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The mechanical properties of sclera play an important role in ocular functions, protection, and disease. Modulating the sclera's properties by exogenous crosslinking offers a way to expand the tissue's range of properties for study of the possible influences on the eye's behavior and diseases such as glaucoma and myopia. The focus of this work was to evaluate the effects of genipin crosslinking targeting the porcine perilimbal sclera (PLS) since the stiffness of this tissue was previously found in a number of studies to influence the eye's intraocular pressure (IOP). The work includes experiments on tensile test specimens and whole globes. The specimen tests showed decreased strain-rate dependence and increased relaxation stress due to the cross-linker. Whole globe perfusion experiments demonstrated that eyes treated with genipin in the perilimbal region had increased IOPs compared to the control globes. Migration of the cross-linker from the target tissue to other tissues is a confounding factor in whole globe, biomechanical measurements, with crosslinking. A novel quantitative genipin assay of the trabecular meshwork (TM) was developed to exclude globes where the TM was inadvertently crosslinked. The perfusion study, therefore, suggests that elevated stiffness of the PLS can significantly increase IOP apart from effects of the TM in the porcine eye. These results demonstrate the importance of PLS biomechanics in aqueous outflow regulation and support additional investigations into the distal outflow pathways as a key source of outflow resistance.

Understanding aqueous outflow resistance at the level of aqueous veins has been a challenge to the management of glaucoma. This study investigated resolving the anatomies of aqueous veins and the textures of surrounding sclera using photoacoustic microscopy (PAM). A dual wavelength PAM system was established and validated using imaging phantoms, porcine and human globes perfused with an optical contrast agent ex vivo . The system shows lateral resolution of 8.23 µm and 4.70 µm at 1200 nm and 532 nm, respectively, and an axial resolution of 27.6 µm. The system is able to separately distinguish the aqueous veins and the sclera with high contrast in full circumference of the porcine and human globes., Competing Interests: The authors declare no conflicts of interest., (© 2023 Optica Publishing Group.)

Purpose: To improve understanding of intraocular pressure (IOP) and its variance, this project identifies systemic and ocular characteristics of healthy eyes of adult volunteers including IOP variation, ocular biometrics, and aqueous humor dynamics (AHDs). These data serve as baseline controls for further studies from the Eye Dynamics and Engineering Network (EDEN) Consortium., Design: Multicenter open-label clinical trial in healthy adults randomized to 1 week treatment with 2 approved glaucoma drugs in a crossover design., Participants: Among 135 healthy participants, 122 participants (aged 55.2 ± 8.8 years; 92 females, 30 males) completed the protocol., Methods: Participants from the University of Michigan, Mayo Clinic, and University of Nebraska Medical Center underwent measurements of ocular biometrics, AHD, and IOP using 4 tonometers. Intraocular pressure data during 3 study visits without glaucoma medications were used in the analysis. The PhenX Toolkit survey acquired standardized data on medical history, surgical history, medications, smoking and alcohol exposures, and physical measures., Main Outcome Measures: The variability of IOP measurements within eyes was assessed as visit-to-visit IOP variation, within-visit IOP variation, and within-visit positional IOP variation. The concordance (or correlation) between eyes was also assessed., Results: Average positional change of > 4.7 mmHg was detected with a range of 0.5-11.0 mmHg. Pearson correlation of IOP between eyes within a visit was 0.87 (95% confidence interval [CI], 0.82-0.91) for Goldmann applanation tonometry, 0.91 (95% CI, 0.88-0.94) for Icare rebound tonometry, and 0.91 (95% CI, 0.88-0.94) for pneumatonometry. There was a 4% to 12% asymmetric fluctuation of 3 mmHg or more between eyes between visits using rebound tonometry, 9% with Goldmann applanation tonometry, and 3% to 4% by pneumotonometry. The coefficient of variation between visits for the same eye ranged from 11.2% to 12.9% for pneumatonometry, from 13.6% to 17.4% for rebound tonometry, and 15.8% to 16.2% for Goldmann applanation tonometry., Conclusions: The current study from the EDEN Consortium describes measurement methods and data analyses with emphasis on IOP variability. Future papers will focus on changes in ocular biometrics and AHD with timolol or latanoprost treatment., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine the visual outcomes and effectiveness of glaucoma surgeries in congenital ectropion uvea., Design: Retrospective interventional case series., Methods: Surgeries and examination findings were collected on 11 eyes of 8 patients with congenital ectropion uvea at 2 academic sites from 2001 to 2021. Visual outcomes, surgical success (intraocular pressure [IOP]: 5-20 mm Hg, no additional IOP-lowering surgery, no visually devastating complications), and survival rates of glaucoma surgeries were assessed., Results: Glaucoma in bilateral congenital ectropion uvea was diagnosed at an earlier age (0.02 ± 0.01 years) than unilateral disease (8.9 ± 5.3 years, P = .002). All eyes required glaucoma surgery with 91% requiring multiple surgeries (3.5 ± 2.1, median 3 surgeries per eye). Trabeculotomy (8 eyes) showed 13% success rate. Although none of the 4 eyes that underwent trabeculectomy with mitomycin C needed repeat trabeculectomy, glaucoma drainage device placement, or cycloablation, 75% required bleb revision surgery. Glaucoma drainage devices (7 eyes) had a 57% success rate with 3 eyes requiring subsequent cycloablation (2) or trabeculectomy (1). At the final follow-up (8.5 ± 6.6 years, median: 7.9 years), all eyes achieved IOP control, and IOP was lower compared with presentation (13.2 ± 2.6 mm Hg vs 32.9 ± 9.9 mm Hg, P = .002). Best-corrected logarithm of the minimum angle of resolution visual acuity at the final follow-up was 0.2 ± 0.2., Conclusions: Bilateral congenital ectropion uvea presents with glaucoma earlier than unilateral cases. The majority of eyes required multiple glaucoma surgeries. Angle surgery was less effective than trabeculectomy or glaucoma drainage devices. IOP control was obtained in all eyes and affected individuals had good visual outcomes., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in developed countries. Identifying patients at high risk of progression to late AMD, the sight-threatening stage, is critical for clinical actions, including medical interventions and timely monitoring. Recently, deep-learning-based models have been developed and achieved superior performance for late AMD prediction. However, most existing methods are limited to the color fundus photography (CFP) from the last ophthalmic visit and do not include the longitudinal CFP history and AMD progression during the previous years' visits. Patients in different AMD subphenotypes might have various speeds of progression in different stages of AMD disease. Capturing the progression information during the previous years' visits might be useful for the prediction of AMD progression. In this work, we propose a C ontrastive- A ttention-based T ime-aware L ong S hort- T erm M emory network ( CAT-LSTM ) to predict AMD progression. First, we adopt a convolutional neural network (CNN) model with a contrastive attention module (CA) to extract abnormal features from CFPs. Then we utilize a time-aware LSTM (T-LSTM) to model the patients' history and consider the AMD progression information. The combination of disease progression, genotype information, demographics, and CFP features are sent to T-LSTM. Moreover, we leverage an auto-encoder to represent temporal CFP sequences as fixed-size vectors and adopt k-means to cluster them into subphenotypes. We evaluate the proposed model based on real-world datasets, and the results show that the proposed model could achieve 0.925 on area under the receiver operating characteristic (AUROC) for 5-year late-AMD prediction and outperforms the state-of-the-art methods by more than 3%, which demonstrates the effectiveness of the proposed CAT-LSTM. After analyzing patient representation learned by an auto-encoder, we identify 3 novel subphenotypes of AMD patients with different characteristics and progression rates to late AMD, paving the way for improved personalization of AMD management. The code of CAT-LSTM can be found at GitHub.

