Racial Differences in Diagnostic Accuracy of Retinal Nerve Fiber Layer Thickness in Primary Open-Angle Glaucoma.

Purpose: To evaluate the diagnostic accuracy of retinal nerve fiber layer thickness (RNFLT) by spectral-domain optical coherence tomography (OCT) in primary open-angle glaucoma (POAG) in eyes of African (AD) and European descent (ED). Design: Comparative diagnostic accuracy analysis by race. Participants: 379 healthy eyes (125 AD and 254 ED) and 442 glaucomatous eyes (226 AD and 216 ED) from the Diagnostic Innovations in Glaucoma Study and the African Descent and Glaucoma Evaluation Study. Methods: Spectralis (Heidelberg Engineering GmbH) and Cirrus (Carl Zeiss Meditec) OCT scans were taken within one year from each other. Main Outcome Measures: Diagnostic accuracy of RNFLT measurements. Results: Diagnostic accuracy for Spectralis-RNFLT was significantly lower in eyes of AD compared to those of ED (area under the receiver operating curve [AUROC]: 0.85 and 0.91, respectively, P=0.04). Results for Cirrus-RNFLT were similar but did not reach statistical significance (AUROC: 0.86 and 0.90 in AD and ED, respectively, P =0.33). Adjustments for age, central corneal thickness, axial length, disc area, visual field mean deviation, and intraocular pressure yielded similar results. Conclusions: OCT-RNFLT has lower diagnostic accuracy in eyes of AD compared to those of ED. This finding was generally robust across two OCT instruments and remained after adjustment for many potential confounders. Further studies are needed to explore the potential sources of this difference.

SDPR expression in human trabecular meshwork and its potential role in racial disparities of glaucoma.

In order to identify how differential gene expression in the trabecular meshwork (TM) contributes to racial disparities of caveolar protein expression, TM dysfunction and development of primary open angle glaucoma (POAG), RNA sequencing was performed to compare TM tissue obtained from White and Black POAG surgical (trabeculectomy) specimens. Healthy donor TM tissue from White and Black donors was analyzed by PCR, qPCR, immunohistochemistry staining, and Western blot to evaluate SDPR (serum deprivation protein response; Cavin 2) and CAV1/CAV2 (Caveolin 1/Caveolin 2). Standard transmission electron microscopy (TEM) and immunogold labeled studies were performed. RNA sequencing demonstrated reduced SDPR expression in TM from Black vs White POAG patients' surgical specimens, with no significant expression differences in other caveolae-associated genes, confirmed by qPCR analysis. No racial differences in SDPR gene expression were noted in healthy donor tissue by PCR analysis, but there was greater expression as compared to specimens from patients with glaucoma. Analysis of SDPR protein expression confirmed specific expression in the TM regions, but not in adjacent tissues. TEM studies of TM specimens from healthy donors did not demonstrate any racial differences in caveolar morphology, but a significant reduction of caveolae with normal morphology and immuno-gold staining of SDPR were noted in glaucomatous TM as compared to TM from healthy donors. Linkage of SDPR expression levels in TM, POAG development, and caveolar ultrastructural morphology may provide the basis for a novel pathway of exploration of the pathologic mechanisms of glaucoma. Differential gene expression of SDPR in TM from Black vs White subjects with glaucoma may further our understanding of the important public health implications of the racial disparities of this blinding disease.

Priorities for health outcomes in glaucoma in an ethnically diverse UK cohort: an observational study.

