A multi-cohort genome-wide association study in African ancestry individuals reveals risk loci for primary open-angle glaucoma.

Primary open-angle glaucoma (POAG), the leading cause of irreversible blindness worldwide, disproportionately affects individuals of African ancestry. We conducted a genome-wide association study (GWAS) for POAG in 11,275 individuals of African ancestry (6,003 cases; 5,272 controls). We detected 46 risk loci associated with POAG at genome-wide significance. Replication and post-GWAS analyses, including functionally informed fine-mapping, multiple trait co-localization, and in silico validation, implicated two previously undescribed variants (rs1666698 mapping to DBF4P2; rs34957764 mapping to ROCK1P1) and one previously associated variant (rs11824032 mapping to ARHGEF12) as likely causal. For individuals of African ancestry, a polygenic risk score (PRS) for POAG from our mega-analysis (African ancestry individuals) outperformed a PRS from summary statistics of a much larger GWAS derived from European ancestry individuals. This study quantifies the genetic architecture similarities and differences between African and non-African ancestry populations for this blinding disease.

DDX58 variant triggers IFN-ß-induced autophagy in trabecular meshwork and influences intraocular pressure.

Singleton-Merten syndrome (SMS) is a rare immunogenetic disorder affecting multiple systems, characterized by dental dysplasia, aortic calcification, glaucoma, skeletal abnormalities, and psoriasis. Glaucoma, a key feature of both classical and atypical SMS, remains poorly understood in terms of its molecular mechanism caused by DDX58 mutation. This study presented a novel DDX58 variant (c.1649A>C [p.Asp550Ala]) in a family with childhood glaucoma. Functional analysis showed that DDX58 variant caused an increase in IFN-stimulated gene expression and high IFN-ß-based type-I IFN. As the trabecular meshwork (TM) is responsible for controlling intraocular pressure (IOP), we examine the effect of IFN-ß on TM cells. Our study is the first to demonstrate that IFN-ß significantly reduced TM cell viability and function by activating autophagy. In addition, anterior chamber injection of IFN-ß remarkably increased IOP level in mice, which can be attenuated by treatments with autophagy inhibitor chloroquine. To uncover the specific mechanism underlying IFN-ß-induced autophagy in TM cells, we performed microarray analysis in IFN-ß-treated and DDX58 p.Asp550Ala TM cells. It showed that RSAD2 is necessary for IFN-ß-induced autophagy. Knockdown of RSAD2 by siRNA significantly decreased autophagy flux induced by IFN-ß. Our findings suggest that DDX58 mutation leads to the overproduction of IFN-ß, which elevates IOP by modulating autophagy through RSAD2 in TM cells.

Assessing Glaucoma Severity and Progression in Individuals with Asymmetric Axial Length: An Intrapatient Comparative Study.

PURPOSE: To investigate whether a difference exists in intereye glaucoma severity and progression in patients with asymmetric axial length. DESIGN: Long-term observational study. PARTICIPANTS: Patients older than 20 years with a diagnosis of glaucoma at Seoul National University Hospital, Seoul, Korea, between 2010 and 2020. METHODS: Patients with a diagnosis of glaucoma in both eyes with an axial length difference of more than 1.0 mm were included. Each individual's eyes were classified into longer eye and shorter eye, and the baseline and follow-up clinical data were analyzed using the paired T-test and McNemar test. MAIN OUTCOME MEASURES: Differences in clinical characteristics in patients with asymmetric axial length. RESULTS: A total of 190 eyes of 95 patients with glaucoma with asymmetric axial length were included in the study. The patients' mean age was 51.2 ± 12.3 years, and the mean follow-up period was 10.1 ± 3.9 years. No difference was found in baseline intraocular pressure (IOP) or central corneal thickness between longer eyes and shorter eyes. Among the baseline disc parameters, ovality index, ß-zone and γ-zone parapapillary atrophy (PPA) area were larger (P < 0.001) in the longer eyes. In the baseline OCT data, the retinal nerve fiber layer (RNFL) thickness (P = 0.009) and ganglion cell-inner plexiform layer (GCIPL) thickness (P < 0.001) were thinner in the longer eyes. According to a baseline visual field (VF) test, the mean deviation and VF index (VFI) values were significantly lower (P < 0.001, P = 0.034) in the longer eyes. Based on an analysis of glaucoma progression, the rate of change of superior GCIPL (longer eyes, -0.65 µm/year; shorter eyes, -0.40 µm/year), mean deviation (longer eyes, -0.40 dB/year; shorter eyes, -0.21 dB/year), and VFI (longer eyes, -0.92%/year; shorter eyes, -0.46%/year) were larger (P = 0.006, P = 0.005, P < 0.001) in the longer eyes. Additionally, the greater the difference in IOP fluctuation, the greater the difference in the rate of change between mean deviation and VFI. CONCLUSIONS: When an axial length difference of more than 1.0 mm was present, glaucoma tended to be more severe and to progress faster in the longer eyes. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Ab-Externo MicroShunt versus Trabeculectomy in Primary Open-Angle Glaucoma: Two-Year Results from a Randomized, Multicenter Study.