Background: Singleton-Merten syndrome (SGMRT) is a rare immunogenetic disorder that variably features juvenile open-angle glaucoma (JOAG), psoriasiform skin rash, aortic calcifications and skeletal and dental dysplasia. Few families have been described and the genotypic and phenotypic spectrum is poorly defined, with variants in DDX58 (DExD/H-box helicase 58) being one of two identified causes, classified as SGMRT2., Methods: Families underwent deep systemic phenotyping and exome sequencing. Functional characterisation with in vitro luciferase assays and in vivo interferon signature using bulk and single cell RNA sequencing was performed., Results: We have identified a novel DDX58 variant c.1529A>T p.(Glu510Val) that segregates with disease in two families with SGMRT2. Patients in these families have widely variable phenotypic features and different ethnic background, with some being severely affected by systemic features and others solely with glaucoma. JOAG was present in all individuals affected with the syndrome. Furthermore, detailed evaluation of skin rash in one patient revealed sparse inflammatory infiltrates in a unique distribution. Functional analysis showed that the DDX58 variant is a dominant gain-of-function activator of interferon pathways in the absence of exogenous RNA ligands. Single cell RNA sequencing of patient lesional skin revealed a cellular activation of interferon-stimulated gene expression in keratinocytes and fibroblasts but not in neighbouring healthy skin., Conclusions: These results expand the genotypic spectrum of DDX58-associated disease, provide the first detailed description of ocular and dermatological phenotypes, expand our understanding of the molecular pathogenesis of this condition and provide a platform for testing response to therapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The purpose of this study was to investigate the mechanism of potential droplet formation in response to air puff deformation with two noncontact tonometers (NCTs)., Methods: Twenty healthy volunteers were examined using two NCTs, Ocular Response Analyzer and Corvis ST, and two contact tonometers, iCare and Tono-Pen. High-speed videos of the tear film response were captured with at spatial resolution of 20 microns/pixel at 2400 fps. Droplet size, droplet velocity, distance between air puff impact location, and the tear meniscus-lid margin were characterized., Results: One subject was excluded due to technical issues. Droplets were detected only in tests with instilled eye drop. Videos showed the tear film rolls away from the apex while remaining adherent to the ocular surface due to the tendency of the fluid to remain attached to a solid surface explained by the Coanda effect. Twelve out of 38 videos with an eye drop administration showed droplet formation. Only one resulted in droplets with predominantly forward motion, which had the shortest distance between air puff impact location and lower meniscus. This distance on average was 5.9 ± 1.1 mm. The average droplet size was 500 ± 200 µm., Conclusions: Results indicate no droplet formation under typical clinical setting. Hence, standard clinical use of NCT tests is not expected to cause droplets. NCT testing with eye drop administration showed droplet formation at the inferior eyelid boundary, which acts as a barrier and interrupts tear flow., Translational Relevance: Study of tear film interaction with NCT air puff shows that these tonometers are not expected to cause droplet formation in standard use and that if external drops are required, both eyelids should be held if patients need assistance to maintain open eyes to avoid droplets with predominantly forward motion.

Purpose: To characterize the effects of timolol and latanoprost on calculated ocular perfusion pressure (OPP) in a multicenter, prospective, crossover-design study. Methods: Nonglaucomatous volunteers were evaluated at baseline, after 1 week of timolol 0.5% dosed twice daily, and after 1 week of latanoprost 0.005% dosed nightly (randomized treatment order; 6-week washout period). Pneumatonometric intraocular pressure (IOP) and brachial blood pressure (BP) were evaluated at each visit. Using 3 commonly used equations, OPP was calculated based on IOP and BP. The OPPs at each visit were compared by using linear mixed-effects models. Results: This analysis includes 121 participants (242 eyes; 75% female, 87% White, mean age 55 years). Mean OPP (standard deviation) calculated with mean arterial pressure was 46.8 (8.1) mmHg at baseline, 48.5 (7.9) mmHg with timolol ( P  = 0.005), and 49.6 mmHg (8.2) with latanoprost ( P  < 0.001). When compared with baseline, OPP calculated with diastolic BP was significantly increased with both timolol (1.3 mmHg) and latanoprost (3.1 mmHg). The OPP calculated with systolic BP was increased with latanoprost (2.8 mmHg) but decreased with timolol (-1.3 mmHg). Timolol reduced systolic BP by 3.2 mmHg. Compared with timolol, latanoprost conferred greater increases in OPP calculated with both systolic and diastolic BP compared with baseline; however, the difference in treatment effects on OPP calculated with mean arterial pressure was not significantly different ( P  = 0.068). Conclusion: In this crossover study of nonglaucomatous volunteers, latanoprost increased OPP. However, timolol's benefit to OPP may be limited in part because it reduced systolic BP. Clinical Trial Registration number: NCT01677507.

Background: In older adults, vision impairment (VI) is associated with worse cognitive function. However, the relationship between midlife vision and future cognitive function remains unknown., Methods: The Study of Women's Health Across the Nation, Michigan site, is a longitudinal cohort of midlife women aged 42-52 years at baseline. Presenting Titmus visual acuity (VA) in the better-seeing eye was assessed at baseline and categorized as no or mild VI (VA ≥20/60), or moderate or worse VI (VA <20/60). Cognitive function was measured 8 times over 15 years using the East Boston Memory Test immediate (EBMTi) and delayed (EBMTd) recall and the Digit Span Backwards (DSB) test. Linear mixed models with a random intercept and slope for age were constructed to detect associations between VI at baseline and future repeated measures of cognitive function, adjusting for age, race, education, financial strain, alcohol use, and tobacco use., Results: About 394 women aged 42-52 at baseline with a maximum follow-up of 20 years were included in this analysis. After covariate adjustment, moderate or worse VI was associated with lower EMBTi (β = -0.56, p = .012), EBMTd (β = -0.60, p = .009), and DSB (β = -0.84, p = .04). While we detected significant associations between VI and levels of cognitive function scores, rates of cognitive decline as individuals aged did not vary by VI status., Conclusion: Moderate or worse VI, assessed during midlife, was associated with lower scores on measures of cognitive function over a 15-year period during which women transitioned from midlife to older adulthood., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A method motivated by the eye's aqueous veins is described for the imaging and strain calculation within soft biological tissues. A challenge to the investigation of the biomechanics of the aqueous vein-perilimbal sclera tissue complex is resolution of tissue deformations as a function of intraocular pressure and the subsequent calculation of strain (a normalized measure of deformation). The method involves perfusion of the eye with a contrast agent during conduction of non-invasive, optical resolution photoacoustic microscopy. This imaging technique permits three-dimensional displacement measurements of tracked points on the inner walls of the veins which are used in a finite element model to determine the corresponding strains. The methods are validated against two standard strain measurement methods. Representative porcine globe perfusion experiments are presented that demonstrate the power of the method to determine complex strain fields in the veins dependent on intraocular pressure as well as vein anatomy. In these cases, veins are observed to move radially outward during increases in intraocular pressure and to possess significant spatial strain variation, possibly influenced by their branching patterns. To the authors' knowledge, these are the only such quantitative, data driven, calculations of the aqueous vein strains available in the open literature., (© 2021. The Author(s).)

