The gut microbiome and primary open angle glaucoma: Evidence for a 'gut-glaucoma' axis?

Glaucoma presents an epidemiological burden as the leading cause of irreversible blindness globally and the most common cause of preventable blindness. While elevated intraocular pressure is the strongest modifiable risk factor, the exact mechanisms of retinal ganglion cell damage leading to progressive vision loss are not entirely understood. Studies of other neurodegenerative diseases show a potential for human gut microbiome dysbiosis to play a pathogenic role. An investigation into whether the microbiome, a potential modifiable risk factor, has significance in glaucoma enables exploration of prophylactic or additive treatments. Elevated population levels of specific bacterial species have been noted in glaucoma patients, particularly Prevotellaceae, Enterobacteriaceae and Escherichia coli, while Megomonas is speculated to be protective. Evidence also points to systemic neuro-inflammation and disruption of autoimmune processes as a result of imbalances in both human and animal models, where heat shock proteins may contribute to pathogenesis. Further research into the influence of gut microbiome on pathogenesis offers a chance to minimise irreversible vision loss in glaucoma.

Assessment of the iCare HOME2, a New Intraocular Pressure Self-Measurement Tonometer.

PRCIS: The iCare HOME2 tonometer generally can be considered reliable for most eyes and clinical settings, although it may produce slightly overestimated or underestimated intraocular pressure (IOP) readings in thicker and thinner corneas, respectively. PURPOSE: To evaluate the accuracy, correlation, and analysis of differences in IOP measurements between the gold standard Goldmann applanation tonometer (GAT) and the new, self-measurement iCare HOME2 tonometer (icare). PATIENTS AND METHODS: In this retrospective study, patients were randomly selected from those who attended a routine examination in our clinic. After a complete ocular examination, each patient's IOP was measured and recorded with GAT and iCare HOME2. Central corneal thickness was measured. Eyes with any corneal morbidity were excluded. Pearson correlation coefficient was used to determine the correlation between paired IOP measurements. Bland-Altman plots were graphed for the analysis of differences in IOP between the instruments. RESULTS: One hundred thirty-five eyes of 70 patients were included in the study. The mean IOP measured with GAT was 16.3 ± 6.5 mm Hg (range: 3-56). The mean IOP measured with iCare HOME2 was 16.5 ± 7.3 mm Hg (range: 3-55), ( P = 0.47). A strong, significant positive correlation was found for paired IOP measurements by the 2 instruments ( r = 0.94; P < 0.0001). A small systematic proportional bias was seen for the paired IOP measurements, meaning that with higher IOPs the iCare HOME2 yielded higher IOP readings than GAT, but this difference was clinically insignificant. The instrument underestimated IOPs with corneas thinner than 522 µm, whereas it overestimated IOPs when corneas were thicker than this. CONCLUSION: The iCare HOME2 could be a reliable tonometer for most eyes and clinical settings. Central corneal thickness measurement is recommended in patients who use the instrument.

Efficient capture of high-quality real-world data on treatments for glaucoma: the Fight Glaucoma Blindness! Registry.

OBJECTIVE: To describe the development and implementation of a web-based high-quality data collection tool to track the outcomes of glaucoma treatments in routine practice. METHODS AND ANALYSIS: This is a prospective observational registry study. An international steering committee undertook an iterative structured process to define a minimum, patient-centred data set designed to track outcomes of glaucoma treatment. The outcomes were coded into a web-based programme allowing easy access for rapid data entry. Clinicians receive personal reports enabling instant audit of their outcomes. Analyses of aggregated anonymised data on real-world outcomes are analysed and periodically reported with the goal of improving patient care. RESULTS: The minimum data set developed by the international steering committee includes the following: a baseline visit captures 13 mandatory fields in order to accurately phenotype each patient's subtype of glaucoma and to allow comparison between services, and a follow-up visit includes only four mandatory fields to allow completion within 30 s.Currently, there are 157 surgeons in 158 ophthalmology practices across Australia and New Zealand who are registered. These surgeons are tracking 5570 eyes of 3001 patients and have recorded 67 074 visits. The median number of eyes per surgeon is 22 eyes with a range of 1-575. The most common glaucoma procedure, excluding cataract surgery, is iStent inject, with 2316 cases. CONCLUSION: This software tool effectively facilitates data collection on safety and efficacy outcomes of treatments for different subgroups of glaucoma within a real-world setting. It provides a template to evaluate new treatments as they are introduced into practice.

