Nazlee Zebardast, MD, MSc: Utility of Genetic Risk Scores for Glaucoma Onset

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At ARVO 2024, Nazlee Zebardast, MD, MSc describes the value of a polygenic risk score to predict the onset of primary open-angle glaucoma.

Highlights

0:19 Genetic risk of glaucoma

1:33 Purpose of analysis

2:33 Link between PRS, glaucoma

4:35 Impact on clinical practice

6:00 Ongoing challenges in glaucoma

7:24 Final thoughts

A new analysis presented at the 2024 Association for Research in Vision and Ophthalmology (ARVO) Meeting evaluated the utility of a polygenic risk score (PRS) for predicting primary open-angle glaucoma (POAG) onset in individuals with ocular hypertension.

Assessing eyes from the Ocular Hypertension Treatment Study (OHTS), the analysis found a lower PRS demonstrated a significantly lower chance of glaucoma development, particularly for those initially considered high-risk. Early treatment proved important for individuals with high genetic risk but exhibited less impact on those with a low genetic risk.

In an interview with HCPLive, Nazlee Zebardast, MD, MSc, described how the cut-off PRS was able to separate people who were at high- or low risk of developing disease, specifically visual field loss or functional changes. Even in a high clinical risk group at baseline, investigators could separate patients by PRS to determine who required early treatment from those who would not benefit.

“I think this is really important, not only from decreasing potential harms of excessive treatment to patients but also reducing cost and the need for monitoring of individuals that probably do not need to be monitored as aggressively,” Zebardast told HCPLive.

From OHTS, 1010 participants with genotype data were used for analysis—eyes were categorized into disease-onset risk tertiles using baseline models of age, intraocular pressure (IOP), vertical cup-to-disc ratio (VCDR), central corneal thickness (CCT), and pattern standard deviation (PSD).

Zebardast and colleagues determined the PRS using summary statistics from a large cross-ancestry POAG genome-wide association study meta-analysis. Among the 2018 eyes of participants, the optimal PRS threshold was –0.05 (48th percentile).

Upon analysis, in the logistic model adjusted for relevant baseline characteristics, a glaucoma PRS under threshold was associated with a 2.15-fold increased risk of remaining disease-free at 20 years (95% CI, 1.65 - 2.81; P <.001).

For individuals randomized to early treatment, those below the PRS threshold exhibited conversion rates of 3.5% at 10 years and 13.2% at 15 years–those above the threshold showed conversion rates of 7.6% at 10 years and 30.1% at 15 years.

In the observation cohort, below-threshold individuals experienced rates of 9.3% at 10 and 29.4% at 15 years. Those above the threshold had rates of 18.8% at 10 and 45.0% at 15 years.

After separating the study population into OHTS baseline risk tertiles, Zebardast and colleagues found the largest differences in survival probability according to the PRS threshold was in eyes in the high-risk tertile (P <.0001). Randomization to early treatment weakened the effect of high genetic risk (P = .002) but had reduced benefit in those with low genetic risk (P = .86).

“I think that’s what is so important about this study is that we show not only is genetic risk important for identifying those that will lose vision, but it’s also potentially a way we could say, you’re low genetic risk and you may not need to be seen once or twice a year to monitor,” Zebardast told HCPLive. “Because your likelihood of needing treatment or losing vision is relatively low.”

Zebardast reports no relevant disclosures.

References

Zebardast N, Sekimitsu S, Aziz K, Zhao Y, Singh R, Fingert JH, et al. Primary open-angle glaucoma polygenic risk score can identify individuals at low risk of disease onset in the Ocular Hypertension Treatment Study. Paper presented at the Association for Research in Vision and Ophthalmology (ARVO) 2024 Meeting, May 5–9, 2024.

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