Features Associated with Visible Lamina Cribrosa Pores in Individuals of African Ancestry with Glaucoma: Primary Open-Angle African Ancestry Glaucoma Genetics (POAAGG) Study.

There are scarce data regarding the rate of the occurrence of primary open-angle glaucoma (POAG) and visible lamina cribrosa pores (LCPs) in the eyes of individuals with African ancestry; the potential impact of these features on disease burden remains unknown. We recruited subjects with POAG to the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study. Through regression models, we evaluated the association between the presence of LCPs and various phenotypic features. In a multivariable analysis of 1187 glaucomatous eyes, LCPs were found to be more likely to be present in eyes with cup-to-disc ratios (CDR) of ≥0.9 (adjusted risk ratio (aRR) 1.11, 95%CI: 1.04-1.19, p = 0.005), eyes with cylindrical-shaped (aRR 1.22, 95%CI: 1.11-1.33) and bean pot (aRR 1.24, 95%CI: 1.13-1.36) cups versus conical cups (p < 0.0001), moderate cup depth (aRR 1.24, 95%CI: 1.06-1.46) and deep cups (aRR 1.27, 95%CI: 1.07-1.50) compared to shallow cups (p = 0.01), and the nasalization of central retinal vessels (aRR 1.33, 95%CI: 1.23-1.44), p < 0.0001). Eyes with LCPs were more likely to have a higher degree of African ancestry (q0), determined by means of SNP analysis (aRR 0.96, 95%CI: 0.93-0.99, p = 0.005 for per 0.1 increase in q0). Our large cohort of POAG cases of people with African ancestry showed that LCPs may be an important risk factor in identifying severe disease, potentially warranting closer monitoring by physicians.

Stress, Allostatic Load, and Neuroinflammation: Implications for Racial and Socioeconomic Health Disparities in Glaucoma.

Glaucoma is the leading cause of irreversible blindness, and its pathophysiology includes neuroinflammatory changes. The present therapies for glaucoma target pressure-lowering mechanisms with limited success, making neuroinflammation a target for future interventions. This review summarizes the neuroinflammatory pathways seen in glaucoma and their interplay with stress. Glucocorticoids have been shown to activate proinflammatory glial cells, contributing to the neuroinflammation in glaucoma. Glucocorticoids have also been shown to increase the IOP directly. Stress-associated autonomic dysfunction can affect the vascular homeostasis in the retina and create oxidative stress. Diabetes, hyperglycemic-mediated endothelial damage, and vascular inflammation also play important roles in the neuroinflammation in glaucoma and diabetic retinopathy. Psychosocial stress has been implicated in an increased IOP and glaucoma outcomes. People who experience maladaptive chronic stress suffer from a condition known as allostatic load, which describes pathologic neuroendocrine dysregulation. The effects of allostatic load and chronic stress have been studied in patients affected by a lower socioeconomic status (SES) and marginalized racial identities. A lower SES is associated with higher rates of glaucoma and also affects the access to care and screening. Additionally, people of African ancestry are disproportionately affected by glaucoma for reasons that are multifactorial. In conclusion, this review explores neuroinflammation in glaucoma, highlighting opportunities for future investigation.

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

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

Risk factors for structural and functional progression of primary open-angle glaucoma in an African ancestry cohort.

BACKGROUND/AIMS: To investigate the rates of structural and functional progression of primary open-angle glaucoma in an African ancestry cohort and identify risk factors for progression. METHODS: This retrospective study included 1424 eyes from glaucoma cases in the Primary Open-Angle African American Glaucoma Genetics cohort, with ≥2 visits for retinal nerve fibre layer (RNFL) thickness and mean deviation (MD) measurements over ≥6-month follow-up. The rates of structural progression (change in RNFL thickness/year) and functional progression (change in MD/year) were calculated from linear mixed effects models, accounting for intereye correlation and longitudinal correlation. Eyes were categorised as slow, moderate or fast progressors. Risk factors for progression rates were assessed using univariable and multivariable regression models. RESULTS: The median (interquartile) rates of progression were -1.60 (-2.05 to -1.15) µm/year for RNFL thickness and -0.40 (-0.44 to -0.34) decibels/year for MD. Eyes were categorised as slow (structural: 19%, functional: 88%), moderate (structural: 54%, functional: 11%) and fast (structural: 27%, functional: 1%) progressors. In multivariable analysis, faster RNFL progression was independently associated with thicker baseline RNFL (p<0.0001), lower baseline MD (p=0.003) and beta peripapillary atrophy (p=0.03). Faster MD progression was independently associated with higher baseline MD (p<0.0001), larger cup-to-disc ratios (p=0.02) and lower body mass index (p=0.0004). CONCLUSION: The median rates of structural and functional progression in this African ancestry cohort were faster than the rates reported from previously published studies in other ethnic groups. Higher baseline RNFL thickness and MD values were associated with faster progression rates. Results highlight the importance of monitoring structural and functional glaucoma progression to provide timely treatment in early disease.