Childhood and Early Onset Glaucoma Classification and Genetic Profile in a Large Australasian Disease Registry.

PURPOSE: To report the relative frequencies of childhood and early onset glaucoma subtypes and their genetic findings in a large single cohort. DESIGN: Retrospective clinical and molecular study. PARTICIPANTS: All individuals with childhood glaucoma (diagnosed 0 to <18 years) and early onset glaucoma (diagnosed 18 to <40 years) referred to a national disease registry. METHODS: We retrospectively reviewed the referrals of all individuals with glaucoma diagnosed at <40 years of age recruited to the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG). Subtypes of glaucoma were determined using the Childhood Glaucoma Research Network (CGRN) classification system. DNA extracted from blood or saliva samples underwent sequencing of genes associated with glaucoma. MAIN OUTCOME MEASURES: The phenotype and genotype distribution of glaucoma diagnosed at <40 years of age. RESULTS: A total of 290 individuals (533 eyes) with childhood glaucoma and 370 individuals (686 eyes) with early onset glaucoma were referred to the ANZRAG. Primary glaucoma was the most prevalent condition in both cohorts. In the childhood cohort, 57.6% of individuals (167/290, 303 eyes) had primary congenital glaucoma (PCG), and 19.3% (56/290, 109 eyes) had juvenile open-angle glaucoma. Juvenile open-angle glaucoma constituted 73.2% of the early onset glaucoma cohort (271/370, 513 eyes). Genetic testing in probands resulted in a diagnostic yield of 24.7% (125/506) and a reclassification of glaucoma subtype in 10.4% of probands (13/125). The highest molecular diagnostic rate was achieved in probands with glaucoma associated with nonacquired ocular anomalies (56.5%). Biallelic variants in CYP1B1 (n = 29, 23.2%) and heterozygous variants in MYOC (n = 24, 19.2%) and FOXC1 (n = 21, 16.8%) were most commonly reported among probands with a molecular diagnosis. Biallelic CYP1B1 variants were reported in twice as many female individuals as male individuals with PCG (66.7% vs. 33.3%, P = 0.02). CONCLUSIONS: We report on the largest cohort of individuals with childhood and early onset glaucoma from Australasia using the CGRN classification. Primary glaucoma was most prevalent. Genetic diagnoses ascertained in 24.7% of probands supported clinical diagnoses and genetic counseling. International collaborative efforts are required to identify further genes because the majority of individuals still lack a clear molecular diagnosis.

Brinzolamide/brimonidine fixed-dose combination bid as an adjunct to a prostaglandin analog for open-angle glaucoma/ocular hypertension.

PURPOSE: To evaluate the additive intraocular pressure-lowering effect of twice-daily brinzolamide 1%/brimonidine 0.2% fixed-dose combination (BBFC) as an adjunct to a prostaglandin analog (PGA) in patients with open-angle glaucoma or ocular hypertension insufficiently controlled with PGA monotherapy. METHODS: In this Phase 4, double-masked trial, patients aged ⩾18 years, with a mean intraocular pressure of ⩾19 and <32 mm Hg in at least one eye were randomized (1:1) to receive BBFC + PGA (n = 96) or vehicle + PGA (n = 92) for 6 weeks. The primary endpoint was the mean change in diurnal intraocular pressure from baseline (averaged over 09:00 and 11:00 h) at Week 6. RESULTS: The mean diurnal intraocular pressure at baseline was similar in the BBFC + PGA (22.8 mm Hg) and vehicle + PGA (22.9 mm Hg) groups. The least squares mean change in diurnal intraocular pressure from baseline at Week 6 was greater with BBFC + PGA (-5.59 mm Hg (95% confidence interval: -6.2 to -5.0)) than with vehicle + PGA (-2.15 mm Hg (95% confidence interval: -2.7 to -1.6)); the treatment difference was statistically significant in favor of BBFC + PGA (-3.44 mm Hg, (95% confidence interval: -4.2 to -2.7); p < 0.001). Ocular adverse events were reported in 21.1% and 8.7% of patients in the BBFC + PGA and vehicle + PGA groups, respectively. The most frequent ocular adverse event was ocular hyperemia (5.3%) in the BBFC + PGA group and blurred vision (2.2%) in the vehicle + PGA group. CONCLUSION: BBFC + PGA significantly reduced mean diurnal intraocular pressure than PGA alone in patients with open-angle glaucoma or ocular hypertension. The safety findings with BBFC + PGA were consistent with the known safety profile of the individual medications.

