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Background & Aims: Inflammation is involved in the pathogenesis of cataract, age-related macular degeneration (AMD), and possibly open-angle glaucoma (OAG). We assessed whether the inflammatory potential of diet (quantified using the dietary inflammatory index; DII) affects the incidence of these common blinding age-related eye diseases. Serum inflammation markers were investigated as possible mediators., Methods: Participants aged >45 years were selected from the prospective, population-based Rotterdam Study. From 1991 onwards, every 4-5 years, participants underwent extensive eye examinations. At baseline, blood samples and dietary data (using food frequency questionnaires) were collected. The DII was adapted based on the data available. Of the 7436 participants free of eye diseases at baseline, 4036 developed incident eye diseases during follow-up (cataract = 2895, early-intermediate AMD = 891, late AMD = 81, OAG = 169)., Results: The adapted DII (aDII) ranged from -4.26 (i.e., anti-inflammatory) to 4.53 (i.e., pro-inflammatory). A higher aDII was significantly associated with increased inflammation. A higher neutrophil-lymphocyte ratio (NLR) was associated with an increased risk of cataract and AMD. Additionally, complement component 3c (C3c) and systemic immune-inflammation index (SII) were associated with increased risks of cataract and late AMD, respectively. Every point increase in the aDII was associated with a 9% increased risk of cataract (Odds ratio [95% confidence interval]: 1.09 [1.04-1.14]). The NLR and C3c partly mediated this association. We also identified associations of the aDII with risk of AMD (early-intermediate AMD, OR [95% CI]: 1.11 [1.03-1.19]; late AMD, OR [95% CI]: 1.24 [1.02-1.53]). The NLR partly mediated these associations. The aDII was not associated with OAG., Conclusions: A pro-inflammatory diet was associated with increased risks of cataract and AMD. Particularly the NLR, a marker of subclinical inflammation, appears to be implicated. These findings are relevant for patients with AMD and substantiate the current recommendations to strive for a healthy lifestyle to prevent blindness., Competing Interests: Conflicts of interest CCWK: Consultant – Bayer, Laboratoires Théa, Novartis., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Testosterone may be a possible modifiable risk factor for open-angle glaucoma (OAG) and intraocular pressure (IOP), but evidence has been scarce and conflicting. In this study we evaluated the association of testosterone and its genetic predisposition with incident (i) OAG, IOP, retinal nerve fiber layer (RNFL), and ganglion cell-inner plexiform layer (GCL +)., Methods: Participants aged 45-100 years were derived from the prospective, population-based Rotterdam Study. Ophthalmic examinations and serum testosterone measurements (including bioavailable and free testosterone) were performed from 1991 onwards. Follow-up took place every 4-5 years. A total of 187 out of 7898 participants were diagnosed with incident (i) OAG during follow-up. Genotyping was performed in 165 glaucoma cases and 6708 controls. We calculated sex-specific weighted genetic risk scores (GRS) for total and bioavailable testosterone. Associations with iOAG were analyzed using multivariable logistic regression. Associations with IOP, RNFL, and GCL + were analyzed with multivariable linear regression. Analyses were stratified on sex and adjusted for at least age, body mass index, and follow-up duration., Results: In men, testosterone was not associated with iOAG. However, the GRS for higher total testosterone was associated with an increased iOAG risk (odds ratio [OR] with 95% confidence interval [95% CI]: 2.48 [1.18; 5.22], per unit). In women, higher values of bioavailable testosterone (2.05 [1.00; 4.18] per nmol/L) and free testosterone (1.79 [1.00; 3.20] per ng/dL) were significantly associated with increased risk of iOAG. Moreover, the GRS for higher bioavailable testosterone was associated with an increased iOAG risk (2.48 [1.09; 5.65], per unit). Higher bioavailable and free testosterone were adversely associated with IOP (0.58 [0.05; 1.10] per nmol/L and 0.47 [0.04; 0.90] per ng/dL). Higher total testosterone was inversely associated with peripapillary RNFL and GCL + (Beta [95% CI]: - 3.54 [- 7.02; - 0.06] per nmol/L and - 2.18 [- 4.11; - 0.25] per nmol/L, respectively)., Conclusions: In women, higher testosterone levels increased the risk of iOAG. Both IOP-dependent and IOP-independent mechanisms may underlie this association. Managing testosterone levels may be particularly relevant for the prevention of neurodegeneration in the eye. Future research should confirm these findings., (© 2023. The Author(s).)

Purpose: The purpose of this study was to describe the genetic relationship between smoking and glaucoma., Methods: We used summary-level genetic data for smoking initiation, smoking intensity (cigarettes per day [CPD]), intraocular pressure (IOP), vertical cup-disc ratio, and open-angle glaucoma (OAG) to estimate global genetic correlations (rg) and perform two-sample Mendelian randomization (MR) experiments that explored relations between traits. Finally, we examined associations between smoking genetic risk scores (GRS) and smoking traits with measured IOP and OAG in Rotterdam Study participants., Results: We identified weak inverse rg between smoking- and glaucoma-related traits that were insignificant after Bonferroni correction. However, MR analysis revealed that genetically predicted smoking initiation was associated with lower IOP (-0.18 mm Hg per SD, 95% confidence interval [CI] = -0.30 to -0.06, P = 0.003). Furthermore, genetically predicted smoking intensity was associated with decreased OAG risk (odds ratio [OR] = 0.74 per SD, 95% CI = 0.61 to 0.90, P = 0.002). In the Rotterdam Study, the smoking initiation GRS was associated with lower IOP (-0.09 mm Hg per SD, 95% CI = -0.17 to -0.01, P = 0.04) and lower odds of OAG (OR = 0.84 per SD, 95% CI = 0.73 to 0.98, P = 0.02) in multivariable-adjusted analyses. In contrast, neither smoking history nor CPD was associated with IOP (P ≥ 0.38) or OAG (P ≥ 0.54). Associations between the smoking intensity GRS and glaucoma traits were null (P ≥ 0.13)., Conclusions: MR experiments and GRS generated from Rotterdam Study participants support an inverse relationship between smoking and glaucoma., Translational Relevance: Understanding the genetic drivers of the inverse relationship between smoking and glaucoma could yield new insights into glaucoma pathophysiology.