OBJECTIVES: To assess whether patients from minority ethnic groups have different perceptions about the quality-of-life outcomes that matter most to them. DESIGN: Cross-sectional observational study. SETTING: High volume eye centres serving the most ethnically diverse region in the UK, recruiting from July 2021 to February 2022. PARTICIPANTS: 511 patients with primary open-angle glaucoma and the predisease state of ocular hypertension. MAIN OUTCOME MEASURES: The main outcome was participants' self-reported priorities for health outcomes. RESULTS: Participants fell into one of four clusters with differing priorities for health outcomes, namely: (1) vision, (2) drop freedom, (3) intraocular pressure and (4) one-time treatment. Ethnicity was the strongest determinant of cluster membership after adjusting for potential confounders. Compared with white patients prioritising vision alone, the OR for black/black British patients was 7.31 (95% CI 3.43 to 15.57, p<0.001) for prioritising drop freedom; 5.95 (2.91 to 12.16, p<0.001) for intraocular pressure; and 2.99 (1.44 to 6.18, p=0.003) for one-time treatment. For Asian/Asian British patients, the OR was 3.17 (1.12 to 8.96, p=0.030) for prioritising intraocular pressure as highly as vision. Other ethnic minority groups also had higher ORs for prioritising health outcomes other than vision alone: 4.50 (1.03 to 19.63, p=0.045) for drop freedom and 5.37 (1.47 to 19.60, p=0.011) for intraocular pressure. CONCLUSIONS: Ethnicity is strongly associated with differing perceptions about the health outcomes that matter. An individualised and ethnically inclusive approach is needed when selecting and evaluating treatments in clinical and research settings.

Association of the SNP rs112369934 near TRIM66 Gene with POAG Endophenotypes in African Americans.

We investigated the association of the single nucleotide polymorphism (SNP) rs112369934 near the TRIM66 gene with qualitative and quantitative phenotypes of primary open-angle glaucoma (POAG) in African Americans (AA). AA subjects over 35 years old were recruited for the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study in Philadelphia, PA. Glaucoma cases were evaluated for phenotypes associated with POAG pathogenesis, and the associations between rs112369934 and phenotypes were investigated by logistic regression analysis and in gender-stratified case cohorts: The SNP rs112369934 was found to have a suggestive association with retinal nerve fiber layer (RNFL) thickness and cup-to-disc ratio (CDR) in 1087 male AA POAG cases, individuals with the TC genotype having thinner RNFL (95% CI 0.85 to 6.61, p = 0.01) and larger CDR (95% CI -0.07 to -0.01, p = 0.02) than those with wildtype TT. No other significant associations were found. In conclusion SNP rs112369934 may play a role in POAG pathogenesis in male AA individuals. However, this SNP has been implicated in higher POAG risk in both male and female AA POAG cases.

Racial and Ethnic Disparities in Primary Open-Angle Glaucoma Clinical Trials: A Systematic Review and Meta-analysis.

Importance: The disease burden for primary open-angle glaucoma (POAG) is highest among racial/ethnic minority groups, particularly Black individuals. The prevalence of POAG worldwide is projected to increase from 52.7 million in 2020 to 79.8 million in 2040, a 51.4% increase attributed mainly to Asian and African individuals. Given this increase, key stakeholders need to pay particular attention to creating a diverse study population in POAG clinical trials. Objective: To assess the prevalence of racial/ethnic minorities in POAG clinical research trials compared with White individuals. Data Sources: This meta-analysis consisted of publicly available POAG clinical trials using ClinicalTrials.gov, PubMed, and Drugs@FDA from 1994 to 2019. Study Selection: Randomized clinical trials that reported on interventions for POAG and included demographic subgroups including sex and race/ethnicity. Data Extraction and Synthesis: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, 2 independent reviewers extracted study-level data for a random-effects meta-analysis. A third person served as the tiebreaker on study selection. Microsoft Excel 2016 (Microsoft Corporation) and SAS, version 9.4 (SAS Institute) were used for data collection and analyses. Main Outcomes and Measures: The primary outcomes were the prevalence of each demographic subgroup (White, Black, Hispanic/Latino, other race/ethnicity groups, and female or male) in each trial according to the trial start year, study region, and study sponsor. Participation rates are expressed as percentages. Results: A total of 105 clinical trials were included in the meta-analysis, including 33 428 POAG clinical trial participants (18 404 women [55.1%]). Overall, 70.7% were White patients, 16.8% were Black patients, 3.4% were Hispanic/Latino patients, and 9.1% were individuals of other races/ethnicities, including Asian, Native Hawaiian or Pacific Islander, American Indian or Alaska Native, and unreported as defined by the US Census. The mean (SD) numbers of participants by race/ethnicity were 236.5 (208.2) for White, 58.4 (70.0) for Black, 29.9 (71.1) for Hispanic/Latino, and 31.1 (94.3) for other race/ethnicity. According to the test for heterogeneity using the Cochrane Risk of Bias tool, the I2 statistic was 98%, indicating high heterogeneity of outcomes in the included trials. A multiple linear regression analysis was performed to assess any trend and significance between participation by Black individuals and the year the study started, the region in which the study took place, and the study sponsor. There was no significant increase of Black participant enrollment from 1994 to 2019 (r2 = 0.11; P = .17) and no significant association between Black participant enrollment and clinical trial region (r2 = 0.16; P = .50), but there was a significant association between Black participant enrollment and study sponsor (r2 = 0.94; P = .03). Conclusions and Relevance: This meta-analysis found that compared with White individuals, individuals from racial/ethnic minority groups had a very low participation rate in POAG clinical trials despite having a higher prevalence among the disease population. Despite measures to increase clinical trial diversity, there has not been a significant increase in clinical trial participation among Black individuals, the group most affected by this disease; this disparity in POAG clinical trial representation can raise questions about the true safety and efficacy of approved medical interventions for this disease and should prompt further research on how to increase POAG clinical trial diversity.