Facilitating Patient-Ophthalmologist Dialog: A Call for a Patient-focused Classification of Glaucoma Diagnosis.

We present a recommended patient-oriented glaucoma classification to facilitate patient-ophthalmologist dialog. By improving patients' understanding of their precise diagnosis, we hope to optimize management outcomes. We invite our colleagues to evolve this classification with us.

Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression.

Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOC variant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases (P = 0.004) and surgical intervention in advanced disease (P = 3.6 × 10-6). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups.

Selective laser trabeculoplasty versus topical medication as initial glaucoma treatment: the glaucoma initial treatment study randomised clinical trial.

BACKGROUND/AIMS: To determine if selective laser trabeculoplasty (SLT) is superior to topical medication as a first-line treatment for glaucoma on quality of life (QoL) and clinical outcomes. METHODS: In this international, longitudinal, multisite randomised controlled trial, treatment naïve mild-to-moderate primary open angle or exfoliation glaucoma patients were randomised 1:1 to SLT or topical medication. Glaucoma-specific QoL (primary outcome) was measured using the Glaucoma Outcomes Assessment Tool (GOAT; 342 items, 12 domains). Secondary outcomes included rate of successful intraocular pressure (IOP) reduction (>25% reduction from baseline) and presence of ocular surface disease including conjunctival hyperaemia and eyelid erythema. Our intention-to-treat analysis was performed at months 12 and 24. RESULTS: Of 167 enrolled patients, 83 and 84 were randomised to SLT and topical medication, respectively; and 145 (n=75 SLT, n=70 medication) completed 24-month follow-up. While both treatment arms achieved significant within-group gains in GOAT outcomes at both endpoints, SLT patients reported a greater between-group improvement in 'social well-being' compared with medication patients (mean±SE=0.28±0.13; p=0.034) at 24 months. At month 24, the rate of successful IOP reduction was 18.6% (95% CI 3.0% to 34.3%, p=0.022) higher (absolute difference) in the medication compared with SLT group. More individuals in the medication group had conjunctival hyperaemia and eyelid erythema compared with SLT at 24 months. CONCLUSION: Overall, we did not find evidence that SLT was superior to medication in improving glaucoma-specific QoL. While we found superior IOP reduction in the medication arm, eyelid erythema and conjunctival hyperaemia were more prevalent in these patients compared with the SLT group. TRIAL REGISTRATION: ACTRN12611000720910.

Current management of glaucoma.

Glaucoma is an irreversible progressive optic neuropathy, for which the major proven treatment is to lower the intraocular pressure (IOP). Five groups of IOP-lowering eye drops have varying mechanisms of action. Some drops, such as ß-blockers and α-2 agonists, have potentially serious systemic side effects. Acetazolamide is the only available oral agent; it is effective at lowering IOP, but significant side effects relegate its use usually to refractory glaucoma. Two new eye drops, netarsudil and latanoprostene bunod, have recently been approved by the United States Food and Drug Administration. Both have novel IOP-lowering mechanisms and target the conventional aqueous outflow system. Selective laser trabeculoplasty is a gentle treatment that enhances conventional aqueous outflow. It may be used as an initial treatment, as a substitute for eye drops, or to delay glaucoma drainage surgery. Recent advancements in glaucoma surgery have seen an influx of minimally invasive glaucoma surgery devices, which are being used more frequently and earlier on in the treatment paradigm. As limited long term data are available, trabeculectomy remains the gold standard IOP-lowering procedure. Improvements in drug delivery are on the horizon. Drug-eluting devices and implants are able to deliver the drug closer to the receptors for an extended period of time. This will improve treatment adherence and efficacy, which are major limitations with current medical therapy.