PURPOSE: To compare the effectiveness and safety of the MicroShunt (Santen Inc) versus trabeculectomy in patients with primary open-angle glaucoma (POAG). DESIGN: Prospective, randomized, multicenter trial conducted in the United States and Europe. PARTICIPANTS: Adult patients (aged 40-85 years) with mild to severe POAG inadequately controlled on maximum tolerated medical therapy and intraocular pressure (IOP) ≥ 15 mmHg and ≤ 40 mmHg. METHODS: Patients were randomized 3:1 to stand-alone MicroShunt implantation (n = 395) or trabeculectomy (n = 132), both augmented with mitomycin C (MMC) 0.2 mg/ml for 2 minutes. MAIN OUTCOME MEASURES: The primary effectiveness end point was surgical success, defined as ≥ 20% reduction in mean diurnal IOP from baseline with no increase in glaucoma medications. Secondary end points included changes in mean IOP and medication use from baseline and the need for postoperative interventions. RESULTS: At 2 years, the rate of surgical success was lower in the MicroShunt group than in the trabeculectomy group (50.6% vs. 64.4%, P = 0.005). Mean diurnal IOP was reduced from 21.1 ± 4.9 mmHg at baseline to 13.9 ± 3.9 mmHg at 24 months in the MicroShunt group and from 21.1 ± 5.0 mmHg at baseline to 10.7 ± 3.7 mmHg at 24 months in the trabeculectomy group (P < 0.001 compared with baseline in both groups). Mean medication use decreased from 3.1 to 0.9 in the MicroShunt group and from 2.9 to 0.4 in the trabeculectomy group (P < 0.001 compared with baseline in both groups). Adverse events at 2 years were generally similar in the 2 groups, except that hypotony was more common in eyes undergoing trabeculectomy (51.1% vs. 30.9%, P < 0.001). Repositioning or explantation of the implant occurred in 6.8% of MicroShunt patients. The majority of these patients had device removal at the time of subsequent glaucoma surgery. Vision-threatening complications were uncommon in both groups. CONCLUSION: At 2 years, both the MicroShunt and trabeculectomy provided significant reductions in IOP and medication use, with trabeculectomy continuing to have greater surgical success. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Genetic Risk Stratification of Primary Open-Angle Glaucoma in Japanese Individuals.

PURPOSE: To assess the impact of genetic risk estimation for primary open-angle glaucoma (POAG) in Japanese individuals. DESIGN: Cross-sectional analysis. PARTICIPANTS: Genetic risk scores (GRSs) were constructed based on a genome-wide association study (GWAS) of POAG in Japanese people. A total of 3625 Japanese individuals, including 1191 patients and 2434 controls (Japanese Tohoku), were used for the model selection. We also evaluated the discriminative accuracy of constructed GRSs in a dataset comprising 1034 patients and 1147 controls (the Japan Glaucoma Society Omics Group [JGS-OG] and the Genomic Research Committee of the Japanese Ophthalmological Society [GRC-JOS]) and 1900 participants from a population-based study (Hisayama Study). METHODS: We evaluated 2 types of GRSs: polygenic risk scores using the pruning and thresholding procedure and a GRS using variants associated with POAG in the GWAS of the International Glaucoma Genetics Consortium (IGGC). We selected the model with the highest areas under the receiver operating characteristic curve (AUC). In the population-based study, we evaluated the correlations between GRS and ocular measurements. MAIN OUTCOME MEASURE: Proportion of patients with POAG after stratification according to the GRS. RESULTS: We found that a GRS using 98 variants, which showed genome-wide significance in the IGGC, showed the best discriminative accuracy (AUC, 0.65). In the Japanese Tohoku, the proportion of patients with POAG in the top 10% individuals was significantly higher than that in the lowest 10% (odds ratio [OR], 6.15; 95% confidence interval [CI], 4.35-8.71). In the JGS-OG and GRC-JOS, we confirmed similar impact of POAG GRS (AUC, 0.64; OR [top vs. bottom decile], 5.81; 95% CI, 3.79-9.01). In the population-based study, POAG prevalence was significantly higher in the top 20% individuals of the GRS compared with the bottom 20% (9.2% vs. 5.0%). However, the discriminative accuracy was low (AUC, 0.56). The POAG GRS was correlated positively with intraocular pressure (r = 0.08: P = 4.0 × 10-4) and vertical cup-to-disc ratio (r = 0.11; P = 4.0 × 10-6). CONCLUSIONS: The GRS showed moderate discriminative accuracy for POAG in the Japanese population. However, risk stratification in the general population showed relatively weak discriminative performance. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Evaluating Primary Treatment for People with Advanced Glaucoma: Five-Year Results of the Treatment of Advanced Glaucoma Study.

