PRS) threshold may be used to identify individuals at low risk of disease onset.

Objective: To assess the utility of a POAG PRS to identify ocular hypertensive individuals at low risk of disease onset.

Design, setting, and participants: This is a post hoc analysis of the Ocular Hypertension Treatment Study (OHTS), a multicenter randomized clinical trial across 22 centers in the US conducted among 1636 participants with ocular hypertension from February 1994 to April 2019 with available genetic data. Of the 1636 original participants, 1077 had available genetic data; after excluding 67 for missing data, data quality concerns, or ancestry other than European or African, 1010 were included in the present analysis. Data for this report were analyzed from November 2023 to June 2024.

Exposure: From 1994-2002, participants were randomized to receive topical intraocular pressure (IOP)-lowering medications. From 2002 onwards, all participants were given topical IOP-lowering medications.

Main outcome and measure: Twenty-year conversion rates by POAG PRS threshold, baseline randomization status, and OHTS clinical risk tertile.

Results: Among the 1010 participants in this study, 563 (65.8%) were female, and the mean (SD) age was 55.9 (9.4) years. In a mixed-effects logistic regression model adjusted for OHTS risk factors for conversion to POAG and randomization status, a PRS under the 48th percentile was associated with a 1.49 times higher likelihood of disease-free status after 20 years of follow-up (95% CI, 1.04-2.15; P = .03; unadjusted hazard ratio [HR], 1.64; 95% CI, 1.13-2.38; P = .009), compared with high polygenic risk. When we stratified the trial cohort into nongenetic OHTS clinical risk tertiles, the largest differences in survival probability at 20 years based on PRS threshold was observed in eyes in the highest tertile, initial observation group (20-year conversion rate: 61.1% in the high polygenic risk group vs 23.8% in the low polygenic risk group; 95% CI, -63.0 to -11.6; P = .01), with randomization to early treatment partially mitigating the effect of high genetic risk (20-year conversion rate: 37.3% in the high polygenic risk group vs 24.1% in the low polygenic risk group; 95% CI, -35.6 to 9.3%; P = .32).

Conclusions and relevance: These findings support considering use of a POAG PRS threshold to identify individuals at low risk of disease onset, with those below the PRS threshold more likely to have lower conversion rates over 20 years. Among those considered at highest risk based on the OHTS clinical risk model, early treatment may partially offset the association with high genetic risk but provide limited benefit for those with low genetic risk.

Trial registration: ClinicalTrials.gov Identifier: NCT00000125.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Gordon reported grants from Washington University during the conduct of the study and Mae E. Gordon Coordinating Center outside the submitted work. Dr Pasquale reported grants from Neuroscience Education Institute during the conduct of the study and served as a paid consultant for Twenty Twenty. Dr Wiggs reported grants from the National Eye Institute during the conduct of the study and served as a consultant for CRISPRTx and Editas outside the submitted work. Dr Brandt reported grants from the National Eye Institute (Ocular Hypertension Treatment Study clinical center grant from 1994-2019 and Childhood Origins of Asthma project clinical center grant, ongoing) during the conduct of the study and grants from Santen (clinical trial support for surgical device), other from Glaukos (stock ownership), and consulting fees from Eyenovia and Thea outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Survival Probability of Progression to Primary Open-Angle Glaucoma (POAG) by POAG Polygenic Risk Score (PRS) Threshold, Based on Overall, Nerve-Based, or Visual Field (VF)–Based POAG Diagnosis
Figure 2.
Figure 2.. Survival Probability of Progression to Primary Open-Angle Glaucoma (POAG) by Ocular Hypertension Treatment Study (OHTS) Risk Tertile, POAG Polygenic Risk Score (PRS) Threshold, and Randomization Status
Figure 3.
Figure 3.. Reclassification of Individuals From Published Ocular Hypertension Treatment Study (OHTS) Risk Tertile to OHTS Risk Tertile Modulated by Primary Open-Angle Glaucoma (POAG) Polygenic Risk Score (PRS)
Figure 4.
Figure 4.. 20-Year Primary Open-Angle Glaucoma (POAG) Conversion Rates by Ocular Hypertension Treatment Study (OHTS) Risk Tertile and OHTS Risk Tertile Modulated by Primary Open-Angle Glaucoma (POAG) Polygenic Risk Score (PRS)
See this image and copyright information in PMC

References

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