Prithvi Sankar

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.

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

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.

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

ABSTRACT 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.

Primary Open-Angle Glaucoma in Individuals of African Descent: A Review of Risk Factors

Objective To identify the major risk factors for primary open-angle glaucoma (POAG) in individuals of African descent. Methods We searched PubMed for relevant articles, with results spanning April 1947 to present. All abstracts were reviewed and, where relevant to POAG and race, articles were catalogued and analyzed. Additional sources were identified through citations in articles returned by our search. Results Numerous potential POAG risk factors were identified and organized into categories by demographics (age, sex, and skin color), lifestyle choices (smoking, alcohol), comorbidities (hypertension, diabetes, and obesity), ophthalmic findings (eye structure, central corneal thickness, corneal hysteresis, elevated intraocular pressure, myopia, cataract, and vascular abnormalities), family history, socioeconomic status, and adherence. Older age, male sex, lower central corneal thickness, decreased corneal hysteresis, elevated intraocular pressure, myopia, vascular abnormalities, and positive family history were definitively associated with increased risk of POAG. Conclusions Individuals at greatest risk for POAG should be screened by an ophthalmologist to allow earlier detection and to slow disease progression. Further studies on the genetics of the disease will provide more insight into underlying pathologic mechanisms and could lead to improved therapeutic interventions. Continued research in urban areas with large populations of blacks is especially needed.

Confidence of ophthalmology residents in obtaining informed consent

&NA; Ophthalmology residents often obtain informed consent for common procedures. In this study, we set out to determine the confidence levels among ophthalmology residents who obtain informed consent. An anonymous online survey was distributed to United States ophthalmology residents across the country. Ninety‐five residents participated, evenly distributed geographically and by postgraduate year (PGY). Residents were frequently obtaining consent for procedures despite not being comfortable doing so. Only 18% of residents reported that they always felt comfortable with the informed consent process. Comfort level increased significantly with PGY (P < .001) and prior training in informed consent (P = .032). Of the residents surveyed, 76% indicated a desire for more formal training in the consent process. Most residents would welcome an informed‐consent formal training curriculum, which would address 5 of the 6 Accreditation Council for Graduate Medical Education core competencies and meet resident milestones in the Next Accreditation System. Financial Disclosure No author has a financial or proprietary interest in any material or method mentioned.

Factors associated with participation by African Americans in a study of the genetics of glaucoma

ABSTRACT Objective: African Americans have been historically underrepresented in research studies. Our aim was to evaluate factors influencing enrollment in the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study. Design: Patients approached to enroll in the POAAGG study were asked to complete a 15-item survey addressing demographic characteristics, knowledge of genetics and glaucoma, and opinions on human research. Survey responses were compared between subjects who enrolled (Enrollers) and did not enroll (Decliners) in the POAAGG study. Results: Enrollers (N = 190) were 3.7 years younger (P = 0.007) and had similar gender, education, and income level to Decliners (N = 117). Knowledge about genetics and glaucoma was similar between groups. Enrollers were more comfortable providing DNA for research studies (93.1% vs 54.1%; P < 0.001) and more likely to have participated in prior studies (P = 0.003) and consider participating in future studies (P < 0.001). Among Decliners, lack of time was the primary reason given for not enrolling. Conclusion: To increase participation of African Americans in genetic research studies, efforts should be made to raise comfort with DNA donation.

The MT-CO1 V83I Polymorphism is a Risk Factor for Primary Open-Angle Glaucoma in African American Men

Purpose We investigate the function of the V83I polymorphism (m.6150G>A, rs879053914) in the mitochondrial cytochrome c oxidase subunit 1 (MT-CO1) gene and its role in African American (AA) primary open-angle glaucoma (POAG). Methods This study used Sanger sequencing (1339 cases, 850 controls), phenotypic characterization of Primary Open-Angle African American Glaucoma Genetics study (POAAGG) cases, a masked chart review of CO1 missense cases (V83I plus M117T, n = 29) versus wild type cases (n = 29), a yeast 2-hybrid (Y2H) cDNA library screen, and quantification of protein–protein interactions by Y2H and ELISA. Results The association of V83I with POAG in AA was highly significant for men (odds ratio [OR] 6.5; 95% confidence interval [CI] 2.0–21.3, P = 0.0001), but not for women (OR 1.1; 95% CI, 0.62–2.00, P = 0.78). POAG cases having CO1 double missense mutation (V83I + M117T, L1c2 haplogroup) had a higher cup-to-disc ratio (0.77 vs. 0.71, P = 0.04) and significantly worse visual function (average pattern standard deviation, 6.5 vs. 4.3, P = 0.009; average mean deviation −10.4 vs. −4.5, P = 0.006) when compared to matched wild type cases (L1b haplogroup). Interaction of the V83I region of CO1 with amyloid beta peptide (Aβ) was confirmed by ELISA assay, and this interaction was abrogated by V83I. A Y2H screen of an adult human brain cDNA library with the V83 region of CO1 as bait retrieved the UBQLN1 gene. Conclusions The V83I polymorphism was associated strongly with POAG in AA men and disrupts Aβ-binding to CO1. This region also interacts with a neuroprotective protein, UBQLN1.

The SCHEIE Visual Field Grading System

Objective No method of grading visual field (VF) defects has been widely accepted throughout the glaucoma community. The SCHEIE (Systematic Classification of Humphrey visual fields-Easy Interpretation and Evaluation) grading system for glaucomatous visual fields was created to convey qualitative and quantitative information regarding visual field defects in an objective, reproducible, and easily applicable manner for research purposes. Methods The SCHEIE grading system is composed of a qualitative and quantitative score. The qualitative score consists of designation in one or more of the following categories: normal, central scotoma, paracentral scotoma, paracentral crescent, temporal quadrant, nasal quadrant, peripheral arcuate defect, expansive arcuate, or altitudinal defect. The quantitative component incorporates the Humphrey visual field index (VFI), location of visual defects for superior and inferior hemifields, and blind spot involvement. Accuracy and speed at grading using the qualitative and quantitative components was calculated for non-physician graders. Results Graders had a median accuracy of 96.67% for their qualitative scores and a median accuracy of 98.75% for their quantitative scores. Graders took a mean of 56 seconds per visual field to assign a qualitative score and 20 seconds per visual field to assign a quantitative score. Conclusion The SCHEIE grading system is a reproducible tool that combines qualitative and quantitative measurements to grade glaucomatous visual field defects. The system aims to standardize clinical staging and to make specific visual field defects more easily identifiable. Specific patterns of visual field loss may also be associated with genetic variants in future genetic analysis.