Myocilin Gene Gln368Ter Variant Penetrance and Association With Glaucoma in Population-Based and Registry-Based Studies.

Importance: The p.Gln368Ter (rs74315329) risk allele in the myocilin gene (MYOC) was initially reported to have high penetrance in glaucoma registry-based studies, but much lower estimates were recently obtained from population-based studies. We investigated this disparity using data from Australia and the United Kingdom. Objectives: To examine the penetrance and effect size of the MYOC p.Gln368Ter variant with glaucoma and ocular hypertension (OHT). Design, Setting, and Participants: This cross-sectional study within the UK Biobank (UKBB) included participants of white British ancestry. Glaucoma cases were defined by International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) diagnoses and self-reported questionnaires. Carriers of the MYOC p.Gln368Ter variant were identified using genotype imputation from arrays. In contrast, 2 Australian registry-based studies, the Australian and New Zealand Registry of Advanced Glaucoma and the Glaucoma Inheritance Study in Tasmania, ascertained glaucoma cases referred by eye care clinicians, with historic control participants recruited from other Australian studies. Samples were either directly sequenced or had genotypes determined by imputation (for the Australian registry and historic control participants). Recruitment to the UKBB occurred between 2006 and 2010, and data analysis occurred from September 2017 to July 2018. Main Outcomes and Measures: The penetrance and odds ratio (OR) were estimated for the MYOC p.Gln368Ter variants in participants with glaucoma and OHT. Results: A total of 411 337 UKBB participants of white British ancestry (mean [SD] age, 56.6 [8.0] years) were included, plus 3071 Australian registry and 6750 historic control participants. In the UKBB, the minor allele frequency of the MYOC p.Gln368Ter variant was 1 in 786 individuals (0.13%). The odds ratio of p.Gln368Ter in patients with primary open-angle glaucoma (POAG) was 6.76 (95% CI, 4.05-11.29); glaucoma (POAG, self-reported glaucoma, and unspecified glaucoma), 4.40 (95% CI, 3.38-5.71); OHT, 3.56 (95% CI, 2.53-4.92); and OHT and glaucoma combined, 4.18 (95% CI, 3.05-5.67). The penetrance of the MYOC p.Gln368Ter variant was 7.6% in patients with glaucoma, 24.3% in patients with OHT, and 30.8% in patients with OHT and glaucoma combined. In the Australian registry studies, the odds of MYOC p.Gln368Ter variant were 12.16 (95% CI, 6.34-24.97) in patients with advanced glaucoma and 3.97 (95% CI, 1.55-9.75) in those with nonadvanced glaucoma; the penetrance of glaucoma was 56.1%, and penetrance in those considered to have glaucoma or be glaucoma suspects was 69.5%. Conclusions and Relevance: The MYOC p.Gln368Ter variant confers a very high-risk effect size for advanced glaucoma; the risk is lower in nonadvanced glaucoma and OHT. In the general population sample, approximately 50% of MYOC p.Gln368Ter carriers 65 years and older had glaucoma or OHT, with higher prevalence in the Australian registry studies.

Oral Memantine for the Treatment of Glaucoma: Design and Results of 2 Randomized, Placebo-Controlled, Phase 3 Studies.