Prevalence and Factors Associated with Optic Disc Tilt in the Primary Open-Angle African American Glaucoma Genetics Study.

PURPOSE: To investigate the prevalence and factors associated with optic disc tilt in the eyes of Black Americans with glaucoma. DESIGN: Cross-sectional. PARTICIPANTS: Subjects with glaucoma participating in the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study. METHODS: Stereo pairs of optic disc images were assessed independently by POAAGG-certified nonphysician graders for quantitative features including maximum and minimum linear disc diameters, and qualitative features including gradeability of images, shape of the cup, rim plane position, ß-peripapillary atrophy, sloping region adjacent to the outer disc margin, and rim pallor. Discrepancies were adjudicated by an ophthalmologist. Descriptive statistics and P values were generated for associations of tilt with demographic and ocular characteristics. Stepwise multivariable analysis was performed with logistic regression using Generalized Estimating Equations (GEEs) to account for inter-eye correlation within subjects. MAIN OUTCOME MEASURES: Tilt Ovality Index (TOI) of >1.30 and Stereoscopically Identified optic disc Tilt (SIT). RESULTS: Among 1251 subjects with data on both eyes, 104 (8.3%) had TOI. Subjects with TOI were less likely to be male (adjusted odds ratio [aOR], 0.46, 95% confidence interval [CI], 0.29-0.74, P < 0.001). Eyes with TOI were less likely to have large cup disc ratios (aOR, 0.18, 95% CI, 0.06-0.53, P < 0.001) and less likely to have cylinder-shaped cups compared with conical-shaped cups (aOR, 0.31, 95% CI, 0.19-0.49, P < 0.001). Among 1007 subjects with data on both eyes, 254 (25.2%) had SIT. Subjects with SIT were younger (aOR, 0.95, 95% CI, 0.93-0.96, P < 0.001), and eyes with SIT were more likely to have oval-shaped discs compared with round discs (aOR, 1.82, 95% CI, 1.32-2.52, P < 0.001), more likely to have a sloping region adjacent to the outer disc margin instead of being flat (aOR, 3.26, 95% CI, 2.32-4.59, P < 0.001), and less likely to have cylinder-shaped cups compared with conical-shaped cups (aOR, 0.59, 95% CI, 0.41-0.85, P < 0.001). Both TOI and SIT were not associated with myopia. CONCLUSIONS: There are substantial numbers of tilted optic discs in glaucoma patients with African ancestry. They occur more frequently in female subjects and younger subjects and are associated with several ocular features but not with myopia.

Recruitment strategies and lessons learned from a large genetic study of African Americans.

Genetic studies must enroll large numbers of participants to obtain adequate statistical power. Data are needed on how researchers can best use limited financial and practical resources to achieve these targets, especially in under-represented populations. This paper provides a retrospective analysis of the recruitment strategies for a large glaucoma genetics study in African Americans. The Primary Open-Angle African American Glaucoma Genetics study enrolled 10,192 African American subjects from the Philadelphia region. Major recruitment approaches included clinic enrollment from University of Pennsylvania (UPenn) sites, clinic enrollment from external sites, sampling of Penn Medicine Biobank (PMBB), and community outreach. We calculated the enrollment yield, cost per subject, and seasonal trends of these approaches. The majority (65%) of subject were enrolled from UPenn sites with an average cost of $133/subject. Over time, monthly case enrollment declined as the pool of eligible subjects was depleted. Expanding to external sites boosted case numbers ($129/subject) and the biobank provided additional controls at low cost ($5/subject), in large part due to the generosity of PMBB providing samples free of cost. Community outreach was costly with low return on enrollment ($978/subject for 220 subjects). Summer months (Jun-Aug) produced the highest recruitment yields (p<0.001). Genetic studies will benefit from a multi-pronged and culturally sensitive recruitment approach. In our experience, the biobank was most cost-effective for control enrollment, while recruitment from clinics (including expansion to new sites) was necessary to recruit fully phenotyped cases.

A Review of Studies of the Association of Vision-Related Quality of Life with Measures of Visual Function and Structure in Patients with Glaucoma in the United States.