Objective: Poor vision affects physical health but the relationship with depressive symptoms among midlife adults (40-65 y), who often present with early stage vision impairment (VI), is not well understood. The goal of this study was to assess the impact of vision on depressive symptoms during midlife., Methods: The Michigan site of the Study of Women's Health Across the Nation conducted assessments of distance visual acuity at six consecutive, near-annual follow-up visits. At each visit, depressive symptoms (Center for Epidemiological Studies-Depression Scale) were assessed. VI was defined as mild (20/30-20/60) or moderate-severe (20/70 or worse). Multivariable logistic regression models using generalized estimating equations were used to assess the association of VI and reporting of depressive symptoms at the subsequent visit., Results: At analytic baseline, the mean age of participants (N = 226) was 50.0 years (standard deviation = 2.6). More than half (53.5%) of women had mild VI and 8.0% had moderate-severe VI. Adjusting for age, preexisting depressive symptoms, race, education, economic strain, body mass index, and smoking, participants with mild and moderate-severe VI had 68% (95% C (0.97-2.90)) and 2.55-fold (95% CI 1.13-5.75) higher odds of reporting depressive symptoms at their subsequent study visit as compared with women without VI. Further adjustment for diabetes, hypertension, and osteoarthritis attenuated the estimates and the associations were no longer statistically significant., Conclusion: VI was associated with increased odds of future depressive symptoms among mid-life women. Timely detection and appropriate correction of VI may be important to consider in maintaining the mental health status of midlife women., Competing Interests: Financial disclosure/conflicts of interest: D.C.M. receives funding from Applied Genetic Technologies Corporation, ClinReg Consulting, ONL Therapeutics, Inc, and Editas Medicine, Inc. S.E.M. receives funding from the NIH for unrelated research, NSF for unrelated research; and has received industry support for glaucoma pharmacology trials while at University of Michigan (Allergan) and book royalties for Shields Textbook of Glaucoma, 6th ed. The other authors have nothing to disclose., (Copyright © 2021 by The North American Menopause Society.)

Purpose: To assess ocular rigidity using dynamic optical coherence tomography (OCT) videos in glaucomatous and healthy subjects, and to evaluate how ocular rigidity correlates with biomechanical and morphological characteristics of the human eye. Methods: Ocular rigidity was calculated using Friedenwald's empirical equation which estimates the change in intraocular pressure (IOP) produced by volumetric changes of the eye due to choroidal pulsations with each heartbeat. High-speed OCT video was utilized to non-invasively measure changes in choroidal volume through time-series analysis. A control-case study design was based on 23 healthy controls and 6 glaucoma cases. Multiple diagnostic modalities were performed during the same visit including Spectralis OCT for nerve head video, Pascal Dynamic Contour Tonometry for IOP and ocular pulse amplitude (OPA) measurement, Corvis ST for measuring dynamic biomechanical response, and Pentacam for morphological characterization. Results: Combining glaucoma and healthy cohorts ( n = 29), there were negative correlations between ocular rigidity and axial length (Pearson R = -0.53, p = 0.003), and between ocular rigidity and anterior chamber volume ( R = -0.64, p = 0.0002). There was a stronger positive correlation of ocular rigidity and scleral stiffness (i.e., stiffness parameter at the highest concavity [SP-HC]) ( R = 0.62, p = 0.0005) compared to ocular rigidity and corneal stiffness (i.e., stiffness parameter at the first applanation [SP-A1]) ( R = 0.41, p = 0.033). In addition, there was a positive correlation between ocular rigidity and the static pressure-volume ratio (P/V ratio) ( R = 0.72, p < 0.0001). Conclusions: Ocular rigidity was non-invasively assessed using OCT video and OPA in a clinic setting. The significant correlation of ocular rigidity with biomechanical parameters, SP-HC and P/V ratio, demonstrated the validity of the ocular rigidity measurement. Ocular rigidity is driven to a greater extent by scleral stiffness than corneal stiffness. These in vivo methods offer an important approach to investigate the role of ocular biomechanics in glaucoma., Competing Interests: SM holds a patent that is not related to this work and receives royalties from Wolters Kluwer Health that is not related to this work. CR is a consultant to OCULUS Optikgerate GmbH and Zeimer Ophthalmic Systems AG. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ma, Moroi and Roberts.)

Precis: The Michigan Screening and Intervention for Glaucoma and eye Health through Telemedicine (MI-SIGHT) program leverages community-engaged research, telemedicine, and health coaching to overcome key logistical and psychosocial barriers to improve glaucoma screening in underserved communities., Purpose: To describe the methodology of the implementation and evaluation of the MI-SIGHT Program., Methods: The MI-SIGHT Program uses community engagement, telemedicine, and health coaching to overcome key logistical and psychosocial barriers to glaucoma identification and care among underserved populations. The MI-SIGHT Program will be evaluated in 2 community clinics: Hamilton Community Health Network, a federally qualified health center in Flint, Michigan, and the Hope Clinic, a free clinic in Ypsilanti, Michigan. A Community Advisory Board including the research team and health care providers, administrators, and patients from both clinics will guide program implementation. An ophthalmic technician at the community clinics will conduct screening tests for glaucoma and eye disease. The data will be transmitted through electronic health record to be reviewed by an ophthalmologist who will make recommendations for follow-up care. The ophthalmic technician will conduct a return visit to fit low-or no-cost glasses, help arrange follow-up with an ophthalmologist, and provide education. Those diagnosed with glaucoma or suspected glaucoma will be randomized to standard education or personalized glaucoma education and coaching. Costs will be assessed., Results: The authors hypothesize that the MI-SIGHT Program will detect a higher prevalence rate of glaucoma than that found in the general population, improve upon presenting visual acuity, enhance vision-related quality of life, and demonstrate that personalized glaucoma education and coaching improve adherence to follow-up care., Conclusion: The MI-SIGHT Program may serve as a model for glaucoma screening and care in high-risk communities., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Phentolamine mesylate ophthalmic solution (PMOS), applied to the eye topically, was shown previously to have beneficial effects in patients with dim light vision disturbances (DLD), including decreased pupil diameter (PD), improved best-corrected distance visual acuity (BCDVA), as well as lower intraocular pressure (IOP). The ORION-1 trial evaluated the long-term safety and efficacy of PMOS in a glaucomatous, presbyopic population., Patients and Methods: In this randomized, double-masked, multi-center, placebo-controlled, multiple-dose Phase 2b trial, 39 patients with elevated IOP were randomized to receive one evening dose of study medication or placebo for 14 days. The primary outcome measure was mean change in diurnal IOP, and the key secondary outcome measures included changes in PD, distance-corrected near visual acuity (DCNVA), and conjunctival hyperemia., Results: Use of 1% PMOS did not lead to a statistically significant decrease in diurnal IOP compared to placebo ( P = 0.89) but trended toward a greater decrease in patients with lower IOP baselines. PMOS produced a statistically significant mean 20% PD reduction under both photopic and mesopic conditions that was sustained for 36 hours post-dosing. A statistically significant number of patients with PMOS compared to placebo demonstrated ≥1 line of improvement in photopic DCNVA at day 8 ( P = 0.0018), day 15 ( P = 0.0072), and day 16 ( P = 0.0163), with a trend for 2- and 3-line improvements at all time points. There was no statistical difference in conjunctival hyperemia compared to placebo., Conclusion: Although mean IOP was not lowered significantly, daily evening dosing of 1% PMOS was found to be well tolerated with no daytime conjunctival redness and demonstrated improvement in DCNVA with sustained PD reduction in a glaucomatous and presbyopic population. Smaller pupil size can have beneficial effects in improving symptoms of presbyopia and DLD, which will be the focus of further studies., Competing Interests: MPS, ARM, RMJ, KC, ATA, JEY, and SAK are or were employees, directors/officers, or paid consultants for Ocuphire Pharma. JSP, ESL, PMK, and MBM are on the medical advisory board for Ocuphire Pharma. PJH, HBD, MAA, RJSM, and SEM were principal investigators for this clinical trial funded by Ocuphire Pharma. CBS serves as Chief Medical Officer of Oculos Development Services, LLC, which was the contract research organization for this clinical trial. Dr Jay S Pepose reportspersonal fees from Acufocus, Kala Pharmaceuticals, Keeler, MG Therapeutics, Mimetogen Pharmaceuticals, Novartis, Ocunexis Therapeutics, Okogen, Stuart Pharmaceuticals, Sun Pharma, Thea Pharma, TearLab, and Ocuphire, outside the submitted work. Dr Robert J Smyth-Medina reports research study site funding from Ora. Dr Sayoko E Moroi reports grants from R01 EY022124 (PI Moroi), R21 EY030363 (MPI Musch + Moroi), R01 EY025752 (PI Komaromy), NSF 1,760,291 (MPI Argento + Moroi), Aerie Pharmaceuticals, Inc, Allergan, Ocuphire, Icare USA, Wolters Kluwer Health: Royalty for Shield’s Textbook of Glaucoma, grants from MCubed, outside the submitted work. Mr Alan R Meyer have patents US 9,789,088 B2, US 9,795,560 B2, and US 10,278,918 assigned to Ocuphire Pharma issued. Dr Konstantinos Charizanis reports a patent PCT/US2019/056324 pending. Dr Marguerite B McDonald reports personal fees from Allergan, Alcon, Bausch and Lomb, Eyevance, Novartis, Tarsus, Visus, Aperta, Ocusoft, OCULUS USA, DOMPE, BioTissue, BlephEx, Akorn, Quidel, ORCA Surgical, TearLab, J&J Vision, TearCare, NuLids, Ocuphire, STROMA, Hellas LTD, Sun Pharma, Avedro, Omeros, Scope, and Sight Sciences, during the conduct of the study; personal fees from Visus and Allergan, outside the submitted work. The authors indicated that they have no other conflicts of interest with regard to the content of this article., (© 2021 Pepose et al.)