PURPOSE: To evaluate the effectiveness and safety of oral memantine as a potential neuroprotective agent in open-angle glaucoma (OAG) at risk for progression. DESIGN: Two randomized, double-masked, placebo-controlled, parallel-group, multicenter, 48-month studies identically designed, initiated 1 year apart, and completed in 2006. Protocol amendments included a 1-year extension (first study) and change in primary endpoint and analysis (second study). PARTICIPANTS: Patients (2298 total) with bilateral OAG; glaucomatous optic disc damage and visual field loss in 1 eye; glaucomatous optic disc damage and/or visual field loss in the contralateral eye (at screening), topically treated or untreated intraocular pressure (IOP) of 21 mmHg or less (at baseline); and at risk of glaucomatous progression (per prespecified criteria). METHODS: Patients were randomized 3:2:2 to receive memantine 20 mg, memantine 10 mg, or placebo tablets daily. Glaucomatous progression was assessed in the intent-to-treat population by full-threshold standard automated perimetry (SAP), frequency doubling technology (FDT), and stereoscopic optic disc photographs, standardized by quality control assessment at centralized reading centers. Safety evaluations included adverse events (AEs), best-corrected visual acuity, biomicroscopy, IOP, and ophthalmoscopy. Efficacy data from each study were analyzed per protocol. Pooled analyses of efficacy and safety data were also performed. MAIN OUTCOME MEASURES: The predefined primary efficacy measure was glaucomatous visual field progression, as measured by SAP. Additional efficacy measures included glaucomatous progression of visual field (FDT) and optic nerve damage (stereoscopic optic disc photographs). RESULTS: The proportion of patients who completed the studies was similar among groups (80%-83%). Compared with placebo, daily treatment with memantine 10 mg or 20 mg for 48 months did not delay glaucomatous progression significantly in the individual studies and pooled analyses. The pooled risk reduction ratio (95% confidence interval) assessed by SAP was -0.13 (-0.40, 0.09) and -0.17 (-0.46, 0.07) for memantine 10 mg and 20 mg, respectively. Results were similar per FDT and stereoscopic optic disc photographs. The most common AEs leading to treatment discontinuations were dizziness, headache, fatigue, and nausea. CONCLUSIONS: With technologies available when the studies were conducted, daily treatment with memantine over 48 months was not shown to prevent glaucomatous progression in this patient population.

Genome-wide association study of intraocular pressure uncovers new pathways to glaucoma.

Intraocular pressure (IOP) is currently the sole modifiable risk factor for primary open-angle glaucoma (POAG), one of the leading causes of blindness worldwide1. Both IOP and POAG are highly heritable2. We report a combined analysis of participants from the UK Biobank (n = 103,914) and previously published data from the International Glaucoma Genetic Consortium (n = 29,578)3,4 that identified 101 statistically independent genome-wide-significant SNPs for IOP, 85 of which have not been previously reported4-12. We examined these SNPs in 11,018 glaucoma cases and 126,069 controls, and 53 SNPs showed evidence of association. Gene-based tests implicated an additional 22 independent genes associated with IOP. We derived an allele score based on the IOP loci and loci influencing optic nerve head morphology. In 1,734 people with advanced glaucoma and 2,938 controls, participants in the top decile of the allele score were at increased risk (odds ratio (OR) = 5.6; 95% confidence interval (CI): 4.1-7.6) of glaucoma relative to the bottom decile.

Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma.

Open-angle glaucoma (OAG) is a major cause of blindness worldwide. To identify new risk loci for OAG, we performed a genome-wide association study in 3,071 OAG cases and 6,750 unscreened controls, and meta-analysed the results with GWAS data for intraocular pressure (IOP) and optic disc parameters (the overall meta-analysis sample size varying between 32,000 to 48,000 participants), which are glaucoma-related traits. We identified and independently validated four novel genome-wide significant associations within or near MYOF and CYP26A1, LINC02052 and CRYGS, LMX1B, and LMO7 using single variant tests, one additional locus (C9) using gene-based tests, and two genetic pathways - "response to fluid shear stress" and "abnormal retina morphology" - in pathway-based tests. Interestingly, some of the new risk loci contribute to risk of other genetically-correlated eye diseases including myopia and age-related macular degeneration. To our knowledge, this study is the first integrative study to combine genetic data from OAG and its correlated traits to identify new risk variants and genetic pathways, highlighting the future potential of combining genetic data from genetically-correlated eye traits for the purpose of gene discovery and mapping.

The thick and thin of the central corneal thickness in glaucoma.

