Dataset Information

Glaucoma Risk Alleles in the Ocular Hypertension Treatment Study.

ABSTRACT: PURPOSE:Primary open-angle glaucoma (POAG) is a major cause of blindness and visual disability. Several genetic risk factors for POAG and optic nerve features have been identified. We measured the relative risk for glaucoma that these factors contribute to participants in the Ocular Hypertension Treatment Study (OHTS). DESIGN:Comparative series. PARTICIPANTS:One thousand fifty-seven of 1636 participants (65%) of the OHTS were enrolled in this genetics ancillary study. METHODS:Samples of DNA were available from 1057 OHTS participants. Of these, 209 developed POAG (cases) and 848 did not develop glaucoma (controls) between 1994 and 2009. The frequencies of 13 risk alleles previously associated with POAG or with optic disc features in other cohorts were compared between POAG cases and controls in the OHTS cohort using analyses of variance. The 2 largest subgroups, non-Hispanic whites (n = 752; 70.7%) and blacks (n = 249, 23.7%), also were analyzed separately. The probability of glaucoma developing over the course of the OHTS was compared between participants stratified for transmembrane and coiled-coil domains 1 (TMCO1) risk alleles using Kaplan-Meier and Cox proportional hazards analyses. MAIN OUTCOME MEASURES:Association of POAG with known genetic factors. RESULTS:No association was detected between the known POAG risk alleles when the OHTS cohort was examined as a whole. However, in the subgroup of non-Hispanic whites, allele frequencies at the TMCO1 locus were statistically different between cases and controls (P = 0.00028). By 13 years, non-Hispanic white participants with TMCO1 risk alleles had a 12% higher cumulative frequency of glaucoma developing than participants with no TMCO1 risk alleles. Moreover, the Cox proportional hazard analysis demonstrated that TMCO1 alleles increased relative risk comparable with that of some previously analyzed clinical measures (i.e., intraocular pressure). CONCLUSIONS:The size of the OHTS cohort and its composition of 2 large racial subgroups may limit its power to detect some glaucoma risk factors. However, TMCO1 genotype was found to increase the risk of glaucoma developing among non-Hispanic whites, the largest racial subgroup in the OHTS cohort, at a magnitude similar to clinical predictors of disease that long have been associated with glaucoma.

SUBMITTER: Scheetz TE

PROVIDER: S-EPMC5121091 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Glaucoma Risk Alleles in the Ocular Hypertension Treatment Study.

Scheetz Todd E TE Faga Ben B Ortega Lizette L Roos Ben R BR Gordon Mae O MO Kass Michael A MA Wang Kai K Fingert John H JH

Ophthalmology 20161001 12

<h4>Purpose</h4>Primary open-angle glaucoma (POAG) is a major cause of blindness and visual disability. Several genetic risk factors for POAG and optic nerve features have been identified. We measured the relative risk for glaucoma that these factors contribute to participants in the Ocular Hypertension Treatment Study (OHTS).<h4>Design</h4>Comparative series.<h4>Participants</h4>One thousand fifty-seven of 1636 participants (65%) of the OHTS were enrolled in this genetics ancillary study.<h4>Me ...[more]

