[ad_1]
Nazlee Zebardast, MD, MSc
Credit: Harvard Ophthalmology
According to new research, a higher polygenic risk score (PRS) was associated with a higher risk of earlier development of primary open-angle glaucoma (POAG) among patients with ocular hypertension (OHTN).1
This post hoc analysis of the Ocular Hypertension Treatment Study (OHTS), which involved more than 1000 participants, revealed that the associated factors remained independent of most ocular phenotypic risk factors, the patient’s genetically determined ancestry, and the follow-up phase of approximately 20 years.
“We demonstrated that high POAG PRS, to our knowledge, meta-analysis of data from the largest genome-wide association study (GWAS), was associated with an increased risk of POAG conversion among patients with OHTN,” the team wrote. investigation. , led by Nazlee Zebardast, MD, MD, Massachusetts Eye and Ear, Harvard Medical School.
Identification of high-risk individuals and the need for therapeutic intervention is important to prevent glaucoma-related vision loss. POAG, a particularly hereditary disease, has been linked to 127 identified common risk variants.2 Each variant contains a small effect on POAG, but a PRS can provide a clinically useful measure of a patient’s aggregate genetic load.
A prediction model, including age, IOP, central corneal thickness (CCT), vertical cup-disc ratio (VCDR), and visual field pattern standard deviation (PSD), developed for POAG, was found feasible for risk stratification in the OHTS.3 The current analysis used genetic data available from the study to determine whether underlying genetic risk improves risk stratification outside of demographic factors and ocular biomarkers used in the prediction model.
The OHTS secondary analysis collected data from 22 US-based sites, with a median follow-up of 14 years. In the OHTS, participants were randomly assigned to receive topical IOP-lowering medication or close observation; After June 2002, all participants received medication. Among the original 1,636 participants enrolled in OHTS, 1,077 were enrolled in an ancillary genetic study and 1,009 met criteria for the current analysis.
Zebardast and colleagues calculated a POAG PRS using summary statistics from the largest known cross-ancestry POAG GWAS meta-analysis. The PRS was trained using 8,813,496 variants from 449,186 cross-ancestry participants in the UK Biobank. Participants were grouped into deciles or tertiles of low risk, intermediate risk, and high risk according to the PRS. z scores
Among the 1,009 participants included for analysis, 562 (55.7%) were women and the mean age was 55.9 years. Upon analysis, the researchers found that the mean PRS was significantly higher for POAG converters (0.24) compared to non-converters (–0.12) (difference, 0.36; 95% CI, 0. 24 – 0.49; P <.001).
Further analysis showed that the risk of POAG increased by 1.36% (95% CI: 1.08 – 1.64) with each higher PRS decile, with linear regression showing an increase of 9, 52% (95% CI: 7.09 – 11.95) in the lowest PRS decile at 21.81. % (95% CI, 19.37 – 24.25) in the highest decile. When stratified by ancestry, a comparison of the low- and high-risk PRS tertile demonstrated a 2.0-fold increase in POAG risk over 20 years for individuals of European and African ancestry.
A subcohort randomized to delayed OHTN treatment showed that each decrease in PRS decile was associated with a 0.52-year (95% CI, 0.01 – 1.03) decrease in age at diagnosis of POAG (P = .047). The early treatment group did not have a significant linear association between PRS and age at POAG diagnosis.
Furthermore, the prediction models were found to be significantly improved with the inclusion of PRS as a covariate (C-index, 0.77), compared to the OHTS reference model (C-index, 0.75) (P <.001). Each PRS higher by 1 SD increased the 20-year risk of POAG by 25% (hazard ratio [HR], 1.25; 95% CI, 1.13 - 1.44) for the appearance of POAG.
Zebardast and colleagues noted that the prediction models showed an improvement in predicting the occurrence of POAG with the addition of PRS, but the absolute increase in performance may be less than expected at baseline.
“As PRS presents a constant level of risk throughout life, its predictive power is likely greater at earlier clinical stages and at a younger age before the development of phenotypic markers,” they wrote.
References
- Singh RK, Zhao Y, Elze T, et al. Polygenic risk scores for glaucoma occurrence in the ocular hypertension treatment study. JAMA Ophthalmol. Published online March 14, 2024. doi:10.1001/jamaophthalmol.2024.0151
- Gharahkhani P, Jorgenson E, Hysi P, et al. Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effects across ancestries. national commune. 2021;12(1):1258. Published February 24, 2021. doi:10.1038/s41467-020-20851-4
- Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: A randomized trial finds that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Ophthalmol Arch. 2002;120(6):701-830. doi:10.1001/archopht.120.6.701