Purpose: To assess the association between the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet and the incidence of open-angle glaucoma (iOAG), as well as the association between iOAG and two other well-established diets in the Netherlands, i.e., the Mediterranean diet and Dutch dietary guidelines., Methods: In the Rotterdam Study, participants were followed for iOAG since 1991, with intervals of approximately 5 years. A total of 170 participants developed iOAG during follow-up. Participants with iOAG were matched with healthy controls on age and sex in a case:control ratio of 1:5. The associations between food frequency questionnaire-derived diet adherences (baseline) and iOAG were analyzed using multivariable conditional logistic regression analyses. The associations between the diet adherences and intraocular pressure (IOP; a risk factor for OAG) were assessed using multivariable linear regression analyses., Results: Greater adherence to the MIND diet was associated with a decreased iOAG risk (odds ratio [95% confidence interval]: 0.80 [0.66 to 0.96], for each 10-percent increase in adherence). Food component analyses showed that, in particular a higher intake of green leafy vegetables, berries and fish tended to be protective for iOAG. No significant associations were observed between adherence to the Mediterranean diet or Dutch dietary guidelines and iOAG. Moreover, none of the three examined diets were associated with IOP., Conclusion: Adherence to the MIND diet was significantly associated with a lower incidence of OAG in contrast to adherence to the Mediterranean diet or the Dutch dietary guidelines. As this association was IOP-independent, the MIND diet may be particularly relevant for the prevention of neurodegeneration in the eye., (© 2022. The Author(s).)

Background: Trabeculectomy is the "gold standard" initial surgical procedure for open-angle glaucoma worldwide. During the last decade, the introduction of less invasive procedures, including new bleb-forming surgery such as the MicroShunt, has altered the approach of glaucoma management. At present, there is insufficient evidence comparing the effectiveness between these procedures nor versus trabeculectomy. Furthermore, there is no data available on patient impact and cost-effectiveness. This study aims to address this gap in evidence and establish whether MicroShunt implantation is non-inferior compared to trabeculectomy with regard to effectiveness and whether it is cost-effective., Methods: A multicentre, non-inferiority, randomised controlled trial (RCT) studying open-angle glaucoma with an indication for surgery will be conducted. Patients with previous ocular surgery except for phacoemulsification are excluded, as are patients with ocular comorbidity compromising the visual field or requiring a combined procedure. After informed consent is obtained, patients will be randomly allocated to the intervention, a PRESERFLO™ MicroShunt implantation, or the control group, trabeculectomy, using block randomisation (blocks of 2, 4 or 6 patients). In total, 124 patients will be randomised in a 1:1 ratio, stratified by centre. The primary endpoint will be intraocular pressure (IOP) one year after surgery. Secondary outcomes include IOP-lowering medication use, treatment failure, visual acuity, visual field progression, additional interventions, adverse events, patient-reported outcome measures (PROMs), and cost-effectiveness. Study outcomes will be measured up to 12 months postoperatively., Discussion: This study protocol describes the design of a multicentre non-inferiority randomised controlled trial. To this date, cost-effectiveness studies evaluating the MicroShunt have not been undertaken. This multicentre RCT will provide more insight into whether MicroShunt implantation is non-inferior compared to standard trabeculectomy regarding postoperative IOP and whether MicroShunt implantation is cost-effective., Trial Registration: ClinicalTrials.gov, Identifier: NCT03931564 , Registered 30 April 2019., (© 2023. The Author(s).)