The Role of Genetic Ancestry as a Risk Factor for Primary Open-angle Glaucoma in African Americans.

Purpose: POAG is the leading cause of irreversible blindness in African Americans. In this study, we quantitatively assess the association of autosomal ancestry with POAG risk in a large cohort of self-identified African Americans. Methods: Subjects recruited to the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study were classified as glaucoma cases or controls by fellowship-trained glaucoma specialists. POAAGG subjects were genotyped using the MEGA Ex array (discovery cohort, n = 3830; replication cohort, n = 2135). Population structure was interrogated using principal component analysis in the context of the 1000 Genomes Project superpopulations. Results: The majority of POAAGG samples lie on an axis between African and European superpopulations, with great variation in admixture. Cases had a significantly lower mean value of the ancestral component q0 than controls for both cohorts (P = 6.14-4; P = 3-6), consistent with higher degree of African ancestry. Among POAG cases, higher African ancestry was also associated with thinner central corneal thickness (P = 2-4). Admixture mapping showed that local genetic ancestry was not a significant risk factor for POAG. A polygenic risk score, comprised of 23 glaucoma-associated single nucleotide polymorphisms from the NHGRI-EBI genome-wide association study catalog, was significant in both cohorts (P < 0.001), suggesting that both known POAG single nucleotide polymorphisms and an omnigenic ancestry effect influence POAG risk. Conclusions: In sum, the POAAGG study population is very admixed, with a higher degree of African ancestry associated with an increased POAG risk. Further analyses should consider social and environmental factors as possible confounding factors for disease predisposition.

Albuminuria and Primary Open-Angle Glaucoma: the Singapore Chinese Eye Study (SCES).

AIMS: To determine the association between albuminuria and primary open-angle glaucoma (POAG). METHODS: Participants of the Singapore Chinese Eye study were recruited and underwent standardised ocular and systemic examinations. Albuminuria was determined using urinary albumin-to-creatinine ratio (UACR, mg/g) based on random spot urinary albumin and creatinine measurements. POAG was defined using the International Society of Geographic and Epidemiological Ophthalmology classification. Multivariable logistic regression with generalised estimating equation model was used to evaluate the association between albuminuria and POAG, while accounting for correlation between eyes. RESULTS: A total of 3009 Chinese adults (5963 eyes), aged 40-80 years, were included in this study, of which, 52 subjects (75 eyes) had POAG. Higher UACR (per 50 mg/g increase) was independently associated with POAG (OR=1.04, 95% CI 1.01 to 1.07, p=0.003) following adjustment for age, gender, intraocular pressure, diabetes mellitus, hyperlipidaemia, hypertension, anti-hypertensive medication, history of cardiovascular disease, current smoking status, alcohol intake, body mass index and estimated glomerular filtration rate. Further stratification revealed that individuals with macroalbuminuria were 8.00 times likely to have POAG (95% CI 2.97 to 21.54, p<0.001), compared with those with normoalbuminuria. Microalbuminuria was not significantly associated with POAG (OR=0.49, 95% CI 0.19 to 1.29, p=0.150). The association between macroalbuminuria and POAG remained significant among individuals who were diabetic (OR=9.89, 95% CI 2.49 to 39.30, p=0.001) and hypertensive (OR=8.39, 95% CI 3.07 to 22.94, p<0.001). CONCLUSION: In this population-based study of Chinese adults, albuminuria was independently associated with POAG. Our findings provide further understanding on the pathogenesis of POAG and may potentially help to better identify individuals at risk of POAG.