Nanophthalmos is a rare condition defined by a small, structurally normal eye with resultant high hyperopia. While six genes have been implicated in this hereditary condition (MFRP, PRSS56, MYRF, TMEM98, CRB1,VMD2/BEST1), the relative contribution of these to nanophthalmos or to less severe high hyperopia (≥ + 5.50 spherical equivalent) has not been fully elucidated. We collected probands and families (n = 56) with high hyperopia or nanophthalmos (≤ 21.0 mm axial length). Of 53 families that passed quality control, plausible genetic diagnoses were identified in 10/53 (18.8%) by high-throughput panel or pooled exome sequencing. These include 1 TMEM98 family (1.9%), 5 MFRP families (9.4%), and 4 PRSS56 families (7.5%), with 4 additional families having single allelic hits in MFRP or PRSS56 (7.5%). A novel deleterious TMEM98 variant (NM&#95;015544.3, c.602G>C, p.(Arg201Pro)) segregated with disease in 4 affected members of a family. Multiple novel missense and frameshift variants in MFRP and PRSS56 were identified. PRSS56 families were more likely to have choroidal folds than other solved families, while MFRP families were more likely to have retinal degeneration. Together, this study defines the prevalence of nanophthalmos gene variants in high hyperopia and nanophthalmos and indicates that a large fraction of cases remain outside of single gene coding sequences.

Purpose: The purpose of this study was to evaluate the ability to screen for glaucoma using a Food Drug Administration (FDA) Class II diagnostic digital fundus photography system used for diabetic retinopathy screening (DRS)., Methods: All research participants underwent a comprehensive eye examination as well as non-mydriatic 45°single photograph retinal imaging centered on the macula. Optic nerve images within the 45° non-mydriatic and non-stereo DRS image were evaluated by two methods: 1) grading by three glaucoma specialists, and 2) a computer-aided automated segmentation system to determine the vertical cup-to-disc ratio (VCDR). Using VCDR from clinical assessment as gold standard, VCDR results from two methods were compared to that from clinical assessment. Inter-grader agreement was assessed by computing intraclass correlation coefficient (ICC). In addition, sensitivity and specificity were calculated., Results: Among 245 fundus photos, 166 images met quality specifications for analysis. Fifty images were not processed by the automated system due to the poor quality of the optic disc, and 29 images did not include the optic nerve head due to the patient movement during the photo acquisition. The ICC value for the VCDR between the gold standard clinical exam and the automated system was 0.41, indicating fair agreement. The ICC value between the three ophthalmologists and the gold standard was 0.51, 0.56, and 0.69, respectively, indicating fair to moderate agreement., Discussion: Assessing the VCDR on non-mydriatic and non-stereo DRS fundus photographs by either the computer-aided automated segmentation system or by glaucoma specialists showed similar fair to moderate agreement. In summary, optic nerve assessment for glaucoma from these 45° non-mydriatic and non-stereo DRS images is not yet suitable for tele-glaucoma screening., Competing Interests: Maria A Woodward reports grants from National Eye Institute, during the conduct of the study. Paula Anne Newman-Casey reports grants from the National Eye Institute, Career Development Award from Research to Prevent Blindness, during the conduct of the study. Dr Manjool M Shah reports personal fees from Allergan, nothing from Glaukos, nothing from Katena, outside the submitted work. Sayoko E Moroi reports grants from University of Michigan, during the conduct of the study; grants from NIH, nothing from Allergan, Royalties unrelated to this manuscript from Wolters Kluwer, outside the submitted work. The authors declare that they have no other actual or potential conflict of interests relevant to the content of this project., (© 2020 Almazroa et al.)

Purpose: Ultrasound biomicroscopy (UBM) has been used to characterize anterior segment dimensions in plateau iris configuration (PIC), but transverse measurements between the recesses of the ciliary sulcus (sulcus-to-sulcus diameter [STSD]) and the ciliary body processes (interplicata diameter [IPD]) have not been reported. We measured STSD and IPD and compared these among eyes with PIC, primary angle closure (PAC), and control eyes with open angles., Design: Retrospective, cross-sectional clinical study., Participants: Sixty-nine participants, 37 PIC, 13 PAC, and 19 controls., Methods: We searched our clinical UBM database for PAC and PIC cases. Controls were assembled by reviewing images obtained for surveillance of ocular surface lesions. Anterior segment measurements were performed using the UBM digital caliper tool. Robust-fit ANOVA identified among-group differences. Pairwise t tests were used to test the significance of between-group differences., Main Outcome Measures: Anterior chamber depth (ACD), angle opening distance (AOD), ciliary body area and thickness, iris area, horizontal and vertical STSD, and horizontal and vertical IPD., Results: Fifty-five left eyes were analyzed (30 PIC, 10 PAC, and 15 controls). ACD was smaller in PAC than in PIC and control eyes (P < 0.05 for PIC vs. PAC; P < 0.01 for control vs. PAC). Mean AOD was smaller in PIC than controls (P < 0.05) and smaller in PAC than PIC (P < 0.001). Vertical STSD was smaller in both PAC and PIC than controls (P = 0.04 for PIC vs. control; P < 0.01 for PAC vs. control). Horizontal STSD was smaller in PIC than controls (P = 0.02). Vertical IPD was smaller in PIC than controls (P = 0.04) and smaller in PAC than PIC eyes (P = 0.02). Horizontal IPD was smaller in PIC and PAC than controls (P = 0.03 for PIC vs. control; P < 0.01 for PAC vs. control)., Conclusions: STSD and IPD are narrower in PIC and PAC than in healthy eyes. Further studies that examine the ratio of white-to-white cornea diameter to the IPD may provide a mechanism for reported cases of in-the-bag uveitis-glaucoma-hyphema syndrome in PIC., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: The surgical management of glaucoma associated with Axenfeld-Rieger Syndrome (ARS) is poorly described in the literature. The goal of this study is to compare the effectiveness of various glaucoma surgeries on intraocular pressure (IOP) management in ARS., Methods: Retrospective cohort study at a university hospital-based practice of patients diagnosed with ARS between 1973 and 2018. Exclusion criterion was follow-up less than 1 year. The number of eyes with glaucoma (IOP ≥ 21 mmHg with corneal edema, Haabs striae, optic nerve cupping or buphthalmos) requiring surgery was determined. The success and survival rates of goniotomy, trabeculotomy±trabeculectomy (no antifibrotics), cycloablation, trabeculectomy with anti-fibrotics, and glaucoma drainage device placement were assessed. Success was defined as IOP of 5-20 mmHg and no additional IOP-lowering surgery or visually devastating complications. Kaplan-Meier survival curves and the Wilcoxon test were used for statistical analysis., Results: In 32 patients identified with ARS (median age at presentation 6.9 years, 0-58.7 years; median follow-up 5.4 years, 1.1-43.7 years), 23 (71.9%) patients were diagnosed with glaucoma at median age 6.3 years (0-57.9 years). In glaucomatous eyes (46 eyes), mean IOP at presentation was 21.8 ± 9.3 mmHg (median 20 mmHg, 4-45 mmHg) on 1.0 ± 1.6 glaucoma medications. Thirty-one eyes of 18 patients required glaucoma surgery with 2.2 ± 1.2 IOP-lowering surgeries per eye. Goniotomy (6 eyes) showed 43% success with 4.3 ± 3.9 years of IOP control. Trabeculotomy±trabeculectomy (6 eyes) had 17% success rate with 14.8 ± 12.7 years of IOP control. Trabeculectomy with anti-fibrotics (14 eyes) showed 57% success with 16.5 ± 13.5 years of IOP control. Ahmed© (FP7 or FP8) valve placement (8 eyes) had 25% success rate with 1.7 ± 1.9 years of IOP control. Baerveldt© (250 or 350) device placement (8 eyes) showed 70% success with 1.9 ± 2.3 years of IOP control. Cycloablation (4 eyes) had 33% success rate with 2.7 ± 3.5 years of IOP control. At final follow-up, mean IOP (12.6 ± 3.8 mmHg, median 11.8 mmHg, 7-19 mmHg) in glaucomatous eyes was significantly decreased (p < 0.0001), but there was no difference in number of glaucoma medications (1.6 ± 1.5, p = 0.1)., Conclusions: In our series, greater than 70% of patients with ARS have secondary glaucoma that often requires multiple surgeries. Trabeculectomy with anti-fibrotics and Baerveldt glaucoma drainage devices showed the greatest success in obtaining IOP control.