Purpose: To investigate the association of quality of life (QoL) with ocular structure and function in glaucoma patients, and to identify which aspects of QoL are most closely tied to Visual Field (VF) and Visual Acuity (VA).Methods: We conducted a comprehensive review of studies on QoL in glaucoma patients using PubMed, Web of Science, and Google Scholar (from 1 January 1997 to 7 December 2019). A total of 21 studies in the United States that used the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ) or 51-item NEI VFQ were included. A descriptive analysis of data from the selected studies was conducted. The association between QoL scores and visual function and structure was investigated by ranking the strength of association on a scale from 1 (weakest) to 12 (strongest).Results: Studies reported correlations between QoL scores and Visual Structure. Associations were also reported between QoL and Visual Function both cross-sectionally and longitudinally, with a stronger association of VF and VA with distance activities (average ranking 9.1 and 9.6), vision-specific dependency (8.7 and 8.9), and driving (8.6 and 9.7). Vision-specific mental health (6.5 and 4.9), vision-specific social functioning (8.4 and 6.2), and vision-specific role difficulties (7.1 and 6.6) domains were more associated with VF than with VA.Conclusion: Our study was the first to quantify and rank the strength of association between visual function and QoL domains. Driving and psycho-social QoL domains tended to be most affected by glaucoma-related deterioration of visual function. QoL scores could be used for more patient-centered disease management.

Primary Open-Angle African American Glaucoma Genetics (POAAGG) Study: gender and risk of POAG in African Americans.

The purpose of this study was to investigate the association between gender and primary open-angle glaucoma (POAG) among African Americans and to assess demographic, systemic, and behavioral factors that may contribute to differences between genders. The Primary Open-Angle African American Glaucoma Genetics (POAAGG) study had a case-control design and included African Americans 35 years and older, recruited from the greater Philadelphia, Pennsylvania. Diagnosis of POAG was based on evidence of both glaucomatous optic nerve damage and characteristic visual field loss. Demographic and behavioral information, history of systemic diseases and anthropometric measurements were obtained at study enrollment. Gender differences in risk of POAG were examined using multivariate logistic regression. A total of 2,290 POAG cases and 2,538 controls were included in the study. The percentage of men among cases was higher than among controls (38.6% vs 30.3%, P<0.001). The subjects' mean age at enrollment was significantly higher for cases compared to controls (70.2±11.3 vs. 61.6±11.8 years, P<0.003). Cases had lower rates of diabetes (40% vs. 46%, P<0.001), higher rates of systemic hypertension (80% vs. 72%, P<0.001), and lower body mass index (BMI) (29.7±6.7 vs. 31.9±7.4, P<0.001) than controls. In the final multivariable model, male gender was significantly associated with POAG risk (OR, 1.64; 95% CI, 1.44-1.87; P<0.001), after adjusting for age, systemic hypertension, diabetes, and BMI. Within the POAAGG study, men were at higher risk of having POAG than women. Pending genetic results from this study will be used to better understand the underlying genetic variations that may account for these differences.

Family History in the Primary Open-Angle African American Glaucoma Genetics Study Cohort.

PURPOSE: To determine the relationship between positive family history (FH) and primary open-angle glaucoma (POAG) diagnosis and clinical presentation in the Primary Open-Angle African American Glaucoma Genetics (POAAGG) cohort. METHODS: FH of POAG in first-degree relatives was assessed in 2365 subjects in the POAAGG cohort. A standardized interview was used to assess FH of glaucoma, demographic characteristics, lifestyle choices, and medical and ocular comorbidities. RESULTS: Positive FH was associated with increased risk of POAG (age-adjusted odds ratio and 95% confidence interval 3.4 [2.8, 4.1]). In age-adjusted analysis among POAG cases, positive FH was associated with younger age (P < .001), female sex (P < .001), hypertension (P = .006), use of hypertension medication (P = .03), and prior glaucoma surgery (P = .02). Cases with positive FH also had thicker retinal nerve fiber layers (P = .03). CONCLUSIONS: The risk conferred by positive FH suggests strong genetic underpinnings for some patients with this disease, which will be investigated by genome-wide association studies and whole exome sequencing. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Risk Factors Associated with Progression to Blindness from Primary Open-Angle Glaucoma in an African-American Population.

