Primary Open-angle Glaucoma Cohort Research Articles

Disparities in glaucoma and macular degeneration healthcare utilization among persons living with dementia in the United States.

Dementia is common among patients with primary open angle glaucoma (POAG) and neovascular age-related macular degeneration (nAMD). This study compares visit frequency, diagnostic test utilization, and treatment patterns for POAG and nAMD among persons with vs. without dementia. Optum's de-identified Clinformatics® Data Mart Database (January 1, 2000-June 30, 2022) was used for this study. Two cohorts were created from newly diagnosed POAG or nAMD patients. Within each cohort, an exposure cohort was created of newly diagnosed dementia patients. The primary outcome was the number of visits to an eye care provider. Secondary analyses for the POAG cohort assessed the number of visual field tests, optical coherence tomography (OCT), and glaucoma medication prescription coverage. The secondary analysis for the nAMD cohort included the number of injections performed. Poisson regression was used to determine the relative rates of outcomes. POAG patients with dementia had reduced rates of eye care visits (RR 0.76, 95% CI: 0.75-0.77), lower rates of testing utilization for visual fields (RR 0.66, 95% CI: 0.63-0.68) and OCT (RR 0.67, 95% CI: 0.64-0.69), and a lower rate of glaucoma prescription medication coverage (RR 0.83, 95% CI: 0.83-0.83). nAMD patients with dementia had reduced rates of eye care visits (RR 0.74, 95% CI: 0.70-0.79) and received fewer intravitreal injections (RR 0.64, 95% CI: 0.58-0.69) than those without dementia. POAG and nAMD patients with dementia obtained less eye care and less monitoring and treatment of their disease. These findings suggest that this population may be vulnerable to gaps in ophthalmic care.

Determination of the Trans-Lamina Cribrosa Pressure Difference in a Community-Based Population and its Association with Open-Angle Glaucoma

To determine the trans-lamina cribrosa pressure difference (TLCPD) in a cohort of normal community-based patients and the relationship to primary open-angle glaucoma (POAG) and normal-tension glaucoma (NTG). Retrospective cohort study of the Mayo Clinic Study of Aging. The Mayo Clinic Study of Aging is a prospective study evaluating the normal aging population. Mayo Clinic Study of Aging patients who underwent routine lumbar puncture (LP) studies with eye examinations were reviewed. The trans-lamina cribrosa pressure difference was calculated in 2 contexts of intraocular pressure (IOP): (1) maximum IOP at eye visit closest in time to the LP (closest-in-time TLCPD); and (2) IOP before IOP-lowering treatment (pretreatment IOP and pretreatment TLCPD) in POAG and NTG patients. Glaucoma patients without POAG or NTG were excluded. Regression analyses were performed to determine the relationship with glaucoma. IOP, intracranial pressure, TLCPD, POAG, normal-tension glaucoma (NTG) diagnosis, glaucoma parameters. Five hundred forty-eight patients were analyzed. Of these, there were 38 treated glaucoma patients (14 POAG and 24 NTG) and 510 nonglaucomatous patients. Cerebral spinal fluid (CSF) opening pressure was 155.0 ± 42.2 mmH2O in nonglaucomatous patients, 144.0 ± 34.0 mmH2O in POAG (P= 0.15 vs. nonglaucomatous patients), and 136.6 ± 29.3 mmH2O in NTG (P= 0.017 vs. nonglaucomatous patients). Intraocular pressure was 15.47 ± 2.9 mmHg in nonglaucomatous patients, 26.6 ± 3.7 mmHg in POAG, and 17.4 ± 3.4 mmHg in NTG. The closest-in-time TLCPD in the nonglaucomatous cohort was 4.07 ± 4.22 mmHg, which was lower than both the POAG cohort (7.19 ± 3.6 mmHg) and the NTG cohort (5.79 ± 4.5 mmHg, P= 0.04). Pretreatment TLCPD for the overall glaucoma cohort was 10.57 ± 6.1 mmHg. The POAG cohort had a higher pretreatment TLCPD (16.05 ± 5.2 mmHg) than the NTG cohort (7.37 ± 4.1 mmHg; P < 0.0001). Closest-in-time TLCPD for the nonglaucoma cohort (4.07± 4.2 mmHg) was significantly lower than pretreatment TLCPDs for both POAG (16.05 ± 5.2 mmHg; P < 0.0001) and NTG (7.37 ± 4.1 mmHg; P < 0.0001) cohorts. This study establishes the baseline TLCPD in a large cohort of normal, community-based patients. The differences in regression analysis between TLCPD and IOP suggests NTG pathophysiology is partially driven by TLCPD, but is also likely multifactorial. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Elevated dimethylarginine, ATP, cytokines, metabolic remodeling involving tryptophan metabolism and potential microglial inflammation characterize primary open angle glaucoma