Importance: Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders., Objectives: To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma., Design, Settings, and Participants: A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma., Exposures: Genetic variants associated with primary open-angle glaucoma., Main Outcomes and Measures: Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data., Results: A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry., Conclusions and Relevance: In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies.

Purpose of Review: Approximately 10% of patients become blind despite using evidence-based guidelines developed from clinical trials and epidemiology studies. Our purpose is to review opportunities to decrease glaucoma-related blindness using the emerging principles of precision medicine., Recent Findings: The current review focuses on three topics: first, candidate biomarkers for angle-based surgeries, second, head-mounted display (HMD) technology for vision and testing, and third, glaucoma risk alleles discovered by genome-wide association studies. First, in angle-based surgeries, tracers injected into the anterior chamber or Schlemm's canal have allowed visualization of aqueous veins. We describe an innovative use of optical coherence tomography angiography to visualize aqueous veins in a case with 6-year successful outcome following catheter-based trabeculotomy. Second, HMD technology can augment perceived vision and can be used for perimetry testing. Third, developing genetic risk scores that characterize patients who are at highest risk for blindness is a priority. Such biomarker risk scores will integrate genome-wide association study-based risk alleles for glaucoma along with well known demographic and clinical risk factors., Summary: As we gain more knowledge, precision medicine will enable clinicians to decrease glaucoma-related blindness by providing more timely interventions to those patients who are at highest risk for progression to blindness. VIDEO ABSTRACT: http://links.lww.com/COOP/A29.

Purpose: To investigate the relationship between central corneal thickness (CCT) and diabetes disease severity among patients with diabetic peripheral neuropathy (DPN) compared with controls., Methods: In this cross-sectional study, 34 participants were examined. DPN status was assessed by clinical examination, nerve conduction studies, and quantitative sensory testing. All participants underwent comprehensive eye examination that included intraocular pressure measured by Goldmann applanation tonometry. CCT was measured by ultrasound pachymetry, and the thickness of corneal layers was assessed by corneal confocal microscopy. Association of CCT and DPN was examined using ANOVA., Results: Among the 34 participants, there were 9 controls, 16 patients with mild DPN, and 9 patients with severe DPN. CCT was significantly increased in the DPN groups compared with controls (P = 0.0003). Mean CCT among controls was 552.7 ± 29.2 μm compared with 583.4 ± 25.0 μm in the mild DPN group and 613.3 ± 28.8 μm in the severe DPN group. In addition, stromal thickness differed significantly between the 3 study groups (P = 0.045). Mean stromal thickness among controls was 439.5 ± 23.5 μm compared with 478.9 ± 37.5 μm in the mild DPN group and 494.5 ± 39.1 μm in the severe DPN group., Conclusions: This study demonstrates that CCT increases with DPN severity because of an increase in stromal thickness. CCT increase associated with DPN has important clinical implications including glaucoma progression, keratoconus susceptibility, and intraocular pressure assessment and should be accounted for when evaluating patients with diabetes.

Purpose: To evaluate biomechanical corneal properties in children with osteogenesis imperfecta (OI)., Methods: A prospective, observational, case-control study was conducted on children 6-19 years of age diagnosed with OI. Patients with OI and healthy control subjects underwent complete ophthalmic examinations. Additional tests included Ocular Response Analyzer (ORA) and ultrasonic pachymetry. Primary outcomes were central corneal thickness (CCT), corneal hysteresis (CH), and corneal resistance factor (CRF). Intraocular pressure (IOP) was measured directly by either iCare or Goldmann applanation and indirectly by the ORA (Goldmann-correlated and corneal-compensated IOP). Statistically significant differences between OI and control groups were determined using independent samples t test., Results: A total of 10 of 18 OI cases (mean age, 13 ± 4.37 years; 8 males) and 30 controls (mean age, 12.76 ± 2.62 years; 16 males) were able to complete the corneal biomechanics and pachymetry testing. Children with OI had decreased CH (8.5 ± 1.0 mm Hg vs 11.6 ± 1.2 mm Hg [P < 0.001]), CRF (9.0 ± 1.9 mm Hg vs 11.5 ± 1.5 [P < 0.001]) and CCT (449.8 ± 30.8 μm vs 568 ± 47.6 μm [P < 0.001]) compared to controls. The corneal-compensated IOP was significantly higher in OI cases (18.8 ± 3.1 mm Hg) than in controls (15.0 ± 1.6 mm Hg, P < 0.004), but there was no significant difference in Goldmann-correlated IOP (16.3 ± 4.2 mm Hg vs 15.8 ± 2.2 mm Hg)., Conclusions: Collagen defects in OI alter corneal structure and biomechanics. Children with OI have decreased CH, CRF, and CCT, resulting in IOPs that are likely higher than measured by tonometry. These corneal alterations are present at a young age in OI. Affected individuals should be routinely screened for glaucoma and corneal pathologies., (Copyright © 2018 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Purpose: Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk., Methods: We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG])., Results: In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations., Conclusions: Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.

Primary open-angle glaucoma (POAG) is the most common chronic optic neuropathy worldwide. Epidemiological studies show a robust positive relation between intraocular pressure (IOP) and POAG and modest positive association between IOP and blood pressure (BP), while the relation between BP and POAG is controversial. The International Glaucoma Genetics Consortium (n=27 558), the International Consortium on Blood Pressure (n=69 395), and the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (n=37 333), represent genome-wide data sets for IOP, BP traits and POAG, respectively. We formed genome-wide significant variant panels for IOP and diastolic BP and found a strong relation with POAG (odds ratio and 95% confidence interval: 1.18 (1.14-1.21), P=1.8 × 10 -27 ) for the former trait but no association for the latter (P=0.93). Next, we used linkage disequilibrium (LD) score regression, to provide genome-wide estimates of correlation between traits without the need for additional phenotyping. We also compared our genome-wide estimate of heritability between IOP and BP to an estimate based solely on direct measures of these traits in the Erasmus Rucphen Family (ERF; n=2519) study using Sequential Oligogenic Linkage Analysis Routines (SOLAR). LD score regression revealed high genetic correlation between IOP and POAG (48.5%, P=2.1 × 10 -5 ); however, genetic correlation between IOP and diastolic BP (P=0.86) and between diastolic BP and POAG (P=0.42) were negligible. Using SOLAR in the ERF study, we confirmed the minimal heritability between IOP and diastolic BP (P=0.63). Overall, IOP shares genetic basis with POAG, whereas BP has limited shared genetic correlation with IOP or POAG.