Peripapillary and Macular Microcirculation in Glaucoma Patients of African and European Descent Using Optical Coherence Tomography Angiography.

PRéCIS:: We found no significant differences in peripapillary and macula microcirculation blood flow metrics in eyes with open-angle glaucoma of African descent (AD) and European descent (ED) as detected by optical coherence tomography angiography (OCTA). PURPOSE: The purpose of this study was to investigate the peripapillary retinal nerve fiber layer (RNFL) and macular vascular microcirculation in subjects of AD and ED with open-angle glaucoma using OCTA. PATIENTS AND METHODS: One eye from each subject was scanned using AngioPlex OCTA system covering both a 6×6 mm scanning area centered at the optic nerve head and at the foveola. Peripapillary RNFL and macular microcirculation were measured by calculating the overall flux and vessel area density excluding the large retinal vessels. Two-sample, independent t tests were used to compare the OCTA metrics between AD and ED eyes. Linear regression models were used to investigate the correlation between OCTA metrics and structural and functional parameters. RESULTS: Twenty-eight eyes of AD and 56 eyes of ED were included in the study. There was no significant difference in age, sex, hypertension, antihypertensive medications, diabetes, systolic and diastolic blood pressure, mean ocular perfusion pressure, RNFL thickness and visual field (VF) mean deviation and VF pattern standard deviation (P≥0.054) between AD and ED eyes included. Both groups had similar OCTA blood flow metrics (P≥0.161). OCTA blood flow metrics were significantly correlated with VF mean deviation (r≥0.466), VF pattern standard deviation (r≤-0.366) and RNFL thickness (r≥0.333). CONCLUSIONS: No significant differences were found in peripapillary and macular microcirculation detected by OCTA between AD and ED glaucomatous eyes. Peripapillary and macular microcirculation were significantly correlated with disease severity in AD and ED glaucomatous eyes.

Molecular Genetics of Glaucoma: Subtype and Ethnicity Considerations.

Glaucoma, the world's leading cause of irreversible blindness, is a complex disease, with differential presentation as well as ethnic and geographic disparities. The multifactorial nature of glaucoma complicates the study of genetics and genetic involvement in the disease process. This review synthesizes the current literature on glaucoma and genetics, as stratified by glaucoma subtype and ethnicity. Primary open-angle glaucoma (POAG) is the most common cause of glaucoma worldwide, with the only treatable risk factor (RF) being the reduction of intraocular pressure (IOP). Genes associated with elevated IOP or POAG risk include: ABCA1, AFAP1, ARHGEF12, ATXN2, CAV1, CDKN2B-AS1, FOXC1, GAS7, GMDS, SIX1/SIX6, TMCO1, and TXNRD2. However, there are variations in RF and genetic factors based on ethnic and geographic differences; it is clear that unified molecular pathways accounting for POAG pathogenesis remain uncertain, although inflammation and senescence likely play an important role. There are similar ethnic and geographic complexities in primary angle closure glaucoma (PACG), but several genes have been associated with this disorder, including MMP9, HGF, HSP70, MFRP, and eNOS. In exfoliation glaucoma (XFG), genes implicated include LOXL1, CACNA1A, POMP, TMEM136, AGPAT1, RBMS3, and SEMA6A. Despite tremendous progress, major gaps remain in resolving the genetic architecture for the various glaucoma subtypes across ancestries. Large scale carefully designed studies are required to advance understanding of genetic loci as RF in glaucoma pathophysiology and to improve diagnosis and treatment options.

