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

Published:March 16, 2018DOI:https://doi.org/10.1016/j.ajo.2018.03.014

      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.
      Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide, affecting approximately 70 million people.
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      Multiple epidemiologic studies have confirmed that African Americans are disproportionately affected by POAG and present earlier
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      with more severe
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      and rapidly progressive disease.
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      Race as a risk factor for progressive glaucomatous damage.
      • Quigley H.A.
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      Rate of progression in open-angle glaucoma estimated from cross-sectional prevalence of visual field damage.
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      Estimating the rate of progressive visual field damage in those with open-angle glaucoma, from cross-sectional data.
      African Americans with glaucoma also face more adverse outcomes, such as worse visual fields and optic disc cupping,
      • Quigley H.A.
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      blindness,
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      decreased vision-related quality of life,
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      and increased mortality.
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      • Wu S.-Y.
      • Nemesure B.
      • Hennis A.
      • et al.
      Open-angle glaucoma and mortality: the Barbados Eye Studies.
      Positive family history (FH) strongly correlates with POAG risk in African Americans,
      • Tielsch J.M.
      • Katz J.
      • Sommer A.
      • Quigley H.A.
      • Javitt J.C.
      Family history and risk of primary open angle glaucoma. The Baltimore Eye Survey.
      reflecting heritability and/or shared environmental factors. Studies in Nigeria,
      • Agbeja-Baiyeroju A.M.
      • Bekibele C.O.
      • Bamgboye E.A.
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      Barbados,
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      Congo,
      • Kaimbo D.K.
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      Risk factors for open-angle glaucoma: a case-control study.
      and Baltimore
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      • Quigley H.A.
      • Javitt J.C.
      Family history and risk of primary open angle glaucoma. The Baltimore Eye Survey.
      found that individuals of African descent with positive FH of glaucoma had up to an 18-fold higher risk of developing the disease.
      • Kaimbo D.K.
      • Buntinx F.
      • Missotten L.
      Risk factors for open-angle glaucoma: a case-control study.
      The Baltimore Eye Survey and the Barbados Eye Study found that siblings of affected patients are at greatest risk of developing POAG, compared to parents or children.
      • Tielsch J.M.
      • Katz J.
      • Sommer A.
      • Quigley H.A.
      • Javitt J.C.
      Family history and risk of primary open angle glaucoma. The Baltimore Eye Survey.
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      • Wu S.-Y.
      • Hennis A.
      • Honkanen R.
      • Nemesure B.
      BESs Study Group. Risk factors for incident open-angle glaucoma: the Barbados Eye Studies.
      Patients report maternal FH more often than paternal FH,
      • Mitchell P.
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      • Lee A.J.
      • Wang J.J.
      Bias in self-reported family history and relationship to glaucoma: the Blue Mountains Eye Study.
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      Analyses of reported family history of glaucoma: a preliminary investigation. The Barbados Eye Study Group.
      which may reflect knowledge bias. The increased risk conveyed by both positive FH and African descent calls for a closer analysis of this group's disease origins and presentation.
      The Primary Open-Angle African American Glaucoma Genetics (POAAGG) study cohort is the largest African-American POAG cohort recruited to date. This study was designed to elucidate the genetic architecture of POAG in African Americans. The objective of this report was to assess the relationship between positive FH and POAG diagnosis in this overaffected population.

      Methods

       Study Design

      The POAAGG study is a 5-year population-based project funded by the National Eye Institute of the National Institutes of Health. The study population consists of self-identified blacks (African American, African descent, or African Caribbean) 35 years or older, identified from the Scheie Eye Institute at the University of Pennsylvania (UPenn) and its research affiliates in Philadelphia. Participants were recruited for the POAAGG study from July 2010 with UPenn institutional review board (IRB) approval. The study design, along with the baseline demographics and socioeconomic background of this population, have been reported elsewhere.
      • Charlson E.
      • Sankar P.
      • Miller-Ellis E.
      • et al.
      The Primary Open-Angle African-American Glaucoma Genetics (POAAGG) Study: baseline demographics.

