Prevalence and factors associated with optic disc grey crescent in the Primary Open-Angle African Ancestry Glaucoma Genetics (POAAGG) Study

Aim To investigate the prevalence and factors associated with optic disc grey crescent (GC) in African Americans with glaucoma.Methods Stereo optic disc image features from subjects with glaucoma in the Primary Open-Angle African Ancestry Glaucoma Genetics Study were evaluated independently by non-physician graders and discrepancies adjudicated by an ophthalmologist. Risk factors for GC were evaluated by logistic regression models with intereye correlation accounted for by generalised estimating equations. Adjusted ORs (aORs) were generated.Results GC was present in 227 (15%) of 1491 glaucoma cases, with 57 (3.82%) bilateral and 170 (11.4%) unilateral. In multivariable analysis, factors associated with GC were younger age (aOR 1.27, 95% CI 1.11 to 1.43 for every decade younger in age, p=0.001), diabetes (aOR 1.46, 95% CI 1.09 to 1.96, p=0.01), optic disc tilt (aOR 1.84, 95% CI 1.36 to 2.48, p<0.0001), a sloping retinal region adjacent to the outer disc margin (aOR 2.37, 95% CI 1.74 to 3.32, p<0.0001) and beta peripapillary atrophy (aOR 2.32, 95% CI 1.60 to 3.37, p<0.0001). Subjects with GC had a lower mean (SD) value of the ancestral component q0 than those without GC (0.22 (0.15) vs 0.27 (0.20), p=0.001), consistent with higher degrees of African ancestry.Conclusions More than 1 in 10 glaucoma cases with African ancestry have GC, occurring more frequently in younger subjects, higher degrees of African ancestry and diabetes. GC was associated with several ocular features, including optic disc tilt and beta peripapillary atrophy. These associations should be considered when evaluating black patients with primary open-angle glaucoma

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

Mitochondrial Sequence Variation in African-American Primary Open-Angle Glaucoma Patients

<div><p>Primary open-angle glaucoma (POAG) is a major cause of blindness and results from irreversible retinal ganglion cell damage and optic nerve degeneration. In the United States, POAG is most prevalent in African-Americans. Mitochondrial genetics and dysfunction have been implicated in POAG, and potentially pathogenic sequence variations, in particular novel transversional base substitutions, are reportedly common in mitochondrial genomes (mtDNA) from POAG patient blood. The purpose of this study was to ascertain the spectrum of sequence variation in mtDNA from African-American POAG patients and determine whether novel nonsynonymous, transversional or other potentially pathogenic sequence variations are observed more commonly in POAG cases than controls. mtDNA from African-American POAG cases (n = 22) and age-matched controls (n = 22) was analyzed by deep sequencing of a single 16,487 base pair PCR amplicon by Ion Torrent, and candidate novel variants were validated by Sanger sequencing. Sequence variants were classified and interpreted using the MITOMAP compendium of polymorphisms. 99.8% of the observed variations had been previously reported. The ratio of novel variants to POAG cases was 7-fold lower than a prior estimate. Novel mtDNA variants were present in 3 of 22 cases, novel nonsynonymous changes in 1 of 22 cases and novel transversions in 0 of 22 cases; these proportions are significantly lower (p<.0005, p<.0004, p<.0001) than estimated previously for POAG, and did not differ significantly from controls. Although it is possible that mitochondrial genetics play a role in African-Americans’ high susceptibility to POAG, it is unlikely that any mitochondrial respiratory dysfunction is due to an abnormally high incidence of novel mutations that can be detected in mtDNA from peripheral blood.</p> </div

Variant rarity.

<p>The 474 different mtDNA variants, binned by number of observations in POAG cases and controls.</p

Heteroplasmic variants.

<p>Two examples of heteroplasmic variants that were detected on the basis of mixed Ion Torrent reads (top) and confirmed by CE, Sanger sequencing (bottom). One was from a POAG case (panel A) and one was from a control (panel B).</p

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

A Precise Method to Evaluate 360 Degree Measures of Optic Cup and Disc Morphology in an African American Cohort and Its Genetic Applications

(1) Background: Vertical cup-to-disc ratio (CDR) is an important measure for evaluating damage to the optic nerve head (ONH) in glaucoma patients. However, this measure often does not fully capture the irregular cupping observed in glaucomatous nerves. We developed and evaluated a method to measure cup-to-disc ratio (CDR) at all 360 degrees of the ONH. (2) Methods: Non-physician graders from the Scheie Reading Center outlined the cup and disc on digital stereo color disc images from African American patients enrolled in the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study. After converting the resultant coordinates into polar representation, the CDR at each 360-degree location of the ONH was obtained. We compared grader VCDR values with clinical VCDR values, using Spearman correlation analysis, and validated significant genetic associations with clinical VCDR, using grader VCDR values. (3) Results: Graders delineated outlines of the cup contour and disc boundaries twice in each of 1815 stereo disc images. For both cases and controls, the mean CDR was highest at the horizontal bisector, particularly in the temporal region, as compared to other degree locations. There was a good correlation between grader CDR at the vertical bisector and clinical VCDR (Spearman Correlation OD: r = 0.78 [95% CI: 0.76–0.79]). An SNP in the MPDZ gene, associated with clinical VCDR in a prior genome-wide association study, showed a significant association with grader VCDR (p = 0.01) and grader CDR area ratio (p = 0.02). (4) Conclusions: The CDR of both glaucomatous and non-glaucomatous eyes varies by degree location, with the highest measurements in the temporal region of the eye. This method can be useful for capturing innate eccentric ONH morphology, tracking disease progression, and identifying genetic associations