PURPOSE: To determine whether primary trabeculectomy or medical treatment produces better outcomes in terms of quality of life (QoL), clinical effectiveness, and safety in patients with advanced glaucoma. DESIGN: Multicenter randomized controlled trial. PARTICIPANTS: Between June 3, 2014, and May 31, 2017, 453 adults with newly diagnosed advanced open-angle glaucoma in at least 1 eye (Hodapp classification) were recruited from 27 secondary care glaucoma departments in the United Kingdom. Two hundred twenty-seven were allocated to trabeculectomy, and 226 were allocated medical management. METHODS: Participants were randomized on a 1:1 basis to have either mitomycin C-augmented trabeculectomy or escalating medical management with intraocular pressure (IOP)-reducing drops as the primary intervention and were followed up for 5 years. MAIN OUTCOME MEASURES: The primary outcome was vision-specific QoL measured with the 25-item Visual Function Questionnaire (VFQ-25) at 5 years. Secondary outcomes were general health status, glaucoma-related QoL, clinical effectiveness (IOP, visual field, and visual acuity), and safety. RESULTS: At 5 years, the mean ± standard deviation VFQ-25 scores in the trabeculectomy and medication arms were 83.3 ± 15.5 and 81.3 ± 17.5, respectively, and the mean difference was 1.01 (95% confidence interval [CI], -1.99 to 4.00; P = 0.51). The mean IOPs were 12.07 ± 5.18 mmHg and 14.76 ± 4.14 mmHg, respectively, and the mean difference was -2.56 (95% CI, -3.80 to -1.32; P < 0.001). Glaucoma severity measured with visual field mean deviation were -14.30 ± 7.14 dB and -16.74 ± 6.78 dB, respectively, with a mean difference of 1.87 (95% CI, 0.87-2.87 dB; P < 0.001). Safety events occurred in 115 (52.2%) of patients in the trabeculectomy arm and 124 (57.9%) of patients in the medication arm (relative risk, 0.92; 95% CI, 0.72-1.19; P = 0.54). Serious adverse events were rare. CONCLUSIONS: At 5 years, the Treatment of Advanced Glaucoma Study demonstrated that primary trabeculectomy surgery is more effective in lowering IOP and preventing disease progression than primary medical treatment in patients with advanced disease and has a similar safety profile. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The clinical utility of a glaucoma polygenic risk score in four population-based European-ancestry cohorts.

OBJECTIVE: We used a polygenic risk score (PRS) to identify high-risk groups for primary open-angle glaucoma (POAG) within population-based cohorts. DESIGN: Secondary analysis of four prospective population-based studies. PARTICIPANTS: We included four European-ancestry cohorts: the United States (US) based Nurses' Health Study (NHS), NHS2, and the Health Professionals Follow-up Study, and the Rotterdam Study (RS) in the Netherlands. The US cohorts included female nurses and male health professionals aged 55+ years. The RS included residents aged 45 years or older living in Rotterdam, the Netherlands. METHODS: PRS weights were estimated by applying the Lassosum method on imputed genotype and phenotype data from the UK-Biobank. This resulted in 144,020 variants, single nucleotide polymorphism (SNPs) and indels, with non-zero betas that we used to calculate a PRS in the target populations. Using multivariable Cox proportional hazard models, we estimated the relationship between the standardized PRS and relative risk for POAG. Additionally, POAG prediction was tested by calculating these models' concordance (Harrell's C-statistic). Finally, we assessed the association between PRS tertiles and glaucoma-related traits. MAIN OUTCOME MEASURES: The relative risk for POAG and Harrell's C-statistic (the equivalent of an area-under-the-curve for longitudinal models). RESULTS: Among 1,046 cases and 38,809‬ controls, the relative risk (95% confidence interval) for POAG for participants in the highest PRS quintile was 3.99 (3.08, 5.18) in the US cohorts, and 4.89 (2.93, 8.17) in the Rotterdam Study, compared with participants with median genetic risk (3rd quintile). In restricted cubic spline analyses, the relation between continuous PRS and POAG risk increased exponentially in the US and Rotterdam cohorts (Pspline<0.05). Combining age, sex, intraocular pressure >25 mmHg, and family history resulted in a meta-analyzed concordance of 0.75 (0.73, 0.75). Adding the PRS to this model improved the concordance to 0.82 (0.80, 0.84). In a meta-analysis of all cohorts, cases in the highest tertile had a larger cup-disc ratio at diagnosis, by 0.11 (0.07, 0.15), and a 2.07-fold increased risk of requiring glaucoma surgery (1.19, 3.60). CONCLUSIONS: Incorporating a PRS into a POAG predictive model improves identification concordance from 0.75 up to 0.82, supporting its potential for guiding more cost-effective screening strategies.

The Impact of Baseline Intraocular Pressure on Initial Treatment Response in the LiGHT Trial: Selective Laser Trabeculoplasty versus Medication.

