A polygenic risk score predicts intraocular pressure fluctuation and readings outside office hours as measured by home tonometry

Abstract

Purpose : Investigate the association between genetic markers of high intraocular pressure (IOP) using a validated IOP polygneic risk score (IOP-PRS) and 24-hour IOP measurements.

Methods : In this cross-sectional study, 207 participants with suspected or established primary open angle glaucoma (POAG) were recruited from the PROGRESSA study and trained to use the Icare HOME tonometer (Icare Finland Oy) to measure IOP four times a day for 4 days. Unreliable measurements were systematically excluded. A minimum of 3 reliable measurements per day for at least 2 days was required. We calculated the mean and maximum IOP during the study period and grouped measurements occurring within and outside office hours, the early morning IOP, and IOP fluctuation: the standard deviation of all measurements. Using published IOP genome-wide association study summary statistics from 133,492 individuals, we developed a PRS derived solely from IOP associated variants at genome-threshold. We used a linear regression model adjusting for central corneal thickness for analysis to investigate associations between the IOP-PRS and the 24-hour IOP parameters.

Results : 151 participants had sufficient reliable measurements for analysis. There was a linear dose-response relationship between the IOP PRS and the mean and maximum diurnal IOP (Figure). The IOP-PRS was most strongly correlated with outside office hours maximum IOP (P = 0.001) and the early morning IOP (P = 0.002), with participants in the highest PRS quintile having IOP on average 3.8 mmHg (standard error = 1.4) higher than the lowest quintile (Figure). The PRS also correlated with greater short-term IOP fluctuation (p = 0.032). The PRS explained 14.5% of the mean IOP variance.

Conclusions : Genes acting via IOP-mediated pathways predict a higher outside office hours IOP, early morning IOP, and a greater short-term IOP fluctuations. These parameters have previously been associted with glaucoma progression, and are hard to measure in the clinic. An IOP PRS may be useful for stratifying progression risk of probable or established POAG patients beyond the snapshot of IOP measured in the clinic.

This is a 2020 ARVO Annual Meeting abstract.

 

Box plot comparison of (A) the mean IOP measured outside office hours, and (B) the peak early morning IOP (5AM - 9AM) between three groups (quintile based) of IOP-derived genetic risk score (n = 152; linear regression P = 0.01 for both).