Central corneal thickness (CCT) is an important parameter in the assessment of any potential glaucoma patient. While it affects prognosis in ocular hypertension, its value in patients diagnosed with glaucoma is less certain. There are several biological factors and genetic components that may influence glaucoma progression, which have been associated with thinner CCT. The CCT itself can be affected by several factors including ethnicity, age, sex, glaucoma medications, genetics, and the subtype of glaucoma. Besides, there is variability in the measurement of CCT between difference types of devices. These factors need to be considered in the evaluation of glaucoma patients' CCT and its effect on interpretation of intraocular pressure levels and risk stratification.

DNA methylation at the 9p21 glaucoma susceptibility locus is associated with normal-tension glaucoma.

PURPOSE: Recent genome-wide association studies reported strong association of genetic variation at the CDKN2B/CDKN2B-AS1 locus on 9p21 with normal-tension glaucoma (NTG) in multiple populations. The mechanism by which this locus causes disease remains to be elucidated. We investigated the association of DNA methylation of CpG islands at this locus with NTG. METHODS: We conducted a retrospective case-control study of 178 NTG cases and 202 unaffected controls from Australia. CDKN2B and CDKN2B-AS1 promoter methylation was measured quantitatively using the MassCleave assay, and assessed for association with the disease, and the genotype of the associated risk variants using IBM SPSS statistics 22.0 CpG sites at which methylation status was associated with NTG were validated using pyrosequencing. RESULTS: We identified one CpG site (F1:13-14) in the CDKN2B promoter which showed significant association with NTG (p = 0.001). The association was highly significant in female cases (p = 0.006) but not in male cases (p = 0.054). The association was validated using an independent method confirming the likely association of DNA methylation with NTG in females (p = 0.015), but not in males (p = 0.497). In addition, methylation at CpG sites in CDKN2B was also associated with genotype at rs1063192, which is known to confer risk for NTG. CONCLUSION: This study reveals an association of methylation status in the CDKN2B promoter with NTG, particularly in females. This suggests that the observed genetic association with the disease at this locus could be in part due to epigenetic mechanisms, and is likely to be independent of the association of nonsynonymous coding variation within the gene.

Brimonidine and brinzolamide for treating glaucoma and ocular hypertension; a safety evaluation.

INTRODUCTION: Brimonidine tartrate and brinzolamide eye drops are often used as third and fourth line treatment options to reduce intraocular pressure (IOP) in the management of glaucoma and ocular hypertension. Better tolerated, more effective topical agents requiring once daily instillation including prostaglandin analogues and beta-blockers usually are preferred as initial therapy, unless there are contraindications. Brimonidine and brinzolamide are often required owing to progressive glaucoma or intolerances to or ineffectiveness of front-line agents. Areas covered: We review the safety of formulations containing brimonidine tartrate and/or brinzolamide. Safety considerations for these agents in higher risk populations are highlighted. Expert opinion: Each class of ocular hypotensive eye drop has a unique set of possible side effects. Brimonidine might have neuro-protective capabilities and offer reasonable IOP control, but its use is limited by a relatively high rate of ocular allergy, hyperemia and discomfort. Brinzolamide is generally well tolerated, but often lacks efficacy. The introduction of brimonidine/brinzolamide fixed combination suspension improves adherence (by simplifying the medical regimen) and reduces preservative load on the ocular surface. New drug delivery systems incorporating brimonidine and brinzolamide are in development and promise to improve the safety profiles of both drugs.

Contribution of Mutations in Known Mendelian Glaucoma Genes to Advanced Early-Onset Primary Open-Angle Glaucoma.