PMID: 27707548

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Project description:Objective or purposePrimary open-angle glaucoma (POAG) is a highly heritable disease with 127 identified risk loci. Polygenic risks score (PRS) offers a measure of aggregate genetic burden. In this study, we assess whether PRS improves risk stratification in patients with ocular hypertension.DesignA post-hoc analysis of the Ocular Hypertension Treatment Study (OHTS) data.Setting participants and/or controls1636 participants were followed from 1994 to 2020 across 22 sites. The PRS was computed for 1009 OHTS participants using summary statistics from largest cross-ancestry POAG metanalysis with weights trained using 8,813,496 variants from 488,395 participants in the UK Biobank.Methods interventions or testingSurvival regression analysis, with endpoint as development of POAG, predicted disease onset from PRS incorporating baseline covariates.Main outcomes and measuresOutcome measures were hazard ratios for POAG onset. Concordance index and time-dependent AUC were used to compare the predictive performance of multivariable Cox-Proportional Hazards models.ResultsMean PRS was significantly higher for POAG-converters (0.24 ± 0.95) than for non-converters (-0.12 ± 1.00) (p < 0.01). POAG risk increased 1.36% with each higher PRS decile, with conversion ranging from 9.5% in the lowest PRS decile to 21.8% in the highest decile. Comparison of low- and high-risk PRS tertiles showed a 1.8-fold increase in 20-year POAG risk for participants of European and African ancestries (p<0.01). In the subgroup randomized to delayed treatment, each increase in PRS decile was associated with a 0.52-year decrease in age at diagnosis, (p=0.05). No significant linear relationship between PRS and age at POAG diagnosis was present in the early treatment group. Prediction models significantly improved with the addition of PRS as a covariate (C-index = 0.77) compared to OHTS baseline model (C-index=0.75) (p<0.01). One standard deviation higher PRS conferred a mean hazard ratio of 1.25 (CI=[1.13, 1.44]) for POAG onset.ConclusionsHigher PRS is associated with increased risk for, and earlier development of POAG in patients with ocular hypertension. Early treatment may mitigate the risk from high genetic burden, delaying clinically detectable disease by up to 5.2 years. The inclusion of a PRS improves the prediction of POAG onset.

Project description:ImportanceAutomated deep learning (DL) analyses of fundus photographs potentially can reduce the cost and improve the efficiency of reading center assessment of end points in clinical trials.ObjectiveTo investigate the diagnostic accuracy of DL algorithms trained on fundus photographs from the Ocular Hypertension Treatment Study (OHTS) to detect primary open-angle glaucoma (POAG).Design, setting, and participantsIn this diagnostic study, 1636 OHTS participants from 22 sites with a mean (range) follow-up of 10.7 (0-14.3) years. A total of 66 715 photographs from 3272 eyes were used to train and test a ResNet-50 model to detect the OHTS Endpoint Committee POAG determination based on optic disc (287 eyes, 3502 photographs) and/or visual field (198 eyes, 2300 visual fields) changes. Three independent test sets were used to evaluate the generalizability of the model.Main outcomes and measuresAreas under the receiver operating characteristic curve (AUROC) and sensitivities at fixed specificities were calculated to compare model performance. Evaluation of false-positive rates was used to determine whether the DL model detected POAG before the OHTS Endpoint Committee POAG determination.ResultsA total of 1147 participants were included in the training set (661 [57.6%] female; mean age, 57.2 years; 95% CI, 56.6-57.8), 167 in the validation set (97 [58.1%] female; mean age, 57.1 years; 95% CI, 55.6-58.7), and 322 in the test set (173 [53.7%] female; mean age, 57.2 years; 95% CI, 56.1-58.2). The DL model achieved an AUROC of 0.88 (95% CI, 0.82-0.92) for the OHTS Endpoint Committee determination of optic disc or VF changes. For the OHTS end points based on optic disc changes or visual field changes, AUROCs were 0.91 (95% CI, 0.88-0.94) and 0.86 (95% CI, 0.76-0.93), respectively. False-positive rates (at 90% specificity) were higher in photographs of eyes that later developed POAG by disc or visual field (27.5% [56 of 204]) compared with eyes that did not develop POAG (11.4% [50 of 440]) during follow-up. The diagnostic accuracy of the DL model developed on the optic disc end point applied to 3 independent data sets was lower, with AUROCs ranging from 0.74 (95% CI, 0.70-0.77) to 0.79 (95% CI, 0.78-0.81).Conclusions and relevanceThe model's high diagnostic accuracy using OHTS photographs suggests that DL has the potential to standardize and automate POAG determination for clinical trials and management. In addition, the higher false-positive rate in early photographs of eyes that later developed POAG suggests that DL models detected POAG in some eyes earlier than the OHTS Endpoint Committee, reflecting the OHTS design that emphasized a high specificity for POAG determination by requiring a clinically significant change from baseline.