Importance: Recent studies suggest that the diabetes drug metformin has a protective effect on open-angle glaucoma (OAG) and age-related macular degeneration (AMD). However, studies have not addressed the critical issue of confounding by indication, and associations have not been evaluated in a large prospective cohort., Objective: To determine the association between diabetes medication and the common eye diseases OAG, AMD, and cataract and to evaluate their cumulative lifetime risks in a large cohort study., Design, Setting, and Participants: This cohort study included participants from 3 independent cohorts from the prospective, population-based Rotterdam Study between April 23, 1990, and June 25, 2014. Participants were monitored for incident eye diseases (OAG, AMD, cataract) and had baseline measurements of serum glucose. Data on diabetes medication use and data from ophthalmologic examinations were gathered., Exposures: Type 2 diabetes (T2D) and the diabetes medications metformin, insulin, and sulfonylurea derivatives., Main Outcomes and Measures: Diagnosis and cumulative lifetime risk of OAG, AMD, and cataract., Results: This study included 11 260 participants (mean [SD] age, 65.1 [9.8]; 6610 women [58.7%]). T2D was diagnosed in 2406 participants (28.4%), OAG was diagnosed in 324 of 7394 participants (4.4%), AMD was diagnosed in 1935 of 10 993 participants (17.6%), and cataract was diagnosed in 4203 of 11 260 participants (37.3%). Untreated T2D was associated with a higher risk of OAG (odds ratio [OR], 1.50; 95% CI, 1.06-2.13; P = .02), AMD (OR, 1.35; 95% CI, 1.11-1.64; P = .003), and cataract (OR, 1.63; 95% CI, 1.39-1.92; P < .001). T2D treated with metformin was associated with a lower risk of OAG (OR, 0.18; 95% CI, 0.08-0.41; P < .001). Other diabetes medication (ie, insulin, sulfonylurea derivates) was associated with a lower risk of AMD (combined OR, 0.32; 95% CI, 0.18 to 0.55; P < .001). The cumulative lifetime risk of OAG was lower for individuals taking metformin (1.5%; 95% CI, 0.01%-3.1%) than for individuals without T2D (7.2%; 95% CI, 5.7%-8.7%); the lifetime risk of AMD was lower for individuals taking other diabetes medication (17.0%; 95% CI, 5.8%-26.8% vs 33.1%; 95% CI, 30.6%-35.6%)., Conclusions and Relevance: Results of this cohort study suggest that, although diabetes was clearly associated with cataract, diabetes medication was not. Treatment with metformin was associated with a lower risk of OAG, and other diabetes medication was associated with a lower risk of AMD. Proof of benefit would require interventional clinical trials.

Previous studies suggest that nitric oxide is involved in the regulation of the intraocular pressure (IOP) and in the pathophysiology of open-angle glaucoma (OAG). However, prospective studies investigating the association between dietary nitrate intake, a source of nitric oxide, and incident (i)OAG risk are limited. We aimed to determine the association between dietary nitrate intake and iOAG, and to evaluate the association between dietary nitrate intake and IOP. From 1991 onwards, participants were followed each five years for iOAG in the Rotterdam Study. A total of 173 participants developed iOAG during follow-up. Cases and controls were matched on age (mean ± standard deviation: 65.7 ± 6.9) and sex (%female: 53.2) in a case:control ratio of 1:5. After adjustment for potential confounders, total dietary nitrate intake was associated with a lower iOAG risk (odds ratio (OR) with corresponding 95% confidence interval (95% CI): 0.95 (0.91-0.98) for each 10 mg/day higher intake). Both nitrate intake from vegetables (OR (95% CI): 0.95 (0.91-0.98) for each 10 mg/day higher intake) and nitrate intake from non-vegetable food sources (OR (95% CI): 0.63 (0.41-0.96) for each 10 mg/day higher intake) were associated with a lower iOAG risk. Dietary nitrate intake was not associated with IOP. In conclusion, dietary nitrate intake was associated with a reduced risk of iOAG. IOP-independent mechanisms may underlie the association with OAG.

Purpose: To evaluate the long-term efficacy and safety of two minimally invasive glaucoma surgery implants with a subconjunctival drainage approach: the XEN45 Gel Stent ® (Xen) implant and the PRESERFLO™ MicroShunt (MicroShunt)., Methods: Retrospective comparative case series of primary open-angle glaucoma (POAG) patients with at least 6 months of follow-up after a MicroShunt or Xen implantation augmented with mitomycin C., Results: Forty-one eyes of 31 patients underwent Xen implantation, and 41 eyes of 33 patients, MicroShunt implantation. Baseline characteristics were similar, except for more combined surgeries with phacoemulsification in the Xen group (37% vs. 2%). Mean baseline IOP ± standard deviation dropped from 19.2 ± 4.4 to 13.8 ± 3.8 mmHg (n = 26) in the Xen group and from 20.1 ± 5.0 to 12.1 ± 3.5 (n = 14) in the MicroShunt group at 24 months of follow-up (p = 0.19, t-test). The number of IOP-lowering medications dropped from 2.5 ± 1.4 to 0.9 ± 1.2 in the Xen group and from 2.3 ± 1.5 to 0.7 ± 1.1 in the MicroShunt group. The probability of qualified success was 73% and 79% at 24 months of follow-up for the Xen and MicroShunt groups, respectively. Postoperative complications were usually mild and self-limiting. The number of bleb needling and secondary glaucoma surgery procedures was similar in both groups; however, in the Xen group more additional MicroPulse ® transscleral cyclophotocoagulation procedures were performed., Conclusion: Xen Gel Stent and PreserFlo MicroShunt implantations achieved comparable results in POAG eyes in terms of IOP-lowering and surgical success, with a similar high safety profile., (© 2020 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Background: We reviewed the literature on the aqueous humor (AH) proteome of primary open angle glaucoma (POAG) patients in order to obtain deeper insight into the pathophysiology of POAG., Methods: We searched Pubmed and Embase up to May 2019 for studies that compared AH protein composition between POAG (cases) and cataract (controls). Untargeted studies (measuring the whole proteome, by LC-MS/MS) were divided into two subgroups depending on the type of surgery during which POAG AH was collected: glaucoma filtration surgery (subgroup 1) or cataract surgery (subgroup 2). We reanalyzed the raw data (subgroup 1) or combined the reported data (subgroup 2) to perform GO enrichment (GOrilla) and pathway analysis (Pathvisio)., Results: Out of 93 eligible proteomic studies, seven were untargeted studies that identified 863 AH proteins. We observed 73 differentially expressed proteins in subgroup 1 and 87 differentially expressed proteins in subgroup 2. Both subgroups were characterized by activation of the acute immune response, dysregulation of folate metabolism and dysregulation of the selenium micronutrient network. For subgroup 1 but not for subgroup 2, proteins of the complement system were significantly enriched., Conclusion: AH proteome of POAG patients shows strong activation of the immune system. In addition, analysis suggests dysregulation of folate metabolism and dysregulation of selenium as underlying contributors. In view of their glaucoma surgery, POAG patients of subgroup 1 most likely are progressive whereas POAG patients in subgroup 2 most likely have stable POAG. The proteome difference between these subgroups suggests that the complement system plays a role in POAG progression., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose/Aim: Many genes have been associated with primary open-angle glaucoma (POAG). Knowing exactly where they are expressed in the eye helps to unravel POAG pathology and to select optimal targets for intervention. We investigated whether RNA in situ hybridization (RNA-ISH) is a convenient technique to obtain detailed pan-ocular expression data of these genes. We tested this for four diverse candidate POAG genes, selected because of unclear ocular distribution ( F5 and Dusp1) and relevance for potential new therapies ( Tnf, Tgfβr3 ). Optn , a POAG gene with well-known ocular expression pattern served as control. Methods: We made a list of candidate glaucoma genes reported in genetic studies. A table of their ocular expression at the tissue level was compiled using publicly available microarray data (the ocular tissue database). To add cellular detail we performed RNA-ISH for Optn, Tnf, Tgfβr3, F5 , and Dusp1 on eyes of healthy, 2-month-old, pigmented, and albino mice. Results: Expression of the Optn control matched with published immunohistochemistry data. Ocular expression of Tnf was generally low, with patches of higher Tnf expression, superficially in the corneal epithelium. F5 had a restricted expression pattern with high expression in the nonpigmented ciliary body epithelium and moderate expression in the peripapillary region. Tgfβr3 and Dusp1 showed ubiquitous expression. Conclusions: RNA-ISH is a suitable technique to determine the ocular expression pattern of POAG genes, adding meaningful cellular detail to existing microarray expression data. For instance, the high expression of F5 in the nonpigmented ciliary body epithelium suggests a role of this gene in aqueous humor dynamics and intraocular pressure. In addition, the ubiquitous expression of Tgfβr3 has implications for designing TGF-β-related glaucoma therapies, with respect to side effects. Creating pan-ocular expression maps of POAG genes with RNA-ISH will help to identify POAG pathways in specific cell types and to select targets for drug development.