Glaucoma of which primary open angle glaucoma (POAG) constitutes 75%, is the second leading cause of blindness. Elevated intra ocular pressure and Nitric oxide synthase (NOS) dysfunction are hallmarks of POAG. We analyzed clinical data, cytokine profile, ATP level, metabolomics and GEO datasets to identify features unique to POAG. N9 microglial cells are used to gain mechanistic insights. Our POAG cohort showed elevated ATP in aqueous humor and cytokines in plasma. Metabolomic analysis showed changes in 21 metabolites including Dimethylarginine (DMAG) and activation of tryptophan metabolism in POAG. Analysis of GEO data sets and previously published proteomic data sets bins genes into signaling and metabolic pathways. Pathways from reanalyzed metabolomic data from literature significantly overlapped with those from our POAG data. DMAG modulated purinergic signaling, ATP secretion and cytokine expression were inhibited by N-Ethylmaleimide, NO donors, BAPTA and purinergic receptor inhibitors. ATP induced elevated intracellular calcium level and cytokines expression were inhibited by BAPTA. Metabolomics of cell culture supernatant from ATP treated sets showed metabolic deregulation and activation of tryptophan metabolism. DMAG and ATP induced IDO1/2 and TDO2 were inhibited by N-Ethylmaleimide, sodium nitroprusside and BAPTA. Our data obtained from clinical samples and cell culture studies reveal a strong association of elevated DMAG, ATP, cytokines and activation of tryptophan metabolism with POAG. DMAG mediated ATP signaling, inflammation and metabolic remodeling in microglia might have implications in management of POAG.

Spatial and Temporal Relationship between Structural Progression and Disc Hemorrhage in Glaucoma in a 3-Year Prospective Study

To investigate the spatial and temporal relationship between disc hemorrhage (DH) and structural progression in patients with primary open-angle glaucoma (POAG) in a 3-year prospective study. Prospective cohort study. Patients with POAG and intraocular pressure of ≤18 mmHg on monotherapy with prostaglandin analogs. Fundus photographs were taken at baseline and every 3 months for 3 years. Disc hemorrhage and structural progression were detected independently by flicker chronoscopy. If present, clock-hour disc locations in the right eye format and colocalization were determined. Statistical comparisons were based on mixed-effects models accounting for the correlation between different disc sites within the same eye and between fellow eyes in the same patient. Relationship between DH and structural progression at the same site. Among 195 eyes of 115 patients, DH appeared in 85 sites in 65 eyes (33.3%) and was most frequently at the 7 o'clock disc location (29.4%, P < 0.0001). Structural progression occurred at 63 sites of 52 eyes (26.7%) comparably in both superior and inferior hemidiscs, which was mostly detected as widening of the retinal nerve fiber layer defects (RNFLDs). Temporal RNFLD widening was common, whereas nasal widening occurred exclusively in the vertical quadrants (P= 0.035). Of 41 progression sites in eyes with DH, 28 sites (68.2%) had both DH and progression. Progression sites with DH were less common in the superior quadrant than in the inferior and temporal quadrants (P= 0.011). Eyes with DH had a significantly higher risk of progression than eyes without DH (hazard ratio, 3.72; P < 0.0001). For 63 progression sites, DH recurrence and more visits with DH at the progression site were significantly associated with shorter time to progression from baseline (P= 0.021, P= 0.017, respectively), whereas colocalization of DH and progression were not. In a 3-year prospective study with a Japanese POAG cohort, the relationship between DH and RNFLD and the pattern of RNFLD progression differed by disc location. The association between more frequent DH at the progression site and shorter time to progression indicates that DH may reflect vulnerability to same-site structural deterioration.