Purpose: Noncoding microRNAs (miRNAs) have been implicated in the pathogenesis of glaucoma. We aimed to identify common variants in miRNA coding genes (MIR) associated with primary open-angle glaucoma (POAG)., Methods: Using the NEIGHBORHOOD data set (3853 cases/33,480 controls with European ancestry), we first assessed the relation between 85 variants in 76 MIR genes and overall POAG. Subtype-specific analyses were performed in high-tension glaucoma (HTG) and normal-tension glaucoma subsets. Second, we examined the expression of miR-182, which was associated with POAG, in postmortem human ocular tissues (ciliary body, cornea, retina, and trabecular meshwork [TM]), using miRNA sequencing (miRNA-Seq) and droplet digital PCR (ddPCR). Third, miR-182 expression was also examined in human aqueous humor (AH) by using miRNA-Seq. Fourth, exosomes secreted from primary human TM cells were examined for miR-182 expression by using miRNA-Seq. Fifth, using ddPCR we compared miR-182 expression in AH between five HTG cases and five controls., Results: Only rs76481776 in MIR182 gene was associated with POAG after adjustment for multiple comparisons (odds ratio [OR] = 1.23, 95% confidence interval [CI]: 1.11-1.42, P = 0.0002). Subtype analysis indicated that the association was primarily in the HTG subset (OR = 1.26, 95% CI: 1.08-1.47, P = 0.004). The risk allele T has been associated with elevated miR-182 expression in vitro. Data from ddPCR and miRNA-Seq confirmed miR-182 expression in all examined ocular tissues and TM-derived exosomes. Interestingly, miR-182 expression in AH was 2-fold higher in HTG patients than nonglaucoma controls (P = 0.03) without controlling for medication treatment., Conclusions: Our integrative study is the first to associate rs76481776 with POAG via elevated miR-182 expression.

Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10(-11)) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10(-10)); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10(-10)). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.

Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from confirming strong evidence of association at CDKN2B-AS1 (rs2157719 [G], odds ratio [OR] = 0.71, P = 2.81 × 10(-33)), we observed one SNP showing significant association to POAG (CDC7-TGFBR3 rs1192415, ORG-allele = 1.13, Pmeta = 1.60 × 10(-8)). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis., (© The Author 2015. Published by Oxford University Press.)

Purpose: We examined the role of DNA copy number variants (CNVs) of known glaucoma genes in relation to primary open angle glaucoma (POAG)., Methods: Our study included DNA samples from two studies (NEIGHBOR and GLAUGEN). All the samples were genotyped with the Illumina Human660W&#95;Quad&#95;v1 BeadChip. After removing non-blood-derived and amplified DNA samples, we applied quality control steps based on the mean Log R Ratio and the mean B allele frequency. Subsequently, data from 3057 DNA samples (1599 cases and 1458 controls) were analyzed with PennCNV software. We defined CNVs as those ≥5 kilobases (kb) in size and interrogated by ≥5 consecutive probes. We further limited our investigation to CNVs in known POAG-related genes, including CDKN2B-AS1, TMCO1, SIX1/SIX6, CAV1/CAV2, the LRP12-ZFPM2 region, GAS7, ATOH7, FNDC3B, CYP1B1, MYOC, OPTN, WDR36, SRBD1, TBK1, and GALC., Results: Genomic duplications of CDKN2B-AS1 and TMCO1 were each found in a single case. Two cases carried duplications in the GAS7 region. Genomic deletions of SIX6 and ATOH7 were each identified in one case. One case carried a TBK1 deletion and another case carried a TBK1 duplication. No controls had duplications or deletions in these six genes. A single control had a duplication in the MYOC region. Deletions of GALC were observed in five cases and two controls., Conclusions: The CNV analysis of a large set of cases and controls revealed the presence of rare CNVs in known POAG susceptibility genes. Our data suggest that these rare CNVs may contribute to POAG pathogenesis and merit functional evaluation., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. Using genome-wide association single-nucleotide polymorphism data from the Glaucoma Genes and Environment study and National Eye Institute Glaucoma Human Genetics Collaboration comprising 3,108 cases and 3,430 controls, we assessed biologic pathways as annotated in the KEGG database for association with risk of POAG. After correction for genic overlap among pathways, we found 4 pathways, butanoate metabolism (hsa00650), hematopoietic cell lineage (hsa04640), lysine degradation (hsa00310) and basal transcription factors (hsa03022) related to POAG with permuted p < 0.001. In addition, the human leukocyte antigen (HLA) gene family was significantly associated with POAG (p < 0.001). In the POAG subset with normal-pressure glaucoma (NPG), the butanoate metabolism pathway was also significantly associated (p < 0.001) as well as the MAPK and Hedgehog signaling pathways (hsa04010 and hsa04340), glycosaminoglycan biosynthesis-heparan sulfate pathway (hsa00534) and the phenylalanine, tyrosine and tryptophan biosynthesis pathway (hsa0400). The butanoate metabolism pathway overall, and specifically the aspects of the pathway that contribute to GABA and acetyl-CoA metabolism, was the only pathway significantly associated with both POAG and NPG. Collectively these results implicate GABA and acetyl-CoA metabolism in glaucoma pathogenesis, and suggest new potential therapeutic targets.

Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene (P = 4.19 × 10(-8) for rs6445055), two on chromosome 9 (P = 2.80 × 10(-11) for rs2472493 near ABCA1 and P = 6.39 × 10(-11) for rs8176693 within ABO) and one on chromosome 11p11.2 (best P = 1.04 × 10(-11) for rs747782). Separate meta-analyses of 4 independent POAG cohorts, totaling 4,284 cases and 95,560 controls, showed that 3 of these loci for IOP were also associated with POAG.

