Nazlee Zebardast, MD, MSc

Credit: Harvard Ophthalmology

A better polygenic danger rating (PRS) was related to an elevated danger for earlier growth of primary open-angle glaucoma (POAG) amongst sufferers with ocular hypertension (OHTN), in line with new analysis.¹

This post-hoc evaluation of the Ocular Hypertension Treatment Study (OHTS), involving greater than 1000 contributors, revealed the related remained impartial of most ocular phenotypic danger components, genetically decided affected person ancestry, and the follow-up section of roughly 20 years.

“We show that a high POAG PRS, based on, to our knowledge, the largest genome-wide association study (GWAS) meta-analysis to data, was associated with increased risk of POAG conversion among patients with OHTN,” wrote the investigative crew, led by Nazlee Zebardast, MD, MD, Massachusetts Eye and Ear, Harvard Medical School.

Identification of high-risk people and the necessity for therapeutic intervention is essential to stop glaucoma-related imaginative and prescient loss. POAG, a very heritable illness, has been linked with 127 recognized frequent danger variants.² Each variant accommodates a small impact on POAG, however a PRS can present a clinically helpful measure of a affected person’s mixture genetic burden.

A prediction mannequin, involving age, IOP, central corneal thickness (CCT), vertical cup-disc ratio (VCDR), and visible subject sample normal deviation (PSD), developed for POAG, proved possible for danger stratification within the OHTS.³ The present evaluation used obtainable genetic knowledge from the research to find out whether or not underlying genetic danger improves danger stratification exterior of the demographic components and ocular biomarkers used within the prediction mannequin.

The secondary evaluation of the OHTS collected knowledge from 22 US-based websites, with a imply follow-up of 14 years. In OHTS, contributors had been randomized to both topical IOP-lowering remedy or shut commentary—after June 2002, all contributors acquired remedy. Among the unique 1636 contributors enrolled in OHTS, 1077 had been enrolled in an ancillary genetics research and 1009 met the factors for the present evaluation.

Zebardast and colleagues calculated a POAG PRS utilizing abstract statistics from the biggest recognized cross-ancestry POAG GWAS meta-analysis. The PRS was educated utilizing 8,813,496 variants from 449,186 cross-ancestry contributors within the UK Biobank. Participants had been grouped into both deciles or low-risk, intermediate-risk, and high-risk tertiles based mostly on PRS z scores

Among the 1009 contributors included for evaluation, 562 (55.7%) had been feminine and the imply age was 55.9 years. Upon evaluation, investigators discovered the imply PRS was considerably greater for POAG converters (0.24) in contrast with non-converters (–0.12) (distinction, 0.36; 95% CI, 0.24 – 0.49; P <.001).

Further evaluation confirmed the POAG danger elevated by 1.36% (95% CI, 1.08 – 1.64) with every greater PRS decile, with linear regression exhibiting a rise from 9.52% (95% CI, 7.09 – 11.95) within the lowest PRS decile to 21.81% (95% CI, 19.37 – 24.25) within the highest decile. When stratified by ancestry, a comparability of low-risk and high-risk PRS tertile demonstrated a 2.0-fold enhance in POAG danger over 20 years for people of European and African descent.

A subcohort randomized to delayed OHTN therapy confirmed every lower in PRS decile was linked with a 0.52-year (95% CI, 0.01 – 1.03) lower within the age at prognosis of POAG (P = .047). The early therapy group offered no vital linear affiliation between PRS and age at POAG prognosis.

Moreover, the prediction fashions had been discovered to considerably enhance with the inclusion of PRS as a covariate (C index, 0.77), in contrast with the OHTS baseline mannequin (C index, 0.75) (P <.001). Each 1-SD greater PRS elevated the 20-year danger for POAG by 25% (hazard ratio [HR], 1.25; 95% CI, 1.13 – 1.44) for POAG onset.

Zebardast and colleagues famous the prediction fashions confirmed enchancment within the prediction of POAG onset with the addition of PRS, however the absolute enhance in efficiency could also be smaller than anticipated at the beginning of the research.

“As PRS presents a constant level of lifetime risk, its predictive power is most likely higher at earlier clinical stages and younger age prior to development of phenotypic markers,” they wrote.

References

1. _{Singh RK, Zhao Y, Elze T, et al. Polygenic Risk Scores for Glaucoma Onset within the Ocular Hypertension Treatment Study. JAMA Ophthalmol. Published on-line March 14, 2024. doi:10.1001/jamaophthalmol.2024.0151}
2. _{Gharahkhani P, Jorgenson E, Hysi P, et al. Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with constant impact throughout ancestries. Nat Commun. 2021;12(1):1258. Published 2021 Feb 24. doi:10.1038/s41467-020-20851-4}
3. _{Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive remedy delays or prevents the onset of main open-angle glaucoma. Arch Ophthalmol. 2002;120(6):701-830. doi:10.1001/archopht.120.6.701}