PURPOSE: To determine the risk factors associated with progression to blindness from primary open-angle glaucoma (POAG) in an African-American population. METHODS: This study examined 2119 patients enrolled in the Primary Open-Angle African-American Glaucoma Genetics (POAAGG) study. A total of 59 eyes were identified as legally blind as a result of POAG (cases) and were age-and sex-matched to 59 non-blind eyes with glaucoma (controls). Chart reviews were performed to record known and suspected risk factors. RESULTS: Cases were diagnosed with POAG at an earlier age than controls (p = 0.005). Of the 59 eyes of cases, 16 eyes (27.1%) presented with blindness at diagnosis. Cases had worse visual acuity (VA) at diagnosis (p < 0.0001), with VA worse than 20/40 conferring a 27 times higher risk of progression to blindness (p = 0.0005). Blind eyes also demonstrated more visual field defects (p = 0.01), higher pre-treatment intraocular pressure (IOP; p < 0.0001), and higher cup-to-disc ratio (p = 0.006) at diagnosis. IOP was less controlled in cases, and those with IOP ≥21 mmHg at more than 20% of follow-up visits were 73 times more likely to become blind (p < 0.0001). Cases missed a greater number of appointments per year (p = 0.003) and had non-adherence issues noted in their charts more often than controls (p = 0.03). However, other compliance data did not significantly differ between groups. CONCLUSION: Access to care, initial VA worse than 20/40, and poor control of IOP were the major risk factors associated with blindness from POAG. Future studies should examine earlier, more effective approaches to glaucoma screening as well as the role of genetics in these significantly younger patients who progress to blindness.

The role of ophthalmology departments in overcoming health care disparities.

Ophthalmology departments can play a unique role in providing care for at-risk patients. This study analyzed the age, gender, and socioeconomic measures for 267,286 unique African American patients seen at University of Pennsylvania Health System (UPHS). Patients seen by the Ophthalmology Department (n=33,801) were older and more likely to be from impoverished zip codes than those seen by other UPHS specialists. These results hint at several inherent advantages of ophthalmology departments in recruiting older, disadvantaged patients to their clinics. We found that supplementing this advantage with strong patient relationships, involvement of community leaders, and customized outreach efforts was key to overcoming access-to-care issues and to reaching these patients. This provides ophthalmologists with a unique opportunity to capture and refer systemic conditions with ocular manifestations and to possibly reduce disparities such as post-hospitalization readmission and mortality observed disproportionately in impoverished populations.

The primary open-angle african american glaucoma genetics study: baseline demographics.

PURPOSE: To describe the baseline characteristics of the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study cohort, the largest African American population with primary open-angle glaucoma (POAG) recruited at a single institution (University of Pennsylvania [UPenn], Department of Ophthalmology, Scheie Eye Institute) to date. DESIGN: Population-based, cross-sectional, case-control study. PARTICIPANTS: A total of 2520 African American subjects aged 35 years or more who were recruited from the greater Philadelphia, Pennsylvania area. METHODS: Each subject underwent a detailed interview and eye examination. The interview assessed demographic, behavioral, medical, and ocular risk factors. Current ZIP codes surrounding UPenn were recorded and US census data were queried to infer socioeconomic status. The eye examination included measurement of visual acuity (VA) and intraocular pressure, and a detailed anterior and posterior segment examination, including gonioscopy, dilated fundus and optic disc examination, visual fields, stereo disc photography, optical coherence tomography, and measurement of central corneal thickness. MAIN OUTCOME MEASURES: The baseline characteristics of gender, age, and glaucoma diagnosis were collected. Body mass index (BMI), hypertension, diabetes, alcohol and tobacco use, ocular conditions (including blindness, cataract, nonproliferative diabetic retinopathy, and age-related macular degeneration), and use of ocular medication and surgery were examined. Median population density, income, education level, and other socioeconomic measures were determined for the study cohort. RESULTS: Of the 2520 African Americans recruited to the POAAGG study to date, 2067 (82.0%), including 807 controls and 1260 POAG cases, met all inclusion criteria and completed the detailed clinical ocular examination. Cases were more likely to have a lower BMI (P < 0.01) and report a history of blindness (VA of ≤20/200; P < 0.001), whereas controls were more likely to have diabetes (P < 0.001), have nonproliferative diabetic retinopathy (P = 0.02), and be female (P < 0.001). Study participants were drawn largely from predominantly African American neighborhoods of low income, high unemployment, and lower education surrounding UPenn. CONCLUSIONS: The POAAGG study has currently recruited more than 2000 African Americans eligible for a POAG genetics study. Blindness and low BMI were significantly associated with POAG. This population was predominantly recruited from neighborhoods whose population income exists at or near the federal poverty level.