Purpose: The CAV1/CAV2 (caveolin 1 and caveolin 2) genomic region previously was associated with primary open-angle glaucoma (POAG), although replication among independent studies has been variable. The aim of this study was to assess the association between CAV1/CAV2 single nucleotide polymorphisms (SNPs) and POAG in a large case-control dataset and to explore associations by gender and pattern of visual field (VF) loss further., Design: Case-control study., Participants: We analyzed 2 large POAG data sets: the Glaucoma Genes and Environment (GLAUGEN) study (976 cases, 1140 controls) and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium (2132 cases, 2290 controls)., Methods: We studied the association between 70 SNPs located within the CAV1/CAV2 genomic region in the GLAUGEN and NEIGHBOR studies, both genotyped on the Illumina Human 660WQuadv1C BeadChip array and imputed with the Markov Chain Haplotyping algorithm using the HapMap 3 reference panel. We used logistic regression models of POAG in the overall population and separated by gender, as well as by POAG subtypes defined by type of VF defect (peripheral or paracentral). Results from GLAUGEN and NEIGHBOR were meta-analyzed, and a Bonferroni-corrected significance level of 7.7 × 10(-4) was used to account for multiple comparisons., Main Outcome Measures: Overall POAG, overall POAG by gender, and POAG subtypes defined by pattern of early VF loss., Results: We found significant associations between 10 CAV1/CAV2 SNPs and POAG (top SNP, rs4236601; pooled P = 2.61 × 10(-7)). Of these, 9 were significant only in women (top SNP, rs4236601; pooled P = 1.59 × 10(-5)). Five of the 10 CAV1/CAV2 SNPs were associated with POAG with early paracentral VF (top SNP, rs17588172; pooled P = 1.07 × 10(-4)), and none of the 10 were associated with POAG with peripheral VF loss only or POAG among men., Conclusions: CAV1/CAV2 SNPs were associated significantly with POAG overall, particularly among women. Furthermore, we found an association between CAV1/CAV2 SNPs and POAG with paracentral VF defects. These data support a role for caveolin 1, caveolin 2, or both in POAG and suggest that the caveolins particularly may affect POAG pathogenesis in women and in patients with early paracentral VF defects., (Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Elevated intraocular pressure (IOP) is a major risk factor for glaucoma and is influenced by genetic and environmental factors. Recent genome-wide association studies (GWAS) reported associations with IOP at TMCO1 and GAS7, and with primary open-angle glaucoma (POAG) at CDKN2B-AS1, CAV1/CAV2, and SIX1/SIX6. To identify novel genetic variants and replicate the published findings, we performed GWAS and meta-analysis of IOP in >6,000 subjects of European ancestry collected in three datasets: the NEI Glaucoma Human genetics collaBORation, GLAUcoma Genes and ENvironment study, and a subset of the Age-related Macular Degeneration-Michigan, Mayo, AREDS and Pennsylvania study. While no signal achieved genome-wide significance in individual datasets, a meta-analysis identified significant associations with IOP at TMCO1 (rs7518099-G, p = 8.0 × 10(-8)). Focused analyses of five loci previously reported for IOP and/or POAG, i.e., TMCO1, CDKN2B-AS1, GAS7, CAV1/CAV2, and SIX1/SIX6, revealed associations with IOP that were largely consistent across our three datasets, and replicated the previously reported associations in both effect size and direction. These results confirm the involvement of common variants in multiple genomic regions in regulating IOP and/or glaucoma risk.

Primary open-angle glaucoma (POAG) is a common disease with complex inheritance. The identification of genes predisposing to POAG is an important step toward the development of novel gene-based methods of diagnosis and treatment. Genome-wide association studies (GWAS) have successfully identified genes contributing to complex traits such as POAG however, such studies frequently require very large sample sizes, and thus, collaborations and consortia have been of critical importance for the GWAS approach. In this report we describe the formation of the NEIGHBOR consortium, the harmonized case control definitions used for a POAG GWAS, the clinical features of the cases and controls, and the rationale for the GWAS study design.

Purpose: Circulating estrogen levels are relevant in glaucoma phenotypic traits. We assessed the association between an estrogen metabolism single nucleotide polymorphism (SNP) panel in relation to primary open angle glaucoma (POAG), accounting for gender., Methods: We included 3,108 POAG cases and 3,430 controls of both genders from the Glaucoma Genes and Environment (GLAUGEN) study and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium genotyped on the Illumina 660W-Quad platform. We assessed the relation between the SNP panels representative of estrogen metabolism and POAG using pathway- and gene-based approaches with the Pathway Analysis by Randomization Incorporating Structure (PARIS) software. PARIS executes a permutation algorithm to assess statistical significance relative to the pathways and genes of comparable genetic architecture. These analyses were performed using the meta-analyzed results from the GLAUGEN and NEIGHBOR data sets. We evaluated POAG overall as well as two subtypes of POAG defined as intraocular pressure (IOP) ≥22 mmHg (high-pressure glaucoma [HPG]) or IOP <22 mmHg (normal pressure glaucoma [NPG]) at diagnosis. We conducted these analyses for each gender separately and then jointly in men and women., Results: Among women, the estrogen SNP pathway was associated with POAG overall (permuted p=0.006) and HPG (permuted p<0.001) but not NPG (permuted p=0.09). Interestingly, there was no relation between the estrogen SNP pathway and POAG when men were considered alone (permuted p>0.99). Among women, gene-based analyses revealed that the catechol-O-methyltransferase gene showed strong associations with HTG (permuted gene p≤0.001) and NPG (permuted gene p=0.01)., Conclusions: The estrogen SNP pathway was associated with POAG among women.

Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10(-8)). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4-1.88, P = 2.7 × 10(-10), and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29-1.68, P = 4.9 × 10(-9)). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10(-4); tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.

Purpose: To assess the association between single nucleotide polymorphisms (SNPs) of the gene region containing cyclin-dependent kinase inhibitor 2B antisense noncoding RNA (CDKN2B-AS1) and glaucoma features among primary open-angle glaucoma (POAG) patients., Design: Retrospective observational case series., Methods: We studied associations between 10 CDKN2B-AS1 SNPs and glaucoma features among 976 POAG cases from the Glaucoma Genes and Environment (GLAUGEN) study and 1971 cases from the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium. For each patient, we chose the feature from the eye with the higher value. We created cohort-specific multivariable models for glaucoma features and then meta-analyzed the results., Results: For 9 of the 10 protective CDKN2B-AS1 SNPs with minor alleles associated with reduced disease risk (eg, the G allele at rs2157719), POAG patients carrying these minor alleles had smaller cup-to-disc ratio (0.05 units smaller per G allele at diagnosis; 95% CI: -0.08, -0.03; P = 6.23E-05) despite having higher intraocular pressure (IOP) (0.70 mm Hg higher per G allele at DNA collection; 95% CI: 0.40, 1.00; P = 5.45E-06). For the 1 adverse rs3217992 SNP with minor allele A associated with increased disease risk, POAG patients with A alleles had larger cup-to-disc ratio (0.05 units larger per A allele at diagnosis; 95% CI: 0.02, 0.07; P = 4.74E-04) despite having lower IOP (-0.57 mm Hg per A allele at DNA collection; 95% CI: -0.84, -0.29; P = 6.55E-05)., Conclusion: Alleles of CDKN2B-AS1 SNPs, which influence risk of developing POAG, also modulate optic nerve degeneration among POAG patients, underscoring the role of CDKN2B-AS1 in POAG., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63-0.75], p = 1.86×10⁻¹⁸), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21-1.43], p = 3.87×10⁻¹¹). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50-0.67], p = 1.17×10⁻¹²) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53-0.72], p = 8.88×10⁻¹⁰). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41-0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54-1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma., Competing Interests: The authors have declared that no competing interests exist.

Background and Objective: To determine whether postoperative use of topical ketorolac tromethamine 0.5% affects intraocular pressure (IOP) following Ahmed glaucoma drainage device (New World Medical, Inc., Rancho Cucamonga, CA) implantation., Patients and Methods: Patients undergoing Ahmed implantation at the University of Michigan from January 2002 to June 2008 were reviewed. Fourteen eyes received ketorolac after surgery; 50 eyes did not. Preoperative and postoperative IOP and glaucoma medications were recorded for both groups; the two-sided Student's t test was used to compare these parameters., Results: Mean preoperative IOP was similar in the two groups (35.1 ± 11.9 vs 37.0 ± 12.2 mm Hg; P = .60). At postoperative month 6, the ketorolac group had significantly lower IOP compared with the no ketorolac group (13.1 ± 3.7 vs 19.5 ± 9.3 mm Hg, respectively; P = .0003). There was no difference in the number of glaucoma medications postoperatively between the two groups., Conclusion: Ketorolac may lead to lower postoperative IOP following Ahmed implantation., (Copyright 2011, SLACK Incorporated.)