Risk Factors for Open-angle Glaucoma in Persons of Latin American Descent.

PURPOSE: The aim of this paper is to concisely summarize what is currently known about OAG among persons of LAD in the United States for the purpose of improving individualized care and highlighting areas requiring further study. MATERIALS AND METHODS: Review of relevant literature was performed through PubMed and Google Scholar from October 1978 through November 11, 2019. RESULTS: As the Latin American population grows within the United States, it is predicted that by 2050, men of LAD will make up the largest demographic group with OAG. Persons of LAD experience a greater increase in OAG prevalence per decade of life compared with persons of African descent and may have unique risk factors. In particular, those with African ancestry and hypertension are at greater risk of elevated intraocular pressure (IOP). Maximum IOP, variability in IOP, and diabetes are also important considerations. Unique anatomic and physiological characteristics such as scleral tensile strain, longer axial length, thin corneas, and corneal hysteresis may play a role in this population's unique risk for the development and progression of OAG. CONCLUSIONS: OAG represents a growing concern among persons of LAD in the United States; however, information on specific risk factors in this population currently remains limited. Studies should be designed to investigate the LAD population and their respective structural, vascular, and social risk factors for the development and progression of OAG to assist clinicians in improving outcomes for this growing population.

Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry.

Importance: Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. Objectives: To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. Design, Settings, and Participants: A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma. Exposures: Genetic variants associated with primary open-angle glaucoma. Main Outcomes and Measures: Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data. Results: A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-ß A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry. Conclusions and Relevance: In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies.

Crystalline lens changes after selective laser trabeculoplasty in Afro-Caribbean patients with open-angle glaucoma; report 4 of the West Indies Glaucoma Laser Study (WIGLS).

PURPOSE: To characterize changes in nuclear, cortical, and posterior subcapsular lens opacities after selective laser trabeculoplasty (SLT) in Afro-Caribbean eyes with primary open-angle glaucoma (POAG). SETTING: Three clinical practices, Saint Lucia and Dominica. DESIGN: Prospective case series. METHODS: Patients with POAG in the West Indies Glaucoma Laser Study (WIGLS) had 360-degree SLT after medication washout. No antiinflammatory therapy was used after SLT. Nuclear, cortical, and posterior subcapsular lens opacities were graded through dilated pupils using the Lens Opacification Classification System III (LOCS III) at baseline and 12, 24, and 36 months after SLT, with the grader masked to all previous values after baseline assessment. Changes in opacity scores from baseline were evaluated using paired t tests. RESULTS: Seventy-two patients (142 phakic eyes) were evaluated. The mean (±SD) baseline LOCS III opacity scores in right eyes and left eyes, respectively, were 2.44 ± 1.23 and 2.40 ± 1.16 (nuclear), 0.39 ± 1.08 and 0.30 ± 0.85 (cortical), and 0.22 ± 0.59 and 0.15 ± 0.36 (posterior subcapsular). Other than a small improvement in bilateral nuclear opacity scores at 12 months, no statistically or clinically significant changes in any opacity score occurred in either eye up to 36 months postoperatively. Three eyes (2.1%) with preexisting lens opacities had cataract surgery for progressive lens changes at 3 months, 21 months, and 26 months, respectively, after SLT. CONCLUSIONS: Selective laser trabeculoplasty was not associated with clinically significant changes in nuclear, cortical, or posterior subcapsular lens opacities in glaucomatous Afro-Caribbean eyes. The rate of cataract surgery is consistent with reported rates from longitudinal natural history studies in Caribbean and non-Caribbean populations.

Estrogen receptor gene polymorphisms and their influence on clinical status of Caucasian patients with primary open angle glaucoma.