PURPOSE: The Laser in Glaucoma and Ocular Hypertension Trial demonstrated the efficacy and safety of selective laser trabeculoplasty (SLT) compared with topical hypotensive medication as first-line therapy for ocular hypertension and open-angle glaucoma. This substudy explored the impact of pretreatment (baseline) intraocular pressure (IOP) on treatment response. DESIGN: Post hoc analysis of randomized control trial data. PARTICIPANTS: A total of 1146 eyes from 662 patients were included in this analysis: 559 eyes in the SLT group and 587 in the medication group. METHODS: Intraocular pressure reduction at 8 weeks after treatment with either SLT or prostaglandin analog (PGA) eye drops was assessed at different levels of baseline IOP, and the groups were compared. Differences in absolute and percentage IOP lowering between SLT and PGA groups were tested with a linear mixed-effects model. Differences in the probability of achieving ≥ 20% IOP lowering between SLT and PGA groups, at different levels of baseline IOP, were estimated using a logistic mixed-effects model. MAIN OUTCOME MEASURE: Intraocular pressure-lowering response to SLT versus PGA eye drops. RESULTS: Mean IOP was not significantly different between the groups at baseline or 8 weeks after treatment initiation. Both treatments showed greater IOP lowering at higher baseline IOP and less IOP lowering at lower baseline IOP. Selective laser trabeculoplasty tended to achieve more IOP lowering than PGA drops at higher baseline IOP. Prostaglandin analog drops performed better at lower baseline IOP, and the difference compared with SLT, in terms of percentage IOP reduction, was significant at baseline IOP of ≤ 17 mmHg. A significant difference was found in the relationship between baseline IOP and probability of ≥ 20% IOP lowering between the two treatments (P = 0.01), with SLT being more successful than PGA at baseline IOP of more than 22.5 mmHg. CONCLUSIONS: We confirm previous reports of greater IOP lowering with higher baseline IOP for both SLT and PGA drops. In treatment-naïve eyes, at higher baseline IOP, SLT was more successful at achieving ≥ 20% IOP lowering than PGA drops. At lower baseline IOP, a statistically greater percentage, but not absolute, IOP lowering was seen with PGA drops compared with SLT, although the clinical significance of this is uncertain. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Progressive Changes in the Neuroretinal Rim and Retinal Nerve Fiber Layer in Glaucoma: Impact of Baseline Values and Floor Effects.

PURPOSE: To determine whether more severe baseline damage impedes measurement of minimum rim width (MRW) and peripapillary retinal nerve fiber layer thickness (RNFLT) change in glaucoma patients because of a floor effect. DESIGN: Prospective, longitudinal cohort study in a hospital-based setting. PARTICIPANTS: The study included patients with open-angle glaucoma and healthy control subjects. Participants had at least 5 years of follow-up with OCT every 6 months. METHODS: Baseline global and sectorial MRW and RNFLT values were classified as within normal limits, borderline, or outside normal limits based on reference normative values. Regression analysis was used to determine the magnitude and significance of MRW and RNFLT change. Additionally, the follow-up period for each participant was divided into 2 equal halves (first and second periods) to determine whether there was attenuation of MRW and RNFLT change with follow-up time. MAIN OUTCOME MEASURES: Rates of global and sectoral MRW and RNFLT changes (slopes). RESULTS: A total of 97 patients with glaucoma (median age, 70.3 years) and 42 healthy subjects (median age, 64.8 years) were followed for a median of 6.9 years and 7.0 years, respectively. The median mean deviation of the visual field in glaucoma patients was -4.30 decibels (dB) (interquartile range, -7.81 to -2.06 dB; range, -20.68 to 1.37 dB). Statistically significant changes in global and sectoral MRW and RNFLT were detected across all baseline classifications; however, there was a tendency for less change with increasing baseline damage. In glaucoma patients, RNFLT slopes, but not MRW slopes, were significantly more positive (less change) in the second period compared with the first. There were also no differences in MRW or RNFLT slopes in the first and second periods in healthy subjects. CONCLUSIONS: Significant MRW and RNFLT changes were detected at all levels of baseline damage. However, an attenuation in the rate of RNFLT change compared with MRW indicates an earlier floor effect in RNFLT measurements globally and in equivalent sectors. Because the axonal component of these measurements should be equivalent, our results suggest important differences in tissue remodeling at the level of the optic nerve head and peripapillary retina. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Comparative Effects of GLP-1 Receptor Agonists and Metformin on Glaucoma Risk in Type 2 Diabetes Patients.