Purpose: To evaluate the extent to which mutations in the optineurin (OPTN) glaucoma gene play a role in glaucoma in different populations., Methods: Case-controlled study of OPTN sequence variants in individuals with or without glaucoma in populations of different ancestral origins and evaluate previous OPTN reports. We analyzed 314 subjects with African, Asian, Caucasian and Hispanic ancestries included 229 cases of primary open-angle glaucoma, 51 cases of juvenile-onset open-angle glaucoma, 33 cases of normal tension glaucoma, and 371 controls. Polymerase chain reaction-amplified OPTN coding exons were resequenced and case frequencies were compared to frequencies in controls matched for ancestry., Results: The E50K sequence variant was identified in one individual from Chile with normal tension glaucoma, and the 691&#95;692insAG variant was found in one Ashkenazi Jewish individual from Russia. The R545Q variant was found in two Asian individuals with primary open-angle glaucoma; one of Filipino ancestry and one of Korean ancestry. In addition to presenting OPTN allele frequencies for Caucasian and Asian populations that have been the subject of previous reports, we also present information for populations of Hispanic and black African ancestries., Conclusions: Our study contributes additional evidence to support the previously reported association of the OPTN E50K mutation with glaucoma. After finding an additional 691&#95;692insAG OPTN variant, we can still only conclude that this variant is rare. Combined analysis of our data with data from more than a dozen other studies indicates no association of R545Q with glaucoma in most populations. Those same studies disagree in their conclusions regarding the role of M98K in glaucoma. Our analysis of the combined data provides statistically significant evidence of association of M98K with normal tension glaucoma in Asian populations, but not in Caucasian populations; however, the validity of this conclusion is questionable because of large differences in allele frequencies between and within populations. It is currently not possible to tell how much of the underlying cause of the allele frequency difference is attributable to demographic, technical, or ascertainment differences among the studies.

Objective: To determine whether the beta(2)-adrenergic receptor (ADRB2) gene is a glaucoma susceptibility locus., Design and Methods: The design was an association study stratified by ancestry (white vs black African) and disease (primary open-angle glaucoma vs control subjects). The ADRB2 single nucleotide polymorphisms were determined by sequencing, and the haplotypes of the common single nucleotide polymorphisms affecting codons 16 and 27 were phased by allele-specific polymerase chain reaction and restriction enzyme digestion. We analyzed the association of single nucleotide polymorphisms and haplotypes by ancestry and disease with the Fisher exact test, chi(2) test, and standardized Pearson residual., Results: A total of 583 subjects underwent genotyping (156 white subjects with primary open-angle glaucoma; 143 subjects of black African ancestry with primary open-angle glaucoma; 148 white controls; and 136 controls of black African ancestry). There were no differences in ADRB2 alleles and haplotypes between the primary open-angle glaucoma and control groups, whether analyzed together or by ancestry. Previously described ancestry-based differences in allele frequencies were found. We also found ancestry-based differences in ADRB2 haplotypes., Conclusion: The ADRB2 gene was not a glaucoma susceptibility locus in our study population., Clinical Relevance: Because this gene is not a disease locus, we can now study the role of ADRB2 haplotypes in the glaucoma risk factor of intraocular pressure fluctuation and variation in intraocular pressure response to beta-blockers.

Purpose: Topical use of dexamethasone has long been associated with steroid induced-glaucoma, although the mechanism is unknown. We applied a strict filtering of comparative microarray data to more than 18,000 genes to evaluate global gene expression of cultured human trabecular meshwork cells in response to treatment with dexamethasone., Methods: Three human trabecular meshwork cell primary cultures from nonglaucomatous donors were incubated with and without dexamethasone for 21 days. Relative gene expression was evaluated by analysis of U133A GeneChip and the results validated using quantitative polymerase chain reaction (PCR)., Results: Application of strict filtering to include only genes with statistically significant differences in gene expression across all three trabecular meshwork cell cultures produced a list of 1,260 genes. Significant changes in signal level were observed, including 23 upregulated and 18 downregulated genes that changed greater than three fold in each of three cell cultures. Using quantitative PCR we found changes greater than a thousand fold for two genes (SLP1 and SAA2) and changes greater than a hundred fold for another five genes (ANGPTL7, MYOC, SAA1, SERPINA3, and ZBTB16)., Conclusions: Expression changes in trabecular meshwork cells in response to dexamethasone treatment indicate that a group of actins and actin-associated proteins are involved in the development of cross-linked actin networks that form in response to dexamethasone. A trend was identified toward decreased expression of protease genes accompanied by an increased expression of protease inhibitors. Such a trend in nonproteasomal proteolysis conceivably affects gene product levels above the level of transcription. Only two genes, MYOC and IGFBP2, showed significantly elevated expression after dexamethasone treatment in our study and the other three previously published reports of primary culture trabecular meshwork cell gene expression.

Posterior polymorphous corneal dystrophy (PPCD, also known as PPMD) is a rare disease involving metaplasia and overgrowth of corneal endothelial cells. In patients with PPCD, these cells manifest in an epithelial morphology and gene expression pattern, produce an aberrant basement membrane, and, sometimes, spread over the iris and nearby structures in a way that increases the risk for glaucoma. We previously mapped PPCD to a region (PPCD3) on chromosome 10 containing the gene that encodes the two-handed zinc-finger homeodomain transcription factor TCF8. Here, we report a heterozygous frameshift mutation in TCF8 that segregates with PPCD in the family used to map PPCD3 and four different heterozygous nonsense and frameshift mutations in TCF8 in four other PPCD probands. Family reports of inguinal hernia, hydrocele, and possible bone anomalies in affected individuals suggest that individuals with TCF8 mutations should be examined for nonocular anomalies. We detect transcripts of all three identified PPCD genes (VSX1, COL8A2, and TCF8) in the cornea. We show presence of a complex (core plus secondary) binding site for TCF8 in the promoter of Alport syndrome gene COL4A3, which encodes collagen type IV alpha 3, and we present immunohistochemical evidence of ectopic expression of COL4A3 in corneal endothelium of the proband of the original PPCD3 family. Identification of TCF8 as the PPCD3 gene provides a valuable tool for the study of critical gene regulation events in PPCD pathology and suggests a possible role for TCF8 mutations in altered structure and function of cells lining body cavities other than the anterior chamber of the eye. Thus, this study has identified TCF8 as the gene responsible for approximately half of the cases of PPCD, has implicated TCF8 mutations in developmental abnormalities outside the eye, and has presented the TCF8 regulatory target, COL4A3, as a key, shared molecular component of two different diseases, PPCD and Alport syndrome.

Purpose: To identify the gene responsible for a complex ocular phenotype of late-onset macular degeneration, long anterior zonules (LAZ), and elevated intraocular pressure (IOP) and to study its expression., Methods: Ocular examination, visual field, fluorescein angiography, and electrophysiology testing were performed. One affected individual was treated with vitamin A. DNA from 55 family members (UM:H389) was used for linkage, mapping, and mutation analysis. Linkage analysis of macular degeneration and LAZ phenotypes was performed independently. Mutations in candidate genes were screened by sequencing. mRNA expression of CTRP5 and MFRP, which are bicistronic genes, was studied by semiquantitative RT-PCR (qRT-PCR) in various human tissues. CTRP5 expression was also evaluated by in situ hybridization., Results: Affected members had LAZ detectable by the third decade and/or macular degeneration by the fourth to fifth decade. A six-month treatment with vitamin A shortened dark adaptation considerably in one affected member. Both conditions mapped independently with zero recombination to 11q23, with maximum lod scores of 3.31 for macular degeneration and 5.41 for LAZ. The same CTRP5 missense mutation was identified in all affected individuals. Retinal pigment epithelium (RPE) and ciliary epithelium (CE) showed highest CTRP5 transcript expression, which was also true for MFRP. CTRP5 tissue expression was confirmed by in situ hybridization., Conclusions: A single locus at 11q23 is implicated in a complex ocular phenotype involving RPE and CE, tissues of neuroectodermal origin. All individuals with either LAZ and/or macular degeneration carry the same CTRP5 S163R mutation, which is transmitted in autosomal dominant manner.