An Intraocular Pressure Polygenic Risk Score Stratifies Multiple Primary Open-Angle Glaucoma Parameters Including Treatment Intensity

To examine the combined effects of common genetic variants associated with intraocular pressure (IOP) on primary open-angle glaucoma (POAG) phenotype using a polygenic risk score (PRS) stratification. Cross-sectional study. For the primary analysis, we examined the glaucoma phenotype of 2154 POAG patients enrolled in the Australian and New Zealand Registry of Advanced Glaucoma, including patients recruited from the United Kingdom. For replication, we examined an independent cohort of 624 early POAG patients. Using IOP genome-wide association study summary statistics, we developed a PRS derived solely from IOP-associated variants and stratified POAG patients into 3 risk tiers. The lowest and highest quintiles of the score were set as the low- and high-risk groups, respectively, and the other quintiles were set as the intermediate risk group. Clinical glaucoma phenotype including maximum recorded IOP, age at diagnosis, number of family members affected by glaucoma, cup-to-disc ratio, visual field mean deviation, and treatment intensity. A dose-response relationship was found between the IOP PRS and the maximum recorded IOP, with the high genetic risk group having a higher maximum IOP by 1.7 mmHg (standard deviation [SD], 0.62 mmHg) than the low genetic risk group (P= 0.006). Compared with the low genetic risk group, the high genetic risk group had a younger age of diagnosis by 3.7 years (SD, 1.0 years; P < 0.001), more family members affected by 0.46 members (SD, 0.11 members; P < 0.001), and higher rates of incisional surgery (odds ratio, 1.5; 95% confidence interval, 1.1-2.0; P= 0.007). No statistically significant difference was found in mean deviation. We further replicated the maximum IOP, number of family members affected by glaucoma, and treatment intensity (number of medications) results in the early POAG cohort (P ≤ 0.01). The IOP PRS was correlated positively with maximum IOP, disease severity, need for surgery, and number of affected family members. Genes acting via IOP-mediated pathways, when considered in aggregate, have clinically important and reproducible implications for glaucoma patients and their close family members.

Multi-trait genome-wide association study identifies new loci associated with optic disc parameters

A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH.

Comprehensive sequencing of the myocilin gene in a selected cohort of severe primary open-angle glaucoma patients

Primary open-angle glaucoma (POAG) is the most common form of glaucoma, prevalent in approximately 1–2% of Caucasians in the UK over the age of 40. It is characterised by an open anterior chamber angle, raised intraocular pressure (IOP) and optic nerve damage leading to loss of sight. The myocilin gene (MYOC) is the most common glaucoma-causing gene, accounting for ~2% of British POAG cases. 358 patients were selected for next generation sequencing (NGS) with the following selection criteria: Caucasian ethnicity, intraocular pressure (IOP) 21–40 mm Hg, cup:disc ratio ≥0.6 and visual field mean deviation ≤−3. The entire MYOC gene (17,321 bp) was captured including the promoter, introns, UTRs and coding exons. We identify 12 exonic variants (one stop-gain, five missense and six synonymous variants), two promoter variants, 133 intronic variants, two 3′ UTR variants and 23 intergenic variants. Four known or predicted pathogenic exonic variants (p.R126W, p.K216K, p.Q368* and p.T419A) were identified across 11 patients, which accounts for 3.07% of this POAG cohort. This is the first time that the entire region of MYOC has been sequenced and variants reported for a cohort of POAG patients.

Rare variants in optic disc area gene CARD10 enriched in primary open-angle glaucoma.

BackgroundGenome‐wide association studies (GWAS) have identified association of common alleles with primary open‐angle glaucoma (POAG) and its quantitative endophenotypes near numerous genes. This study aims to determine whether rare pathogenic variants in these disease‐associated genes contribute to POAG.MethodsParticipants fulfilled strict inclusion criteria of advanced POAG at a young age of diagnosis. Myocilin mutation carriers were excluded using direct sequencing. Whole exome sequencing was performed on 187 glaucoma cases and 103 local screened nonglaucoma controls then joint‐called with exomes of 993 previously sequenced Australian controls. GWAS‐associated genes were assessed for enrichment of rare predicted pathogenic variants in POAG. Significantly enriched genes were compared against Exome Aggregation Consortium (ExAC) public control.ResultsEighty‐six GWAS disease or trait‐associated glaucoma genes were captured and sequenced. CARD10 showed enrichment after Bonferroni correction for rare variants in glaucoma cases (OR = 13.2, P = 6.94 × 10−5) with mutations identified in 4.28% of our POAG cohort compared to 0.27% in controls. CARD10 was significantly associated with optic disc parameters in previous GWAS. The whole GWAS gene set showed no enrichment in POAG overall (OR = 1.12, P = 0.51).ConclusionWe report here an enrichment of rare predicted pathogenic coding variants within a GWAS‐associated locus in POAG (CARD10). These findings indicate that both common and rare pathogenic coding variants in CARD10 may contribute to POAG pathogenesis.