       Ascertainment, Eligibility, and Phenotyping

      Certified clinical research coordinators screened potential subjects based on IRB-approved inclusion/exclusion criteria
      • Charlson E.
      • Sankar P.
      • Miller-Ellis E.
      • et al.
      The Primary Open-Angle African-American Glaucoma Genetics (POAAGG) Study: baseline demographics.
      and approached eligible patients during regularly scheduled appointments to Department of Ophthalmology physicians.
      • Salowe R.
      • O’Keefe L.
      • Merriam S.
      • et al.
      Cost and yield considerations when expanding recruitment for genetic studies: the primary open-angle African American glaucoma genetics study.
      Subjects provided a signed informed consent and genomic DNA, which was extracted from peripheral blood or saliva. All enrolled patients underwent a full onsite examination, which included the following: (1) verification of name, age at enrollment, date of birth, street address, sex, and informed consent with signature; (2) completion of a questionnaire in clinic; (3) evaluation of height and weight; (4) explanation of procedure for blood or saliva collection for DNA analysis; (5) visual acuity (VA) measured using Snellen chart at 20 feet; (6) automated refraction with a Reichert Phoropter RS Automatic Refractor (Reichert Technologies, Depew, New York, USA) if the presented VA was not 20/20 in either eye, followed by manual refraction; (7) near vision assessed using the Snellen chart at near with the participant's present reading prescription; (8) intraocular pressure (IOP) measured with a Goldmann applanation tonometer; (9) anterior and posterior segment examinations by slit lamp with a 90-diopter lens for optic nerve examination and indirect ophthalmoscopy; (10) gonioscopy confirming the presence of an open angle; (11) central corneal thickness (CCT) and axial length measurements assessed with an ultrasonic A-scan/pachymeter DGH 4000B SBH IOL Computation module (DGH Tech Inc, Exton, Pennsylvania, USA); (12) visual field test using the Humphrey Automated Field Analyzer (Standard 24-2 Swedish interactive thresholding algorithm); (13) stereo disc photographs and fundus photography using the Topcon TRC 50EX Retinal Camera (Topcon Corp. of America, Paramus, New Jersey, USA); (14) optical coherence topography (OCT) using either Cirrus or Stratus OCT (Carl Zeiss Meditec, Dublin, California, USA). The outcomes of the procedures and all diagnoses were discussed with the patient at the conclusion of the examination.
      Fellowship-trained glaucoma specialists defined cases and controls based on the following criteria. POAG cases were defined as having an open iridocorneal angle and (1) characteristic glaucomatous optic nerve findings in 1 or both eyes consisting of at least 1 of the following: notching, neuroretinal rim thinning, excavation, or a nerve fiber layer defect; (2) characteristic visual field defects in at least 1 eye detected on 2 consecutive reliable visual field tests and consistent with observed optic nerve defects in that same eye, as determined by fellowship-trained glaucoma specialists; and (3) all secondary causes of glaucoma excluded. Normal controls were defined as subjects older than 35, without any of the following: (1) high myopia (greater than -8.00 diopters); (2) high hyperopia (+8.00 diopters); (3) abnormal visual field; (4) IOP greater than 21 mm Hg; (5) neuroretinal rim thinning, excavation, notching, or nerve fiber layer defects; (6) optic nerve asymmetry; or (7) a cup-to-disc ratio (CDR) difference between eyes greater than 0.2. A preliminary masked concordance study among glaucoma specialists at 3 institutions found a 97% concordance rate in diagnosis of 120 glaucoma cases and controls.
      • Charlson E.
      • Sankar P.
      • Miller-Ellis E.
      • et al.
      The Primary Open-Angle African-American Glaucoma Genetics (POAAGG) Study: baseline demographics.
      Subjects were excluded from the analysis if they had withdrawn from the study or had disease status as glaucoma suspect. The suspects often represent potential glaucoma patients who do not yet meet the inclusion criteria of characteristic and corresponding visual field defects on 2 consecutive visual fields, as the second visual field test is scheduled in the future. Also excluded were patients with self-report of unknown FH of glaucoma or lack of recorded FH information.