PURPOSE: To compare effects of glucagon-like peptide-1 (GLP-1) receptor agonists and metformin on the risk of primary open-angle glaucoma (POAG), ocular hypertension, and the need for first-line glaucoma treatments in patients with type 2 diabetes. DESIGN: A retrospective cohort study was conducted using electronic medical records (EMR) data from the from an international electronic health record network, covering a period from May 2006 to May 2024. PARTICIPANTS: Patients diagnosed with type 2 diabetes mellitus (T2DM) who were treated with either GLP-1 receptor agonists or metformin. METHODS: Data from 120 healthcare organizations across 17 countries were analyzed. Patient outcomes were assessed at 1, 2, and 3 years. Propensity score matching (PSM) was used to balance covariates such as demographics, comorbidities, and medication usage. Risk ratios (RR) with 95% confidence intervals (CI) were calculated. MAIN OUTCOME MEASURES: Incidence of POAG, ocular hypertension, and the need for first-line treatments including beta-blockers, prostaglandin analogues, brimonidine, brinzolamide, dorzolamide, netarsudil, and laser trabeculoplasty. RESULTS: After PSM, both groups included 61,998 patients at the 1-year follow-up, 27,414 at the 2-year follow-up, and 14,100 at the 3-year follow-up. Patients treated with GLP-1 receptor agonists had a significantly decreased risk of developing POAG compared to those on metformin at 1 year (RR 0.59, 95% CI 0.39-0.88), 2 years (RR 0.50, 95% CI 0.32-0.78), and 3 years (RR 0.59, 95% CI 0.37-0.94). Similar protective effects were observed for ocular hypertension with risk reductions of 56% at 1 year (RR 0.44, 95% CI 0.31-0.62), 57% at 2 years (RR 0.43, 95% CI 0.30-0.62), and 49% at 3 years (RR 0.51, 95% CI 0.34-0.75). The risk of first-line therapy initiation was also lower in the GLP-1 receptor agonists group at 1 year (RR 0.63, 95% CI 0.53-0.74), 2 years (RR 0.71, 95% CI 0.59-0.85), and 3 years (RR 0.75, 95% CI 0.62-0.91). CONCLUSIONS: GLP-1 receptor agonists are associated with a significantly lower incidence of POAG, ocular hypertension, and the need for first-line glaucoma treatments compared to metformin in patients with type 2 diabetes. These findings highlight the potential ocular benefits of GLP-1 receptor agonists and their expanding role in the clinical management of diabetic patients.

Causal relationships between Gut microbiota and primary open-angle Glaucoma: A Mendelian randomization and mediation analysis of Glaucoma endophenotypes.

Primary open-angle glaucoma (POAG) is a widespread condition responsible for irreversible blindness, and its prevalence is expected to increase substantially in the coming decades. Despite its significance, the exact cause of POAG remains elusive, necessitating a comprehensive exploration of its pathogenesis. Emerging research suggests a potential link between alterations in gut microbiota composition and POAG. However, establishing causality in these associations remains a challenge. In this study, we employed Mendelian randomization (MR) analysis to investigate the potential causal relationships between gut microbiota (GM) and POAG. Significant bacteria taxa were further analyzed with POAG endophenotypes. We utilized data from genome-wide association studies (GWAS) for GM and POAG, as well as for glaucoma endophenotypes, including intraocular pressure (IOP), retinal nerve fiber layer (RNFL) thickness, vertical cup-to-disc ratio (VCDR), and central corneal thickness (CCT). Univariable, multivariable MR and mediation effect analysis were conducted. Our analysis revealed that certain taxa, including phylum Euryarchaeota, genus Odoribacter, Rumnicoccaceae UCG009, Ruminiclostridium9, unknown genus id.2071, and Eubacterium rectale group, were associated with an increased risk of POAG. On the other hand, family Victivallaceae, Lacchnospiraceae, genus Lachnoclostridium, Oscillospira, Ruminococcaceae UCG011, Alloprevotella, and Faecalibacterium were found to be associated with a decreased risk of POAG. Furthermore, some of these taxa were found to be connected to glaucoma endophenotypes. Through further multivariable MR analysis, it was determined that IOP, VCDR, and CCT might played mediating roles between GM and POAG. In conclusion, this study utilizes MR analysis to elucidate potential causal associations between GM and POAG, providing insights into specific GM taxa that influence POAG risk and related endophenotypes. These findings emphasize the potential role of the gut microbiota in the pathogenesis of POAG and pave the way for future research and therapeutic interventions.

Causal relationship between central corneal thickness and open-angle glaucoma: Evidence from Mendelian randomization.