Background: The aim of is to determine the association of vitamins with glaucoma by performing a systematic review and meta-analyses., Methods: Studies on the relation of vitamins and glaucoma published up to December 2017 were identified in the PubMed and Embase database. Data on vitamins (method of assessment), glaucoma (type and method of assessment), study characteristics and quality were recorded. In case of multiple studies for one nutrient a meta-analysis was performed., Results: A total of 629 articles were identified of which 36 were included in the systematic review. The meta-analysis included five of them (940 open-angle glaucoma (OAG) cases and 123,697 controls in total) and resulted in an odds ratio [95% confidence interval] (OR [95% CI]) of 0.58 [0.37-0.91] for dietary vitamin A, though heterogeneity was high (I² = 51%). After omitting studies that contributed significantly to the heterogeneity, the pooled OR [95% CI] was 0.45 [0.30-0.68] for dietary vitamin A on OAG (I² = 0%). For vitamin B1, C and E no significant association with OAG was found (OR [95% CI]: 0.84 [0.47-1.51]; 0.68 [0.38-1.22]; 0.95 [0.75-1.19]; respectively). However, after addressing heterogeneity, vitamin C showed a protective effect as well. Especially, foods high in these vitamins (e.g., dark green vegetables) were protective for OAG., Conclusions: Dietary intake of vitamin A and C showed a beneficial association with OAG; however, findings on blood levels of vitamins do not show a clear relation with OAG., Competing Interests: The authors declare no conflict of interest.

To determine the incidence of glaucomatous visual field loss (GVFL) two decades after the start of the Rotterdam Study, and to compare known risk factors for open-angle glaucoma (OAG) between different clinical manifestations of OAG. Of 6806 participants aged 55 years and older from the population-based Rotterdam Study, 3939 underwent visual field testing at baseline and at least one follow-up round. The ophthalmic examinations included optic disc assessment and measurements of intraocular pressure (IOP), refractive error, diastolic blood pressure (DBP), and height and weight. The incidence rate of GVFL was calculated. Associations with the risk factors age, gender, baseline IOP, family history, myopia, DBP, and body-mass index [BMI] were assessed using Cox regression, with different clinical manifestations of OAG as outcome measure (glaucomatous optic neuropathy (GON), GVFL, GVFL and GON, GVFL without GON, and GON without GVFL). Median follow-up was 11.1 (IQR 6.8-17.2; range 5.0-20.3) years. The incidence rate of GVFL was 2.9 (95% confidence interval 2.4-3.4) per 1000 person years (140 cases with incident GVFL in one (n = 113) or both (n = 27) eyes). Baseline IOP and age were significantly associated with all OAG outcomes (all p < 0.001); BMI showed a non-significant protective effect in all outcomes (p = 0.01 to p = 0.09). Gender, myopia, and DBP were not associated with any outcome. Our study provides an estimate of the long-term incidence of GVFL in a predominantly white population. The development of GVFL was strongly associated with baseline IOP and age. Risk factor profiles were similar for the different outcomes.

Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Glaucoma is an optic neuropathy characterized by loss of retinal ganglion cells (RGCs) and consequently visual field loss. It is a complex and heterogeneous disease in which both environmental and genetic factors play a role. With the advent of genome-wide association studies (GWASs), the number of loci associated with primary open-angle glaucoma (POAG) have increased greatly. There has also been major progress in understanding the genes determining the vertical cup-disc ratio (VCDR), disc area (DA), cup area (CA), intraocular pressure (IOP), and central corneal thickness (CCT). In this review, we will update and summarize the genetic loci associated so far with POAG, VCDR, DA, CA, IOP, and CCT. We will describe the pathways revealed and supported by genetic association studies, integrating current knowledge from human and experimental data. Finally, we will discuss approaches for functional genomics and clinical translation.

Primary open angle glaucoma (POAG) is a complex progressive optic nerve neuropathy triggered by both environmental and genetic risk factors. Several ocular tissues, including the ciliary body, trabecular meshwork and optic nerve head, and perhaps even brain tissues, are involved in a chain of pathological events leading to POAG. Genetic risk evidence for POAG came from family linkage-studies implicating a small number of disease genes (MYOC, OPTN, WDR36). Recent Genome Wide Association Studies (GWAS) identified a large number of new POAG loci and disease genes, such as CAV1, CDKN2B and GAS7. In the current study, we reviewed over 120 family and GWA studies. We selected in total 65 (candidate) POAG disease genes and proceeded to assess their function, mRNA expression in POAG relevant eye tissues and possible changes in disease state. We found that the proteins corresponding to these 65 (candidate) POAG disease genes take part in as few as four common functional molecular networks. Functions attributed to these 4 networks were developmental (dys)function, lipid metabolism, and inflammatory processes. For the 65 POAG disease genes, we reviewed the available (transgenic) mouse models of POAG, which may be useful for future functional studies. Finally, we showed that the 65 (candidate) POAG genes substantially increased the specificity and sensitivity of a discriminative POAG risk test. This suggests that personal risk assessment and personalized medicine for POAG are on the horizon. Taken together, the data presented are essential to comprehend the role of genetic variation in POAG, and may provide leads to understand the pathophysiology of POAG as well as other neurodegenerative disorders, such as Alzheimer's disease., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Purpose: To determine, first, which regions of 3-D optical coherence tomography (OCT) volumes can be segmented completely in the majority of subjects and, second, the relationship between analyzed area and thickness measurement test-retest variability., Methods: Three-dimensional OCT volumes (6 × 6 mm) centered around the fovea and optic nerve head (ONH) of 925 Rotterdam Study participants were analyzed; 44 participants were scanned twice. Volumes were segmented into 10 layers, and we determined the area where all layers could be identified in at least 95% (macula) or 90% (ONH) of subjects. Macular volumes were divided in 2 × 2, 4 × 4, 6 × 6, 8 × 8, or 68 blocks. We placed two circles around the ONH; the ONH had to fit into the smaller circle, and the larger circle had to fit into the segmentable part of the volume. The area between the circles was divided in 3 to 12 segments. We determined the test-retest variability (coefficient of repeatability) of the retinal nerve fiber layer (RNFL) and ganglion cell layer (RGCL) thickness measurements as a function of size of blocks/segments., Results: Eighty-two percent of the macular volume could be segmented in at least 95% of subjects; for the ONH, this was 65% in at least 90%. The radii of the circles were 1.03 and 1.84 mm. Depending on the analyzed area, median test-retest variability ranged from 8% to 15% for macular RNFL, 11% to 22% for macular RGCL, 5% to 11% for the two together, and 18% to 22% for ONH RNFL., Conclusions: Test-retest variability hampers a detailed analysis of 3-D OCT data. Combined macular RNFL and RGCL thickness averaged over larger areas had the best test-retest variability.

Background: It is largely unknown if corticosteroid-induced open-angle glaucoma (OAG) is an entity that is limited to a few susceptible individuals or whether it contributes significantly to the overall population burden of OAG., Objective: The aim of this study was to determine whether there is an association between corticosteroid use and the incidence of OAG in the general elderly population., Methods: A prospective population-based cohort study was conducted in a general community setting. 3,939 participants of the Rotterdam Study aged 55 years and older for whom data from ophthalmic examinations at baseline and follow-up were available and who did not have glaucoma at baseline were included (baseline examination from 1991 to 1993; follow-up examinations from 1997 to 1999 and from 2002 to 2006). Ophthalmic examinations, including measurement of the intraocular pressure, assessment of the optic nerve head and perimetry, were performed at baseline and follow-up. The use of corticosteroids was monitored continuously during follow-up. Corticosteroids were stratified into five groups: ophthalmic steroids, inhaled steroids, nasal steroids, oral steroids and steroid ointments. Associations between the use of corticosteroids and incident OAG were assessed using logistic regression models. The study outcome measures were the odds ratios (ORs) of associations between the use of corticosteroids and incident OAG., Results: During a mean follow-up of 9.8 years, 108 participants (2.8%) developed OAG. The median number of steroid prescriptions during follow-up was 2 for ophthalmic, 7 for inhaled, 2 for nasal and 2 for oral steroids, and 3 for steroid ointments. The OR of the use of ophthalmic steroids was 1.04 [95% confidence interval (CI) 0.66, 1.65; p = 0.86], inhaled steroids 0.79 (95% CI 0.42, 1.48; p = 0.46), nasal steroids 1.26 (95% CI 0.74, 2.13; p = 0.40), oral steroids 1.03 (95% CI 0.65, 1.64; p = 0.89) and steroid ointments 0.70 (95% CI 0.47, 1.05; p = 0.086). These analyses were adjusted for age, sex, high myopia and family history of glaucoma. The small median numbers of prescriptions made it difficult to evaluate dose-response relationships., Conclusion: None of the classes of steroids were associated with the incidence of OAG in this elderly population.