       Data Collection

      During the enrollment process, subjects were asked a series of standardized, detailed questions about FH of glaucoma.
      Over the course of the POAAGG study, the research team transitioned from the use of a case-report form (CRF) to the electronic database REDCap (Research Electronic Data Capture). From July 2010 to November 2012, FH data were recorded in the CRFs. Patients were asked in an interview to report a positive, negative, or unknown FH of glaucoma in their first-degree relatives, as well as the name and relationship to the subject of each affected family member. With the introduction of REDCap in November 2012, additional questions were added to obtain a more detailed FH of glaucoma. These questions included positive, negative, or unknown history of glaucoma in first-degree relatives (children, siblings, parents) and second-degree relatives (parent's siblings, grandparents).
      To supplement CRF data after transitioning to REDCap, electronic medical records (EMRs) were reviewed for all subjects enrolled prior to November 2012. These records were used to update the database with answers to the new questions added during the transition to REDCap. If detailed FH data were not available in the EMRs, patients were then recontacted for more detailed FH information.
      All ocular characteristics obtained during the onsite examination (described above) were stored in REDCap. This study specifically examined VA, CDR, maximum IOP, CCT, retinal nerve fiber layer (RNFL), and mean deviation (MD) in cases. For maximum IOP, cut-off ranges of <21, 21-30, and >30 mm Hg were used, as 21 mm Hg is the arbitrary cut-off for POAG screening worldwide and 30 mm Hg is correlated with considerable increase in POAG prevalence.
      • Sommer A.
      • Tielsch J.M.
      • Katz J.
      • et al.
      Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans. The Baltimore Eye Survey.
      RNFL thickness cut-off ranges of <60, 60-80, and >80 μm were used because a value <60 μm typically implies glaucoma/glaucoma suspect, while 70-79 μm is considered suspicious and >80 μm is characteristic of normal nonglaucomatous eyes.
      • Bowd C.
      • Weinreb R.N.
      • Williams J.M.
      • Zangwill L.M.
      The retinal nerve fiber layer thickness in ocular hypertensive, normal, and glaucomatous eyes with optical coherence tomography.

       Cross-checking of Family History Data

      To verify FH data across sources, a random sample of 200 subjects (97 cases and 103 controls) were drawn. For each patient, glaucoma FH in the REDCap database was compared to glaucoma FH reported in either CRFs or EMRs (Epic at UPenn).
      In REDCap, positive FH in any relatives was present in 90 subjects, absent in 101 subjects, and unknown in 9 subjects (Supplementary Table 1; Supplemental Material available at AJO.com). FH data in REDCap had an 83.5% agreement with Epic and CRFs (weighted kappa and 95% confidence interval 0.7 [0.6, 0.8]). Specifically, 81 of 90 patients (90%) had positive FH in REDCap that was verifiable in Epic or CRFs, and 83 of 101 subjects (82%) had negative FH in REDCap that was verifiable in Epic or CRFs. FH records had an 89.7% concordance rate (0.8 [0.7-0.9]) among POAG cases and 77.7% concordance rate (0.6 [0.5-0.7]) among controls.

       Statistical Analysis

      This analysis was performed on a total of 2365 subjects (1041 controls and 1324 cases), who were enrolled as of year 5 of study initiation. We assessed the association of FH of glaucoma with POAG diagnosis using odds ratios and their 95% confidence intervals from univariate and age-adjusted logistic regression models. Patient and ocular characteristics were compared between POAG cases with vs without FH of glaucoma using generalized linear models with and without age adjustment. In the comparison of ocular characteristics, the inter-eye correlation was accounted for by using the generalized estimating equations. All the statistical comparisons were performed in SAS v9.4 (SAS Institute Inc, Cary, North Carolina, USA), and 2-sided P < .05 was considered statistically significant.

      Results

       Demographics

      Cases were an average of 10 years older than controls, with mean ages (±standard deviation) of 70.9 ± 11.3 years and 61.1 ± 11.7 years, respectively (Table 1). Approximately two thirds of cases and controls were female (61% and 68%, respectively).
      Table 1Characteristics of African-American Cases and Controls in the Study Cohort
      CharacteristicControls