Glaucoma is the leading cause of irreversible blindness worldwide. Previous observational studies have suggested a relationship between central corneal thickness (CCT) and glaucoma; however, the results are inconsistent. This study aimed to investigate whether CCT is associated with a risk for developing open-angle glaucoma (OAG). We employed two-sample Mendelian randomization to assess the relationship between CCT and OAG, namely, primary open-angle glaucoma (POAG) and suspected glaucoma. Genetic instruments composed of variants associated with CCT at genome-wide significance (P < 5 × 10-8) were obtained from published genome-wide association studies from Iglesias et al. for discovery and Bonnemaijer et al. for replication. Summary-level statistics for these instruments for the OAG were obtained from the FinnGen Project (Release 10). Inverse-variance-weighted regression of genetic susceptibility predicted that increased CCT was positively associated with an increased risk for POAG (odds ratio [OR], 1.005; 95% confidence interval [CI], 1.002-1.008; P = 0.001) and suspected glaucoma (OR, 1.006; 95% CI, 1.003-1.009; P < 0.001). In the replication sample of CCT, increased CCT was also positively associated with an increased risk for POAG (OR, 1.004; 95% CI, 1.000-1.008; P = 0.029) and suspected glaucoma (OR, 1.005; 95% CI, 1.001-1.008; P = 0.013). We found genetic evidence supporting a potential causal association between increased CCT and the risk of POAG and suspected glaucoma in the European population. This findings indicates the clinical significance of CCT in the diagnosis and treatment of glaucoma. Further studies are needed to elucidate the underlying mechanisms of this causal relationship.

Genetic association of IL1B gene variants with primary glaucoma in a North Indian Punjabi cohort: An original study and meta-analysis.

Interleukin (IL) 1B is an important candidate gene in glaucoma pathogenesis as it affects the survival of retinal ganglion cells (RGCs). In the present study, -511T/C and +3953C/T polymorphisms in the IL1B were assessed as genetic risk factors for primary open angle (POAG) and angle closure glaucoma (PACG) in a North Indian Punjabi cohort comprising 867 samples (POAG cases = 307; PACG cases = 133 and controls = 427). Genetic association, diplotype and linkage disequilibrium (LD) analyses were performed. Corrections for confounding variables and multiple testing were applied. An updated meta-analysis was also performed. Pooled OR with 95% CI was calculated for dominant, over dominant, and recessive models. Level of heterozygosity among studies was tested using I2 statistic with fixed or random effect model based on the extent of heterogeneity. For -511T > C polymorphism, a positive association was observed with PACG under dominant (p = 0.038; OR = 0.65; pcorr = 0.011; OR = 0.55) and over dominant models (p = 0.010; OR = 0.59; pcorr = 0.001; OR = 0.46). Significant association of +3953C > T was also observed with POAG under dominant (p = 0.011; OR = 1.46; pcorr = 0.018; OR = 1.48) and PACG under recessive models (p < 0.0001; OR = 4.47; pcorr<0.0001; OR = 4.06). While C-C diplotype provided protection against primary glaucoma (0.67-fold; p = 0.0004), T-T and T-C diplotypes predisposed individuals to higher risk (1.31-fold; p = 0.030 and 1.36-fold; p = 0.022 respectively). In meta-analysis, a significant association between +3453 C>T and POAG was observed under dominant (pooled OR = 1.33, p = 0.0046) and over dominant (pooled OR = 1.25; p = 0.0269) models with overall heterogeneity of 15% and 0% respectively. The study provides strong evidence of IL1B variants in modifying genetic susceptibility to primary glaucoma in the targeted North Indian Punjabi population. Replication of the present findings in other populations, and functional studies are warranted to further assess the relevance of IL1B variants in the pathogenesis of primary glaucoma.

Development and characterization of a chronic high intraocular pressure model in New Zealand white rabbits for glaucoma research.

Glaucoma is a neurodegenerative disease characterized by visual field loss associated with optic nerve damage and ocular hypertension. The biological basis for the elevated intraocular pressure (IOP) is largely unknown, such that lowering the IOP is currently the only established treatment. Several animal models have been developed to elucidate the mechanism underlying the increased IOP and for use in drug discovery research, but their utility is often limited by the occurrence of severe intraocular inflammation and by technical challenges. In this study, we developed a rabbit glaucoma model that does not require experimental disease induction. Rabbits were chosen as the model because their eyeballs are similar in size to those of humans, and they are easy to breed. By crossing rabbit strains with inherited glaucoma, as indicated by obvious buphthalmos, we produced a strain that exhibits ocular hypertension. The IOP of the Ocular Hypertension (OH) rabbits was significantly higher than that of the wild type (WT; normal New Zealand white rabbits) from the age of 3 weeks to at least 22 weeks. The significantly larger corneal diameter of the OH rabbits indicated ocular enlargement, whereas there was no significant difference in corneal thickness compared with WT rabbits. Anterior segment ocular coherence tomography and gonioscopic observations revealed an open angle in the OH rabbits. Hematoxylin and eosin (HE) staining together with Masson's trichrome staining showed abnormal collagen accumulation in the angle of the OH rabbit's eyes. Furthermore, aqueous humor (AH) outflow imaging following an intravitreal injection of a fluorescent probe into the anterior chamber for tissue-section analysis revealed retention of the probe in the area of collagen deposition in the OH eyes. The OH rabbits also had a time-dependent increase in the cup/disc ratio. In conclusion, investigations using our newly developed rabbit model of open-angle ocular hypertension showed that abnormal accumulation of extracellular matrix at the angle increased AH outflow resistance in the conventional outflow pathway, leading to a high IOP. Furthermore, the OH rabbits exhibited glaucomatous optic disc cupping over time. These findings suggest the utility of the OH rabbits as a model for open-angle glaucoma (OAG).