Associations between primary open angle glaucoma, Alzheimer’s disease and vascular dementia: record linkage study

AimsThe potential association between primary open angle glaucoma (POAG) and Alzheimer's disease (AD) is uncertain and has implications for understanding disease pathogenesis, referral and treatments. The aim was to determine...

Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma.

Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma and IOP variability may herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multiethnic participants for IOP. We confirm genetic association of known loci for IOP and primary open angle glaucoma (POAG) and identify four new IOP loci located on chromosome 3q25.31 within the FNDC3B gene (p=4.19×10−08 for rs6445055), two on chromosome 9 (p=2.80×10−11 for rs2472493 near ABCA1 and p=6.39×10−11 for rs8176693 within ABO) and one on chromosome 11p11.2 (best p=1.04×10−11 for rs747782). Separate meta-analyses of four independent POAG cohorts, totaling 4,284 cases and 95,560 controls, show that three of these IOP loci are also associated with POAG.

Genomic copy number variations in glaucomatous neurodegeneration.

Copy number variation (CNV) is one of the major factors contributing to genomic diversity and diseases. It has been shown especially for neurodegenerative diseases that CNVs can play a very important role in genetic predisposition of the disease. Glaucoma is a major neurodegenerative disease causing irreversible vision loss across the globe. We wanted to analyze the impact of CNVs in a genome-wide scale in patients of primary open angle glaucoma (POAG) collected from the West Bengal state of India and reproduce our results in another cohort of Caucasian origin. Genome-wide data was generated on 347 POAG cases and 345 controls on Illumina 660W-Quad arrays and CNVs were called using PennCNV. The CNVs were classified as small ( 100 kb) and analyzed seprately for their involvement in the disease. A publicly available dataset of POAG cohort of 624 cases and 404 controls from Caucasian origin (GLAUGEN study) was used as a validation cohort and genome-wide CNV data of 208 HAPMAP samples was used as global control. We analyzed genome-wide CNV from 1928 samples. For the large CNVs distribution was significantly skewed toward larger size (>1 Mb) in cases compared to controls and this was replicated in the GLAUGEN data. We found that CNVs >1 Mb are enriched for gene rich regions in POAG patients with 125 genes while for controls a similar percentage of large CNVs overlapped with only 5 genes. In 208 HAPMAP samples CNV >1 Mb overlapped with 95 genes. Interestingly, genes found in the patients were unique and did not overlap with controls or HAPMAP samples. Within CNVs of >1 Mb gene-rich large deletions were ~2 fold enriched in patients compared to duplications irrespective of their ethnic background. Such a bias was not observed in the controls. In the smaller CNV range we performed association analysis and identifed novel regions to be under significantly higher CNV in patients’ comapred to controls. Particularly, a CNV encompassing the transcription factor FOXE3 was significantly enriched in patients of both Indian and Caucasian POAG patietns comapred to their respective controls. A sequence analysis of the gene revealed novel missense mutation in the patients. We have shown that genomic CNVs >1 Mb has significantly higher burden in POAG patient’s genome compared to controls irrespective of the population background. We have also identified candidate genes/regions which are uniquely present in POAG cases and absent in controls from all over the world. Our data provide new insights into role of CNV in pathogenesis of POAG.

Higher Prevalence of Myocilin Mutations in Advanced Glaucoma in Comparison with Less Advanced Disease in an Australasian Disease Registry

To determine the proportion of all Myocilin coding mutations responsible for advanced primary open-angle glaucoma (POAG) in early-age-at-onset individuals and to investigate the prevalence of exon 3 Myocilin mutations in advanced POAG at any age at onset in a large Australasian cohort. Cross-sectional study using a national disease registry. One thousand sixty individuals with advanced POAG (103 with age at onset of 40 years or younger) and 320 with nonadvanced POAG all recruited by the Australian and New Zealand Registry of Advanced Glaucoma. Participants were examined and referred by their eye practitioner, and Myocilin genetic testing was performed by direct sequencing. Cascade genetic testing was made available for relatives of participants found to carry a Myocilin mutation. Advanced glaucoma diagnosis based on strict visual field entry criteria. Prevalence and spectrum of Myocilin mutations in individuals with advanced and nonadvanced POAG. This is the first study to report Myocilin mutations in an advanced POAG cohort. No pathogenic Myocilin mutations were identified in exons 1 and 2 in early-age-at-onset advanced POAG cases. Exon 3 Myocilin mutations were identified in 45 advanced POAG patients (4.2%), which is significantly higher (P = 0.02) compared with nonadvanced POAG patients (1.6%). A novel mutation (Trp373X) and a new variant of uncertain pathogenicity (Ala447Thr) also were reported. The prevalence of Myocilin mutations rose from 16% to 40% in selected advanced POAG subgroups based on different thresholds of maximum recorded intraocular pressure, age at diagnosis, and the presence and strength of positive family history. Twenty-six individuals with Myocilin mutations were identified through cascade genetic testing of first-degree relatives of affected mutation carriers. The prevalence of Myocilin mutations in glaucoma cases with severe visual field loss is significantly greater than in nonadvanced glaucoma patients. Myocilin screening in phenotypically selected cases can have a much higher yield than in previous unselected series. Identifying individuals who have Myocilin mutations provides an opportunity to screen at-risk clinically unaffected relatives and to reduce glaucoma blindness through early management and intervention. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Healthcare charges in patients with glaucoma who undergo laser trabeculoplasty