Purpose: To determine the associations between the use of antithrombotic drugs and incident open-angle glaucoma (OAG)., Methods: Ophthalmic examinations including measurements of the IOP and perimetry were performed at baseline and follow-up in 3939 participants of the prospective population-based Rotterdam Study who did not have OAG at baseline. The use of antithrombotic drugs was monitored continuously during follow-up. Antithrombotic drugs were stratified into anticoagulants and platelet aggregation inhibitors. Associations between incident OAG and the use of antithrombotic drugs were assessed using Cox regression; the model was adjusted for age, sex, baseline IOP and IOP-lowering treatment, family history of glaucoma, and myopia. Associations between antithrombotic drugs and IOP at follow-up were analyzed with multiple linear regression., Results: During a mean follow-up of 9.8 years, 108 participants (2.7%) developed OAG. The hazard ratio for anticoagulant use was 0.90 (95% confidence interval [CI], 0.55-1.48; P = 0.69) and for platelet aggregation inhibitors 0.80 (0.53-1.21; P = 0.28). There was no trend towards a reduced or increased risk of incident OAG with prolonged anticoagulant use (P value for trend 0.84) or platelet aggregation inhibitor use (0.59). There was a significant IOP-lowering effect of anticoagulants (-0.31 mm Hg; 95% CI, -0.58 to -0.04 mm Hg; P = 0.025) but not of platelet aggregation inhibitors (P = 0.06). The IOP-lowering effect of anticoagulants disappeared after additional adjustment for the use of systemic beta-blockers., Conclusions: Use of anticoagulants or platelet aggregation inhibitors appears not to be associated with incident OAG.

Open-angle glaucoma (OAG) is the commonest cause of irreversible blindness worldwide. Apart from an increased intraocular pressure (IOP), oxidative stress and an impaired ocular blood flow are supposed to contribute to OAG. The aim of this study was to determine whether the dietary intake of nutrients that either have anti-oxidative properties (carotenoids, vitamins, and flavonoids) or influence the blood flow (omega fatty acids and magnesium) is associated with incident OAG. We investigated this in a prospective population-based cohort, the Rotterdam Study. A total of 3502 participants aged 55 years and older for whom dietary data at baseline and ophthalmic data at baseline and follow-up were available and who did not have OAG at baseline were included. The ophthalmic examinations comprised measurements of the IOP and perimetry; dietary intake of nutrients was assessed by validated questionnaires and adjusted for energy intake. Cox proportional hazard regression analysis was applied to calculate hazard ratios of associations between the baseline intake of nutrients and incident OAG, adjusted for age, gender, IOP, IOP-lowering treatment, and body mass index. During an average follow-up of 9.7 years, 91 participants (2.6%) developed OAG. The hazard ratio for retinol equivalents (highest versus lowest tertile) was 0.45 (95% confidence interval 0.23-0.90), for vitamin B1 0.50 (0.25-0.98), and for magnesium 2.25 (1.16-4.38). The effects were stronger after the exclusion of participants taking supplements. Hence, a low intake of retinol equivalents and vitamin B1 (in line with hypothesis) and a high intake of magnesium (less unambiguous to interpret) appear to be associated with an increased risk of OAG.

Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p=1.4×10(-8)), and with rs7555523, located in TMCO1 at 1q24.1 (p=1.6×10(-8)). In a meta-analysis of 4 case-control studies (total N = 1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p=2.4×10(-2) for rs11656696 and p=9.1×10(-4) for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation., Competing Interests: The authors have declared that no competing interests exist.

Background: Open-angle glaucoma (OAG) is a progressive neurodegenerative disease that may lead to blindness. An elevated intraocular pressure (IOP) is its major risk factor. OAG treatment is currently exclusively directed towards the lowering of the IOP. IOP lowering does not prevent disease progression in all patients and thus other treatment modalities are needed. Earlier studies reported cholesterol-lowering drugs to have neuroprotective properties. The aim of this study was to determine the associations between the use of cholesterol-lowering drugs and incident OAG., Methodology/principal Findings: Participants in a prospective population-based cohort study underwent ophthalmic examinations, including IOP measurements and perimetry, at baseline and follow-up. The use of statins and non-statin cholesterol-lowering drugs was monitored continuously during the study. Associations between the use of cholesterol-lowering drugs and incident OAG were analyzed with Cox regression; associations between cholesterol-lowering drugs and IOP at follow-up were analyzed with multiple linear regression. During a mean follow-up of 9.8 years, 108 of 3939 eligible participants (2.7%) developed OAG. The hazard ratio for statin use was 0.54 (95% confidence interval 0.31-0.96; P = 0.034) and for non-statin cholesterol-lowering drugs 2.07 (0.81-5.33; P = 0.13). The effect of statins was more pronounced with prolonged use (hazard ratio 0.89 [0.41-1.94; P = 0.77] for use two years or less; 0.46 [0.23-0.94; P = 0.033] for use more than two years; P-value for trend 0.10). The analyzes were adjusted for age and gender, baseline IOP and IOP-lowering treatment, the family history of glaucoma, and myopia. There was no effect of statins on the IOP., Conclusions/significance: Long-term use of statins appears to be associated with a reduced risk of OAG. The observed effect was independent of the IOP. These findings are in line with the idea that statins have neuroprotective properties and may open a way to a new OAG treatment modality.