Prescription of glucagon-like peptide 1 agonists and risk of subsequent open-angle glaucoma in individuals with type 2 diabetes mellitus.

Background: The glucagon-like peptide 1 receptor agonist (GLP-1RA) is an antidiabetic medication with vascular protection and anti-inflammatory properties. Theoretically, the use of GLP-1RA should inhibit the development of open-angle glaucoma (OAG) as both vascular damage and inflammation are associated with OAG. Therefore, our objective was to investigate the association between the application of GLP-1RA and the subsequent OAG in individuals with type 2 diabetes mellitus (T2DM). Methods: We conducted a retrospective cohort study by using data from the National Health Insurance Research Database (NHIRD) of Taiwan. Participants with T2DM were divided into those who used GLP-1RA and those who did not, forming the GLP-1RA and control groups. The primary outcome was the occurrence of OAG based on diagnostic codes. Cox proportional hazard regression was employed to calculate the adjusted hazard ratio (aHR) and 95% confidence interval (CI) for OAG. Results: 91 patients in the control group developed OAG, and 40 patients in the GLP-1RA group developed OAG. After adjustment for all covariates, the GLP-1RA group exhibited a significantly lower incidence of OAG compared with the control group (aHR: 0.712, 95% CI: 0.533-0.936. P = 0.0025). In the subgroup analyses, the association between GLP-1RA use and OAG incidence was more pronounced in patients with T2DM using GLP-1RA and aged younger than 60 years (P = 0.0438). Conclusion: The prescription of GLP-1RA is associated with a lower incidence of subsequent OAG in individuals with T2DM, and this association was more significant in patients with T2DM under the age of 60 years.

Phacoemulsification combined with Kahook Dual Blade Goniotomy versus with Trabectome in the treatment of open angle glaucoma.

PURPOSE: To compare the surgical effectiveness and safety of phacoemulsification combined with KDB (Phaco-KDB) and with Trabectome (Phaco-Trabectome) at 6 months follow-up in patients with open-angle glaucoma (OAG) METHODS: This comparative case series was conducted at Beijing Tongren Hospital, including patients diagnosed with OAG who underwent Phaco-KDB from November 2021 to April 2022 and Phaco-Trabectome from April 2017 to December 2017. Surgical success was defined as an IOP reduction ≥ 20% or a postoperative IOP ≤ 21 mmHg. Kaplan-Meier methods were used to calculate cumulative rates of success among groups RESULTS: A total of 35 eyes from 29 patients were included in the analysis. At 6-month, Both groups exhibited a significant reduction in IOP and the number of IOP-lowering medications compared to preoperative (P=0.01 and P<0.01, respectively). There were no significant differences among groups in terms of reducing IOP and the number of IOP-lowering medications (all P values<0.05). In the Phaco-KDB and Phaco-Trabectome groups, 53.8% and 45.0% of patients achieved an IOP reduction of ≥ 20%, while 92.3% and 85% achieved a mean IOP ≤ 21 mmHg 6 months after surgery. The incidence of IOP spike was 20%, and 3 eyes (8.6%) needed further surgery to control the IOP CONCLUSIONS: Both Phaco-KDB and Phaco-Trabectome demonstrate a significant reduction in IOP and the number of IOP-lowering medications. Phaco-Trabectome appears to provide a more predictable postoperative course in the early postoperative period compared to Phaco-KDB, and the postoperative mean IOP is lower in Phaco-KDB compared to Phaco-Trabectome, despite not being statistically significant.

Combined versus standalone XEN45 Gel Stent implantation in either phakic or pseudophakic patients: a case-matched study.

PURPOSE: To determine differing outcomes among either phakic or pseudophakic patients who received standalone XEN45 Gel Stent (Allergan, an AbbVie Company, CA, USA) implantation and patients who underwent combined surgery with phacoemulsification. METHODS: This retrospective single-center study involved 180 eyes of 180 participants who underwent XEN45 Gel Stent implantation, of which 60 eyes received combined surgery with phacoemulsification (combined group). Standalone stent implantation was performed on 60 phakic (phakic group) and on 60 pseudophakic eyes (pseudophakic group). The groups were matched in a ratio of 1:1:1 based on multiple criteria. Successful surgery was defined by three scores: IOP at the longest follow-up of < 21 mmHg (Score A) or < 18 mmHg (Score B) and an IOP reduction > 20% or IOP ≤ 15 mmHg and an IOP reduction ≥ 40% (Score C). In all scores, one open conjunctival revision was allowed, and additional repeat surgery was considered a failure. RESULTS: After an average follow-up time interval of 20.6 ± 12.6 months, there was a mean IOP-reduction by 37% among the entire cohort. Comparative analysis between the three groups did not show significant differences regarding postoperative IOP, postoperative medication score, side effects, revision rate, repeat surgery rate or success rate. A dysfunctional stent was detected in eight eyes (4%) during open conjunctival revision in 76 eyes. CONCLUSION: The clinical endpoints investigated did not differ significantly among either phakic or pseudophakic patients who received standalone stent implantation and patients who underwent combined surgery. However mean latency between primary stent implantation and first revision surgery after combined surgery was markedly shorter.