Project description:In an elegant example of bench-to-bedside research, a hypothesis that cells in the outflow pathway actively regulate conventional outflow resistance was proposed in the 1990s and systematically pursued, exposing novel cellular and molecular mechanisms of intraocular pressure (IOP) regulation. The critical discovery that pharmacologic manipulation of the cytoskeleton of outflow pathway cells decreased outflow resistance placed a spotlight on the Rho kinase pathway that was known to regulate the cytoskeleton. Ultimately, a search for Rho kinase inhibitors led to the discovery of several molecules of therapeutic interest, leaving us today with 2 new ocular hypotensive agents approved for clinical use: ripasudil in Japan and netarsudil in the United States. These represent members of the first new class of clinically useful ocular hypotensive agents since the US Food and Drug Administration approval of latanoprost in 1996. The development of Rho kinase inhibitors as a class of medications to lower IOP in patients with glaucoma and ocular hypertension represents a triumph in translational research. Rho kinase inhibitors are effective alone or when combined with other known ocular hypotensive medications. They also offer the possibility of neuroprotective activity, a favorable impact on ocular blood flow, and even an antifibrotic effect that may prove useful in conventional glaucoma surgery. Local adverse effects, however, including conjunctival hyperemia, subconjunctival hemorrhages, and cornea verticillata, are common. Development of Rho kinase inhibitors targeted to the cells of the outflow pathway and the retina may allow these agents to have even greater clinical impact. The objectives of this review are to describe the basic science underlying the development of Rho kinase inhibitors as a therapy to lower IOP and to summarize the results of the clinical studies reported to date. The neuroprotective and vasoactive properties of Rho kinase inhibitors, as well as the antifibrotic properties, of these agents are reviewed in the context of their possible role in the medical and surgical treatment of glaucoma.

Project description:BACKGROUND:Both glaucoma and obstructive sleep apnea (OSA) are widespread diseases. OSA may presumably partly cause or worsen glaucoma, although the etiopathogenesis is unclear. Here we analyze for the first time the possible association between different glaucoma phenotypes and OSA. METHODS:110 patients (47 females, 63 males; median age 64.3?years, median BMI 26.62?kg/m2) with suspected glaucoma and without any prior diagnosis of OSA were prospectively studied by one-night home sleep apnea testing (HSAT), 101 of the patients were analyzed. HSAT parameters, like apnea hypopnea index (AHI) and oxygen desaturation index as well as opthalmological parameters like intraocular pressure (IOP) and mean defect depth (MD) were collected. Moreover, HSAT results were compared across four phenotypic groups: primary open angle glaucoma (POAG), low-tension-glaucoma (LTG), ocular hypertension (OH), and controls. RESULTS:There was no strong correlation between IOP or MD and AHI. BMI, age and gender did not differ between groups. Significant differences between POAG and LTG were found for all HSAT parameters. The AHI showed the most prominent group difference (Wilcoxon-Kruskal-Wallis rank sum test was highly significant with chi2?=?22, df?=?3 p?<?0.0001) with severely lower event rates in the LTG (9.45/h) compared to POAG (22.7/h) and controls (21.9/h; p?<?0.0001 and 0.02, respectively). Highly significant differences were found between the four groups regarding AHI (Chi2?=?22, df?=?3, p?<?0.0001) with significantly lower events per hour in the LTG compared to POAG (Hodges-Lehmann?=?-?13.8, 95% CI (-?18.6 - -?8.8; p?<?0.0001) and to controls (Hodges-Lehmann?=?12.1, 95% CI -19.9 - -?2.4; p?<?0.02). Severe and moderate OSA was more prevalent in POAG (69.8%) and OH (33.3%) than in LTG (9%). The effect of the glaucoma phenotype on the AHI was more prominent in females (p?=?0.0006) than in males (p?=?0.011). CONCLUSION:Although physical endpoints, such as MD and IOP, do not correlate with AHI, there was a strong correlation between the POAG and OH clinical glaucoma phenotypes and the AHI. Further studies should investigate the necessity to test routine screening for OSA by HSAT in patients with diagnosed POAG and OH. Besides, some characteristics of LTG differed widely from other glaucoma types and controls. LTG patients had a significantly lower rate of OSA compared to other glaucoma types and even controls. This might be due to a different pathogenesis of LTG. TRIAL REGISTRATION:Retrospectively registered at DRKS ( nr. S00021201 ) on April 9th 2020.

Dataset Information

Glaucoma Risk Alleles in the Ocular Hypertension Treatment Study.

Publications

Glaucoma Risk Alleles in the Ocular Hypertension Treatment Study.

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