Objective: Genome-wide association studies have revealed new insights into the genetic determinants of open-angle glaucoma (OAG). This study was performed to determine to what extent variants within established genes (MYOC, OPTN, and WDR36) and newly identified common genetic variants (ATOH7, CDKN2B, and SIX1) contribute to the risk of OAG., Design: Population-based setting, family-based setting, and a case-control study., Participants: The Rotterdam Study I cohort (N = 5312; mean age±standard deviation [SD], 68.0±8.4 years). Findings were replicated in the Genetic Research in Isolated Populations combined with the Erasmus Rucphen Family study (N = 1750; mean age±SD, 48.3±15.2 years), and a cohort from Southampton (N = 702; mean age±SD, 72.5±10.7 years)., Methods: After identifying common variants associated with OAG within the established genes, the risk of OAG was analyzed using logistic regression. Discriminative accuracy was assessed by comparing the area under the receiver operator characteristic curve (AUC) for models, including the number of risk alleles, intraocular pressure, age, and gender, with the AUC for the same model but without the risk alleles., Main Outcome Measures: Odds ratios and AUCs of individual and combined risk alleles., Results: No consistent significant associations for the established genes (MYOC, OPTN, and WDR36) with OAG were found. However, when comparing the load of risk variants between cases and controls, 2 of 3 studies showed a significant increased risk of OAG for participants carrying more risk alleles of the 3 established genes. When combining all 6 genes, participants carrying a high number of risk alleles (highest tertile) had a 2.29-fold to 3.19-fold increase in risk of OAG compared with those carrying only a few risk alleles. The addition of the newly identified genes to IOP, age, and gender resulted in a higher AUC compared with the AUC without the newly identified genes (P = 0.027)., Conclusions: A significant contribution to the risk of OAG was found for the new common variants identified by recent genome-wide association studies, but not for variants within the established genes. Participants carrying a high number of risk alleles had an approximately 3-fold increase in the risk of OAG compared with those with a low number of risk alleles., Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article., (Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine the association between the ocular perfusion pressure (OPP; essentially the difference between the blood pressure and the intraocular pressure [IOP]) and incident open-angle glaucoma (OAG)., Methods: A subset of 3882 participants of the population-based Rotterdam Study for whom data from ophthalmic examinations at baseline and follow-up and blood pressure measurements at baseline were available, and who did not have OAG at baseline, were included. Associations between the mean, systolic and diastolic OPP, and incident OAG were assessed using Cox regression models adjusted for age and sex, with and without adjustment for IOP., Results: During a mean follow-up of 9.8 years, 103 participants (2.7%) developed OAG. The association between the mean OPP and incident OAG was not significant (hazard ratio 0.995 per mm Hg increase in mean OPP; 95% confidence interval 0.971-1.019) when adjusted for IOP, but became significant if not adjusted for IOP (0.968; 0.945-0.992). The systolic and diastolic OPP showed a pattern similar to that of the mean OPP, though less significant., Conclusions: The OPP appears to be associated with incident OAG but this association seems to be due to the fact that the IOP, a strong risk factor for OAG, is part of the OPP, rather than that OPP is an independent OAG risk factor itself.

Open-angle glaucoma (glaucoma) is a major eye disorder characterized by optic disc pathology. Recent genome-wide association studies identified new loci associated with clinically relevant optic disc parameters, such as the optic disc area and vertical cup-disc ratio (VCDR). We examined to what extent these loci are involved in glaucoma. The loci studied include ATOH7, CDC7/TGFBR3 and SALL1 for optic disc area, and CDKN2B, SIX1, SCYL1/LTBP3, CHEK2, ATOH7 and DCLK1 for VCDR. We performed a meta-analysis using data from six independent studies including: the Rotterdam Study (n= 5736), Genetic Research in Isolated Populations combined with Erasmus Rucphen Family study (n= 1750), Amsterdam Glaucoma Study (n= 296) and cohorts from Erlangen and Tübingen (n= 1363), Southampton (n= 702) and deCODE (n= 36 151) resulting in a total of 3161 glaucoma cases and 42 837 controls. Of the eight loci, we found significant evidence (P= 1.41 × 10(-8)) for the association of CDKN2B with glaucoma [odds ratio (OR) for those homozygous for the risk allele: 0.76; 95% confidence interval (CI): 0.70-0.84], for the role of ATOH7 (OR: 1.28; 95% CI: 1.12-1.47) and for SIX1 (OR: 1.20; 95% CI: 1.10-1.31) when adjusting for the number of tested loci. Furthermore, there was a borderline significant association of CDC7/TGFBR3 and SALL1 (both P= 0.04) with glaucoma. In conclusion, we found consistent evidence for three common variants (CDKN2B, ATOH7 and SIX1) significantly associated with glaucoma. These findings may shed new light on the pathophysiological protein pathways leading to glaucoma, and point to pathways involved in the growth and development of the optic nerve.