The objective of this study was to assess the impact of laser trabeculoplasty (LTP) on healthcare charges in patients with primary open-angle glaucoma (POAG). Using a managed care database (PharMetrics; Watertown, MA, USA), we formed a case-control group nested within a POAG cohort (n=72,412) formed using International Classification of Disease, Ninth Edition (ICD-9) coding data. Cases (n=1145) had LTP (Current Procedural Terminology code: 65855) with ≥1 year of continuous enrollment both prior to, and following LTP index date in PharMetrics from 1998-2005. Using the date of LTP as the index date, controls (n=2290) without LTP were matched to cases on gender, age, and index year in a 2:1 ratio. Cases and controls had ≥6 months of continuous enrollment in PharMetrics prior to receiving a diagnosis of POAG (ICD-9 code: 365.11). One-year total and ophthalmology healthcare charges were calculated in the year pre- and post-index date (excluding charges for LTP at the index date). Conditional logistic regression models and multiple linear regression models determined the impact of LTP on healthcare charges, while controlling for glaucoma duration and other key covariates. While the mean age of cases (60.1±13.1 years) and controls (60.3±13.6 years) was similar (P=0.5589), cases had more comorbid systemic conditions (P<0.05) and underwent more cataract surgery in the year after index date (4.4% vs. 2.1%; P=0.002). In the year after index date, ophthalmology-related charges increased by $1364 for cases vs. $30 for controls (P=0.0003). Total healthcare charges increased by $5084 for cases and $1594 for controls in the year after index date (P=0.0085). Cases and controls experienced similar increases in ophthalmology-related pharmacy charges from the year pre- to the year post-index date ($26 vs. $43, P=0.385). In both logistic regression and linear regression models, which adjusted for several covariates, performing LTP was associated with increased total healthcare and ophthalmology-related charges. Among patients with POAG in this study, performing LTP was associated with increased total and ophthalmology-related healthcare charges, while ophthalmology pharmacy charges did not decline.

Pharmacotherapy Compliance in Patients with Ocular Hypertension or Primary Open-Angle Glaucoma

The aim of this study was to compare rates of pharmacotherapy coverage in patients with ocular hypertension (OH) and patients with primary open-angle glaucoma (POAG). Retrospective cohort study analysis of a nationally representative, multimanaged health plan database (PharMetrics; 1998-2005) which included 4818 medicated OH patients and 52,985 medicated POAG patients with at least 1 year of continuous enrollment and at least one prescription for IOP-lowering medication during the first year of follow-up. Patients selected for the current study were nested within the cohort of OH patients (n = 36,767) and POAG patients (n =72,412) previously reported. Of the previously reported OH cohort, only 13.1% of patients filled at least one prescription, as compared to 73.2% of the previously reported POAG cohort. Medication coverage was defined as the percent of days during which a patient was in possession of IOP-lowering therapy over the first year of follow-up (medication coverage = number of covered days/365). Compliant patients were defined as those with >or= 75th percentile medication coverage. POAG patients had slightly longer mean length of enrollment in the database (2.5 years, SD = 1.2) than did OH patients (2.4 years, SD = 1.1; P < 0.0001). The mean medication coverage was 50% for the POAG cohort (SD = 0.26) and 40% for the OH cohort (SD = 0.25; P < 0.0001). In multivariate models controlling for key covariates of interest, POAG patients were 1.9 (95% CI: 1.7 to 2.0) times more likely to be compliant with their pharmacotherapy than OH patients. In general, pharmacotherapy coverage was poor. Patients with POAG, a more severe condition, were significantly more covered with pharmacotherapies than patients with OH. It is important to implement strategies to help improve patient coverage prior to occurrence of more severe disease.