Purpose: The aim of this study was to evaluate the frequency of single nucleotide polymorphisms (SNP) of estrogen receptor genes (ESR1: rs12154178, rs1884054 and ESR2: rs1268656, rs7159462) and to assess their possible influence on the clinical phenotype of primary open angle glaucoma (POAG). Methods: The study included 235 patients with POAG (143 patients with normal-tension glaucoma [NTG] and 92 patients with high-tension glaucoma [HTG]), and 165 healthy controls. DNA was isolated from peripheral blood, and SNP genotyping was performed using the Real-Time Polymerase Chain Reaction method to analyze the frequency of selected polymorphic variants of estrogen receptor genes. The clinical phenotype (best-corrected visual acuity, intraocular pressure [IOP], mean deviation [MD], cup to disc ratio, disc hemorrhages, notches, peripapillary atrophy, cold extremities) of participants were examined for association with the polymorphisms. Results: A similar frequency of the polymorphic variants of the studied genes was observed in patients with NTG, HTG and control group. Initial intraocular pressure was the lowest in NTG patients with GG variant of rs1268656 (p = 0.044). The lowest maximal IOP in HTG patients was observed in CC variant of rs12154178 (p = 0.039). Patients with HTG and CC variant of ESR1 polymorphism rs1884054 had the best visual acuity (p = 0.009), similar tendency was also observed in the NTG group. This polymorphic variant of ESR1 gene in HTG was also related to earlier damage in visual field assessed according to MD values and higher percentage of notches. For rs12154178, homozygotic variant CC was related to earlier glaucoma damage according to MD in HTG patients (p = 0.006). For polymorphism rs12154178, disc hemorrhages were found only for those with the AC variant. Cold extremities were most frequent in NTG patients with TT variant of rs1268656 comparing to other variants (p = 0.021). Notches on optic disc were less frequent in patients with CC variant of rs12154178 of ERS-1 gene (p = 0.022). Conclusions: The studied polymorphic variants of ESR1 and ESR2 genes may have an influence on the clinical phenotype of patients with POAG.

Gene-based sequential burden association test.

Detecting the association between a set of variants and a phenotype of interest is the first and important step in genetic and genomic studies. Although it attracted a large amount of attention in the scientific community and several related statistical approaches have been proposed in the literature, powerful and robust statistical tests are still highly desired and yet to be developed in this area. In this paper, we propose a powerful and robust association test, which combines information from each individual single-nucleotide polymorphisms based on sequential independent burden tests. We compare the proposed approach with some popular tests through a comprehensive simulation study and real data application. Our results show that, in general, the new test is more powerful; the gain in detecting power can be substantial in many situations, compared to other methods.

Identification of Candidate miRNA Biomarkers for Glaucoma.

Purpose: Glaucoma, a leading cause of blindness worldwide, often remains undetected until irreversible vision loss has occurred. Treatments focus on lowering intraocular pressure (IOP), the only modifiable and readily measurable risk factor. However, IOP can vary and does not always predict disease progression. MicroRNAs (miRNAs) are promising biomarkers. They are abundant and stable in biological fluids, including plasma and aqueous humor (AqH). We aimed to identify differentially expressed miRNAs in AqH and plasma from glaucoma, exfoliation syndrome (XFS), and control subjects. Methods: Plasma and AqH from two ethnic cohorts were harvested from glaucoma or XFS (often associated with glaucoma, n = 33) and control (n = 31) patients undergoing elective surgery. A custom miRNA array measured 372 miRNAs. Molecular target prediction and pathway analysis were performed with Ingenuity Pathway Analysis (IPA) and DIANA bioinformatical tools. Results: Levels of miRNAs in plasma, a readily accessible biomarker source, correlated with miRNA levels in AqH. Twenty circulating miRNAs were at least 1.5-fold higher in glaucoma or XFS patients than in controls across two ethnic cohorts: miR-4667-5p (P = 4.1 × 10-5), miR-99b-3p (P = 4.8 × 10-5), miR-637 (P = 5.1 × 10-5), miR-4490 (P = 5.7 × 10-5), miR-1253 (P = 6.0 × 10-5), miR-3190-3p (P = 3.1 × 10-4), miR-3173-3p (P = 0.001), miR-608 (P = 0.001), miR-4725-3p (P = 0.002), miR-4448 (P = 0.002), and miR-323b-5p (P = 0.002), miR-4538 (P = 0.003), miR-3913-3p (P = 0.003), miR-3159 (P = 0.003), miR-4663 (P = 0.003), miR-4767 (P = 0.003), miR-4724-5p (P = 0.003), miR-1306-5p (P = 0.003), miR-181b-3p (P = 0.004), and miR-433-3p (P = 0.004). miR-637, miR-1306-5p, and miR-3159, in combination, allowed discrimination between glaucoma patients and control subjects (AUC = 0.91 ± 0.008, sensitivity 85.0%, specificity 87.5%). Conclusions: These results identify specific miRNAs as potential biomarkers and provide insight into the molecular processes underlying glaucoma.