Objective: To determine whether lifestyle-related risk factors, such as socioeconomic status, smoking, alcohol consumption, and obesity, are associated with open-angle glaucoma (OAG)., Methods: Participants from the Rotterdam Study, a prospective population-based cohort study, were considered eligible if they participated at both baseline and follow-up and if they had no OAG at baseline. All participants underwent an identical ophthalmologic examination at all visits, including intraocular pressure measurements, optic nerve head assessment, and perimetry. Lifestyle-related factors were assessed by questionnaires by trained research assistants or measured during the examinations (body mass index and waist to hip ratio). Cox proportional hazard regression analysis was applied to calculate hazard ratios., Results: Of 3939 eligible participants, 108 (2.7%) developed OAG during 9.7 years' mean follow-up. No statistically significant effect of socioeconomic status, smoking, or alcohol intake was found. In women, each unit increase in body mass index resulted in a 7% decrease in the risk of developing OAG (P = .04). There was a significant increasing effect of body mass index on intraocular pressure (P < .001) in women., Conclusions: Obesity appears to be associated with a higher intraocular pressure and a lower risk of developing OAG. These associations were only present in women. Other lifestyle-related factors, such as socioeconomic status, smoking, and alcohol consumption, were not associated with OAG.

Background: Although the vertical cup-disc ratio (VCDR) and intraocular pressure (IOP) are important determinants of open angle glaucoma (OAG), it is unclear to what extent the genetic origin of these traits overlap with those of OAG. We evaluated whether the same genes that determine VCDR and IOP also predict OAG., Methods: Genetic risk scores were constructed from single nucleotide polymorphisms (SNPs) using genome wide association data of 9326 participants from the Rotterdam Study cohorts (mean ± SD age: 64.6 ± 9.1 years). These risk scores were used to calculate the explained variance of VCDR and IOP in an independent cohort (Erasmus Rucphen Family study) consisting of 1646 participants (mean ± SD age: 46.8 ± 14.1 years) and the OAG risk in a subset of the Rotterdam Study cohorts. To evaluate false positive findings, we generated two new variables containing randomly sampled values to serve as a negative control., Results: The explained variance of VCDR increased when increasing the number of SNPs included in the risk score, suggesting a polygenic model. We found no clear evidence for a similar model for IOP, suggesting that a small number of SNPs determine the susceptibility to IOP. The SNPs related to IOP in terms of p values contributed little to VCDR. The risk scores associated with VCDR were also associated significantly with OAG. This suggests a common polygenic background for VCDR and OAG CONCLUSIONS: We found evidence for a polygenic model underlying one of the major traits of OAG, VCDR, and OAG itself. The IOP did not show any evidence for such a model.

Purpose: To determine the 10-year incidence of glaucomatous visual field loss (GVFL) and to investigate the influence of risk factors for open-angle glaucoma on this incidence., Design: Population-based cohort study., Participants: Participants aged > or =55 years from the Rotterdam Study., Methods: Of the 7983 participants in the Rotterdam Study, 6806 underwent ophthalmic examinations at baseline (1990-1993). In 6723 of these 6806 participants (99%), both visual field screening and an assessment of the optic disc were performed. After exclusion of 93 participants with GVFL at baseline, 6630 participants at risk of developing GVFL remained. These participants underwent similar ophthalmic examinations during 2 follow-up visits (1997-1999 and 2002-2006). The incidence of GVFL was determined as an incidence rate and recalculated to a 10-year risk. Risk factors for open-angle glaucoma (age, gender, positive family history of glaucoma, baseline intraocular pressure (IOP), myopia, and baseline vertical cup-to-disc ratio [VCDR]) were assessed using Cox regression. The dependent variable was the development of GVFL., Main Outcome Measures: Ten-year risk and incidence rates of GVFL. Hazard ratios of the above-mentioned risk factors., Results: Of 6630 participants, 3939 (59%) completed at least 1 follow-up examination and 2571 (39%) completed both; 108 participants developed GVFL. The overall incidence rate and 10-year risk of GVFL were 2.9 per 1000 person-years (95% confidence interval [CI], 2.4-3.5) and 2.8% (2.3-3.4), respectively. The 10-year risk increased from 1.9% at age 55 to 59 years to 6.4% at age > or =80 years (P<0.001). The incidence increased by 11% per millimeter of mercury increase in IOP (hazard ratio 1.11; 95% CI, 1.06-1.15). Male gender (1.62; 1.10-2.38), high myopia (spherical equivalent < or =-4 D myopic; 2.31; 1.19-4.49), and a baseline VCDR above the 97.5th percentile (4.64; 2.72-7.91) were associated with the development of GVFL. A positive family history was only significantly associated with the development of GVFL if IOP was removed from the model (2.0; 1.2-3.3; P = 0.012)., Conclusions: These data provide an estimate of the incidence of GVFL in a white population. The development of GVFL was related to higher IOP, older age, high myopia, male gender, a positive family history of glaucoma, and a larger baseline VCDR., (Copyright © 2010 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Glaucoma, a main cause of blindness in the developed world, is characterized by progressive degeneration of retinal ganglion cells (RGCs), resulting in irreversible loss of vision. Although members of the neurotrophin gene family in various species are known to support the survival of numerous neuronal populations, including RGCs, it is less clear whether they are also required for survival and maintenance of adult neurons in humans. Here, we report seven different heterozygous mutations in the Neurotrophin-4 (NTF4) gene accounting for about 1.7% of primary open-angle glaucoma patients of European origin. Molecular modeling predicted a decreased affinity of neurotrophin 4 protein (NT-4) mutants with its specific tyrosine kinase receptor B (TrkB). Expression of recombinant NT-4 carrying the most frequent mutation was demonstrated to lead to decreased activation of TrkB. These findings suggest a pathway in the pathophysiology of glaucoma through loss of neurotrophic function and may eventually open the possibility of using ligands activating TrkB to prevent the progression of the disease.