Purpose: Primary open-angle glaucoma (POAG) and primary congenital glaucoma (PCG) with Mendelian inheritance are caused by mutations in at least nine genes. Utilizing whole-exome sequencing, we examined the disease burden accounted for by these known Mendelian glaucoma genes in a cohort of individuals with advanced early-onset POAG. Methods: The cases exhibited advanced POAG with young age of diagnosis. Cases and examined local controls were subjected to whole-exome sequencing. Nine hundred ninety-three previously sequenced exomes of Australian controls were called jointly with our dataset. Qualifying variants were selected based on predicted pathogenicity and rarity in public domain gene variant databases. Case-control mutational burdens were calculated for glaucoma-linked genes. Results: Two hundred eighteen unrelated POAG participants and 103 nonglaucomatous controls were included in addition to 993 unexamined controls. Fifty-eight participants (26.6%) harbored rare potentially pathogenic variants in known glaucoma genes. Enrichment of qualifying variants toward glaucoma was present in all genes except WDR36, in which controls harbored more variants, and TBK1, in which no qualifying variants were detected in cases or controls. After multiple testing correction, only MYOC showed statistically significant enrichment of qualifying variants (odds ratio [OR] = 16.62, P = 6.31×10-16). Conclusions: Rare, potentially disease-causing variants in Mendelian POAG genes that showed enrichment in our dataset were found in 22.9% of advanced early-onset POAG cases. MYOC variants represented the largest monogenic cause in POAG. The association between WDR36 and POAG was not supported, and the majority of POAG cases did not harbor a potentially disease-causing variant in the remaining Mendelian genes.

Whole exome sequencing implicates eye development, the unfolded protein response and plasma membrane homeostasis in primary open-angle glaucoma.

PURPOSE: To identify biological processes associated with POAG and its subtypes, high-tension (HTG) and normal-tension glaucoma (NTG), by analyzing rare potentially damaging genetic variants. METHODS: A total of 122 and 65 unrelated HTG and NTG participants, respectively, with early onset advanced POAG, 103 non-glaucoma controls and 993 unscreened ethnicity-matched controls were included in this study. Study participants without myocilin disease-causing variants and non-glaucoma controls were subjected to whole exome sequencing on an Illumina HiSeq2000. Exomes of participants were sequenced on an Illumina HiSeq2000. Qualifying variants were rare in the general population (MAF < 0.001) and potentially functionally damaging (nonsense, frameshift, splice or predicted pathogenic using SIFT or Polyphen2 software). Genes showing enrichment of qualifying variants in cases were selected for pathway and network analysis using InnateDB. RESULTS: POAG cases showed enrichment of rare variants in camera-type eye development genes (p = 1.40×10-7, corrected p = 3.28×10-4). Implicated eye development genes were related to neuronal or retinal development. HTG cases were significantly enriched for key regulators in the unfolded protein response (UPR) (p = 7.72×10-5, corrected p = 0.013). The UPR is known to be involved in myocilin-related glaucoma; our results suggest the UPR has a role in non-myocilin causes of HTG. NTG cases showed enrichment in ion channel transport processes (p = 1.05×10-4, corrected p = 0.027) including calcium, chloride and phospholipid transporters involved in plasma membrane homeostasis. Network analysis also revealed enrichment of the MHC Class I antigen presentation pathway in HTG, and the EGFR1 and cell-cycle pathways in both HTG and NTG. CONCLUSION: This study suggests that mutations in eye development genes are enriched in POAG. HTG can result from aberrant responses to protein misfolding which may be amenable to molecular chaperone therapy. NTG is associated with impaired plasma membrane homeostasis increasing susceptibility to apoptosis.

Applications of the water drinking test in glaucoma management.

Intraocular pressure (IOP) peaks and means have been considered important factors for glaucoma onset and progression. However, peak IOP detection depends only on appropriated IOP checks at office visits, whereas the mean IOP requires longitudinal IOP data collection and may be affected by the interval between visits. Also, IOP peak assessment is necessary to verify if the peak pressure of a given patient is in target range, to evaluate glaucoma suspect risk, the efficacy of hypotensive drugs and to detect early loss of IOP control. The water-drinking test has gained significant attention in recent years as an important tool to evaluate IOP peaks and instability. The main objective of this review was to present new findings and to discuss the applicability of the water-drinking test in glaucoma management.

A Novel Method for Laser Suture Lysis Using Multispot Laser System.

Although often uncomplicated, the current technique for laser suture lysis after filtration surgery requires patient cooperation and appropriate care taken by the surgeon. In cases with suboptimal cooperation, steadying the 50-µm laser aiming beam exactly over a thin 10-0 nylon suture, can be exhausting, difficult for both the patient and the surgeon; it may prove to be ineffective or even precipitate complications. We describe a novel method for laser suture lysis using a multispot laser system, which requires less patient cooperation and surgeon skills and yields excellent results.