Vision-related Quality of Life in Glaucoma Patients and its Correlations With Psychological Disturbances and Visual Function Indices.

PURPOSE: The purpose of this study was to assess the vision-related quality of life (VR-QoL) in glaucoma patients and its correlations with psychological disturbances and visual function components. MATERIALS AND METHODS: The 25-item National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25) and Hospital Anxiety and Depression Scale (HADS) questionnaires were administered to 428 Chinese glaucoma patients to evaluate their VR-QoL and anxiety and depression disorders, respectively. Sociodemographical and clinical factors were collected at the same time. Univariate analyses were used to investigate the associations between the variables and the VR-QoL. Multivariate linear regression analyses were used to identify the independent psychological and visual functional predictors of the VR-QoL. Standardized partial regression analyses were used to reveal the variables that mostly relevant to the VR-QoL. RESULTS: The composite score (mean±SD) was 71.88±14.44 for NEI VFQ-25 and 13.17±6.56 for HADS. Visual function indices, including best-corrected visual acuity and mean deviation of both eyes in addition to psychological symptoms including anxiety and depression were both correlated with VR-QoL significantly, even after adjusting for sociodemographical and clinical factors. Standardized partial regression analyses further suggested that psychological disorders, especially anxiety rather than visual function components, were mostly relevant to VR-QoL. CONCLUSIONS: Deterioration of vision impairment and visual field defects in addition to increased recognition of psychological disturbances reduce the VR-QoL of glaucoma patients significantly. Alleviating psychological symptoms, especially anxiety, perhaps have a greater influence on the improvement of VR-QoL.

Prevalence of Normal-Tension Glaucoma in the Chinese Population: A Systematic Review and Meta-Analysis.

PURPOSE: To investigate the prevalence of normal-tension glaucoma (NTG) in the Chinese population through systematic review and meta-analysis. DESIGN: Systematic review and meta-analysis. METHODS: All Chinese population-based studies that reported the prevalence of NTG were identified. We searched PubMed and Chinese databases including Wanfang, China National Knowledge Infrastructure, and VIP for studies published before December 31, 2017. Random effects meta-analysis was conducted to estimate the pooled prevalence of NTG. RESULTS: Twelve studies were included in this review and meta-analysis, including 9 population-based studies and 3 studies from glaucoma clinics and managed care networks. The 9 population-based studies included a total of 30,892 subjects with 498 patients with primary open-angle glaucoma (POAG) and 354 patients with NTG. The prevalence of estimated NTG ranged from 0.36% to 1.98% and the percentage of NTG among POAG ranged from 51.43% to 83.58%. In the glaucoma clinic and managed care network studies, NTG prevalence was much lower. The overall pooled proportion of NTG among POAG in the Chinese population was 70.0% (95% confidence interval [CI] 62.0-77.0%). The overall pooled prevalence of POAG and NTG was 2.0% (95% CI 1.0-2.0%) and 1.0% (95% CI 1.0-1.0%), respectively. For the meta-regression of the NTG/POAG proportion, we found that age, gender, intraocular pressure, and China versus not China were not significantly associated with NTG/POAG prevalence, although the proportional prevalence decreased with increasing age category. CONCLUSIONS: In this systematic review, we found that NTG is common among patients with POAG in the Chinese population. Our findings can help guide future glaucoma studies and public health guidelines in the Chinese population.

[Selective laser trabeculoplasty in African blacks]. / Trabéculoplastie sélective chez le mélanoderme africain.