Contributing factors for intraocular pressure control in patients with mostly normal-tension glaucoma after initial Ex-PRESS drainage device implantation.

PURPOSE: To investigate the postoperative intraocular pressure (IOP) control and identify the factors associated with failure of initial Ex-PRESS surgery in patients with open-angle glaucoma for 3 years. METHODS: A total of 79 patients with medically uncontrolled open-angle glaucoma (55 normal-tension glaucoma and 24 primary open-angle glaucoma) were enrolled. All patients underwent Ex-PRESS implantation (including combined cataract surgery). The outcome measure was the survival rate using life table analysis, the failure was defined as IOP of > 18 mmHg (criterion A), > 15 mmHg (criterion B) or > 12 mmHg (criterion C) and/or IOP reduction of < 20% from baseline (each criterion) without any glaucoma medications. The Cox proportional hazards model was used to identify risk factors for IOP management defined as the above criterion.  RESULTS: The mean preoperative IOP was 19.3 ± 5.8 mmHg. At 36 months, the mean IOP was 11.8 ± 3.6 mmHg with a mean IOP change of 7.5 mmHg (reduction rate 39.0%). The cumulative probability of success was 58% (95%CI: 42-64%) (criterion A), 48% (95%CI: 37-59%) (criterion B) and 30% (95%CI: 20-40%) (criterion C). In multivariate analyses, factors that predicted poor IOP control included the intervention of bleb needling after 6 months after the surgery (HR: 2.43; 95%CI: 1.35-4.37; P = 0.032). Transient hypotony was observed in 4 patients. CONCLUSION: The implementation of bleb needling after Ex-PRESS surgery in the late postoperative period was suggested to be the main risk factor for achieving lower IOP.

An eternal hunt for glaucoma.

In the first issue of Graefe's Archive from 1854, Albrecht von Graefe wrote about glaucoma. Glaucoma comes from the Greek word "glaukos," gleaming, which was first used by Homer around 800 BCE. Since then, glaukos and glaucoma have taken on many different meanings. The terms blindness, cataract and glaucoma were used interchangeably and twisted together in incomprehensible contexts. Over 2500 years of glaucoma theories were upset by the discovery of the ophthalmoscope in 1851. The first reports of increased intraocular pressure appeared in the mid-seventeenth century, but it took over 200 years for this elevated pressure to be accepted by the ophthalmological community. The discovery of glaucoma simplex in 1861 was an important step forward. What did doctors know about glaucoma before 1850 and why did it take so long to classify glaucoma in its various categories? And why is it that we still do not know what the cause is for primary open angle glaucoma? I will try to answer some of these questions after a historical overview.

Choroidal thickness in juvenile open angle glaucoma: insights from a south asian case-control study.

PURPOSE: The purpose of this study is to compare choroidal thickness in juvenile open angle glaucoma (JOAG) and healthy controls using spectral domain optical coherence tomography (SD-OCT) and study its correlations. METHODS: In this case-control study, 56 eyes of 28 JOAG patients and an equal number of controls were recruited. SD-OCT was used to measure the choroidal thickness (ChT), in the macular region at 5 locations: subfoveal, 1500 µm and 3000 µm nasal and temporal to the foveal center, and in the peripapillary region at 6 locations: up to 1500 µm, nasal and temporal to the disc, respectively. The ChT and its correlations with age, intraocular pressure, cup-to-disc ratio, central corneal thickness, mean deviation, and axial length were studied. RESULTS: The average macular ChT in JOAG was 306.30 ± 56.49 µm vs. 277.12 ± 64.68 µm in controls. The average peripapillary ChT in JOAG was 197.79 ± 44.05 µm vs. 187.24 ± 38.89 µm in controls. The average total ChT (p = 0.042), the average macular ChT (p = 0.022), the subfoveal ChT (p = 0.022), the ChT 1500 µm (p < 0.001), and 3000 µm temporal to the fovea (p = 0.002) were significantly thicker in the JOAG group. In the JOAG group, the average macular ChT had a significant negative correlation with age, whereas axial length was positively correlated with the average peripapillary ChT. CONCLUSIONS: In this South Asian cohort of JOAG, the average total ChT, average macular ChT, subfoveal ChT, and ChT at 1500 µm, and 3000 µm temporal to the fovea were significantly thicker when compared to healthy controls.