INTRODUCTION: The treatment of primary open angle glaucoma (POAG) is preferably medical. However, when medical therapy fails, alternative or complementary treatments may be considered. In this regard, selective laser trabeculoplasty is a widely popular procedural treatment whose accepted benefits have been very little studied in African blacks. The objective of this study was to assess the efficacy of selective laser trabeculoplasty on the reduction of intraocular pressure (IOP) in African blacks with POAG. METHODS: We conducted a retrospective study of black patients treated with selective laser trabeculoplasty between March 2010 and March 2011. All patients had POAG with trabecular meshwork accessible over 360°. The treatment protocol consisted of a 360°treatment in two sessions (180°/session) 15 days apart. Success was defined as decrease from the initial IOP≥3mm Hg without additional medications. RESULTS: We included 44 patients, corresponding to 82 eyes. The mean age of the patients was 55.94±11.66 years with extremes of 19 years and 76 years. The mean intraocular pressure before laser treatment (initial IOP) was 18.43±4.81mm Hg. After laser treatment, the mean pressure reduction was (i) 3.81mm Hg (20.67%) at 15 days ; (ii) 4.08mm Hg (22.14%) at 1 month; (iii) 4.45mm Hg (24.14%) at 3 months; and (iv) 4.95mm Hg (26.86%) at 6 months. The success rate after laser treatment was 67.60% at 15 days, 83.78% at 1 month, 72.09% at 3 months and 80.43% at 6 months. CONCLUSION: Selective laser trabeculoplasty is effective in African blacks. Its efficacy is comparable to that of a carbonic anhydrase inhibitor or even a prostaglandin. It could be a complementary or substitutive alternative to POAG medications in African blacks.

[Association of ZP4 gene polymorphism with primary open-angle glaucoma in an ethnic Chinese population from Sichuan province].

OBJECTIVE: To assess the association of single nucleotide polymorphisms (SNP) rs547984, rs540782, rs693421 and rs2499601 of Zona Pellucida Glycoprotein 4 (ZP4) gene with primary open-angle glaucoma (POAG) among ethnic Han Chinese from Sichuan Province. METHODS: A dye terminator-based SNaPshot method was used to genotype 336 patients with POAG and 768 healthy controls. RESULTS: No significant difference was detected in allelic frequencies of rs547984, rs540782, rs693421 and rs2499601 between the two groups (P>0.05). Haplotypic analysis showed a significant difference in G-G-A-G haplotype formed by the 4 SNPs between the POAG and the control groups (P<0.05). CONCLUSION: ZP4 gene SNPs rs547984, rs540782, rs693421, rs2499601 are not associated with POAG among ethnic Hans from Sichuan.

Local genetic ancestry in CDKN2B-AS1 is associated with primary open-angle glaucoma in an African American cohort extracted from de-identified electronic health records.

BACKGROUND: Glaucoma is a leading cause of blindness in developed countries. Primary open-angle glaucoma (POAG), the most prevalent clinical subtype of glaucoma in the United States, affects African Americans at a higher rate compared with European Americans. Risk factors identified for POAG include increased age and family history, which coupled with heritability estimates, suggest this complex condition is associated with genetic and environmental factors. To date, several genome-wide studies have identified loci significantly associated with POAG risk, but most of these studies were performed in populations of European-descent. METHODS: To identify population-specific and trans-population genetic associations for POAG, we genotyped 11,521 African Americans using the Illumina Metabochip as part of the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) study accessing BioVU, the Vanderbilt University Medical Center's biorepository linked to de-identified electronic health records. Among this study population, we identified 138 cases of POAG and 1376 controls and performed Metabochip-wide tests of association. We also estimated local genetic ancestry at CDKN2B-AS1, a POAG-associated locus established in European-descent populations. RESULTS: Overall, we did not identify significant single SNP-POAG associations after adjusting for multiple testing. We did, however, detect a significant association between POAG risk and local African genetic ancestry at CDKN2B-AS1, where on average cases were of 90% African descent compared with controls at 58% (p = 2 × 10- 6). CONCLUSIONS: These data suggest that CDKN2B-AS1 is an important locus for POAG risk among African Americans, warranting further investigation to identify the variants underlying this association.