      N = 1041 (44%)
      Cases

      N = 1324 (56%)
      Age (years)
       <50202 (19.4%)46 (3.5%)
       50-59283 (27.2%)197 (14.9%)
       60-69306 (29.4%)350 (26.4%)
       70-79192 (18.4%)422 (31.9%)
       ≥8058 (5.6%)309 (23.3%)
      Mean (SD)61.1 (11.7)70.9 (11.3)
      Median (min, max)60.9 (33.9, 89.4)71.8 (36.4, 98.4)
      Sex
       Male330 (32%)515 (39%)
       Female711 (68%)809 (61%)
      BMI, mean (SD)31.7 (7.3%)29.6 (6.7%)
      Hypertension
       No280 (27%)254 (19%)
       Yes761 (73%)1069 (81%)
      Taking hypertension medication
       No298 (29%)273 (21%)
       Yes730 (71%)1043 (79%)
      Diabetes
       No583 (56%)797 (60%)
       Yes458 (44%)524 (40%)
      Taking diabetes medication
       No597 (59%)843 (64%)
       Yes423 (41%)472 (36%)
      Smoking status
       Never smoker437 (47%)551 (45%)
       Former smoker349 (37%)527 (43%)
       Current smoker147 (16%)157 (13%)
      History of alcohol use
       No499 (53%)812 (66%)
       Yes443 (47%)424 (34%)
      Past retinal surgery
       No971 (93%)1212 (92%)
       Yes70 (7%)112 (8%)
      Taking nonglaucoma ocular medications
       No1011 (97%)1305 (99%)
       Yes30 (3%)19 (1%)
      Any ocular comorbidities
       No174 (18%)78 (6%)
       Yes813 (82%)1225 (94%)
      Age-related macular degeneration
       No981 (99%)1296 (99%)
       Yes6 (1%)7 (1%)
      Blind (VA 20/200 or worse)
       No968 (98%)1177 (90%)
       Yes19 (2%)126 (10%)
      Cataract (nuclear sclerosis)
       No388 (39%)393 (30%)
       Yes599 (61%)910 (70%)
      Pseudophakia
       No863 (83%)912 (69%)
       Yes178 (17%)412 (31%)
      Diabetic retinopathy
       No893 (90%)1201 (92%)
       Yes94 (10%)102 (8%)
      Optic neuropathy
       No984 (100%)1293 (99%)
       Yes3 (0%)10 (1%)
      Glaucoma diagnosis
       Unilateral0 (0%)66 (5%)
       Bilateral0 (0%)1239 (95%)
      Normal (low) tension glaucoma
       No987 (100%)1263 (97%)
       Yes0 (0%)40 (3%)
      Mixed-mechanism glaucoma
       No987 (100%)1270 (97%)
       Yes0 (0%)33 (3%)
      Past glaucoma surgery
       No1039 (100%)857 (65%)
       Yes2 (0%)467 (35%)
      Taking glaucoma medications
       No1040 (100%)438 (33%)
       Yes1 (0%)886 (67%)
      Results are n (%), unless otherwise indicated.
      BMI = body mass index; VA = visual acuity.

       Family History and Primary Open-Angle Glaucoma Risk

      Self-reported FH was associated with increased risk of POAG (age-adjusted odds ratio and 95% confidence interval 3.4 [2.8, 4.1], Table 2). This association was observed in patients with a sibling (3.5 [2.7, 4.7]), mother (2.3 [1.8, 2.9]), father (3.3 [2.3, 4.7]), or child (2.6 [1.2, 6.1]) with glaucoma.
      Table 2Association of Family History of Glaucoma With Primary Open-Angle Glaucoma Risk in African Americans
      CharacteristicCase vs Control
      Total

      (N = 2365)
      Controls

      N = 1041 (44%)
      Cases

      N = 1324 (56%)
      OR (95% CI)Age-adjusted OR (95% CI)
      Any family member
       Positive1133 (47.9%)357 (34.3%)776 (58.6%)2.71 (2.29, 3.21)3.38 (2.80, 4.09)
       Negative1232 (52.1%)684 (65.7%)548 (41.4%)ReferenceReference
      First-degree relative
       Positive830 (35.1%)214 (20.6%)616 (46.5%)3.36 (2.80, 4.05)3.43 (2.81, 4.19)
       Negative1535 (64.9%)827 (79.4%)708 (53.5%)ReferenceReference
      Parent
       Positive581 (24.6%)170 (16.3%)411 (31.0%)2.31 (1.89, 2.83)2.75 (2.21, 3.42)
       Negative1784 (75.4%)871 (83.7%)913 (69.0%)ReferenceReference
      Mother
       Positive429 (18.1%)129 (12.4%)300 (22.7%)2.07 (1.66, 2.60)2.30 (1.81, 2.93)
       Negative1936 (81.9%)912 (87.6%)1024 (77.3%)ReferenceReference
      Father
       Positive206 (8.7%)53 (5.1%)153 (11.6%)2.44 (1.77, 3.39)3.28 (2.33, 4.68)
       Negative2159 (91.3%)988 (94.9%)1171 (88.4%)ReferenceReference
      Siblings
       Positive399 (16.9%)77 (7.4%)322 (24.3%)4.02 (3.11, 5.27)3.52 (2.68, 4.67)
       Negative1966 (83.1%)964 (92.6%)1002 (75.7%)ReferenceReference
      Child
       Positive54 (2.3%)8 (0.8%)46 (3.5%)4.65 (2.31, 10.7)2.56 (1.23, 6.06)
       Negative2311 (97.7%)1033 (99.2%)1278 (96.5%)ReferenceReference
      OR = odds ratio.
      The relationship of FH with POAG risk did not vary significantly across age groups (2.9 [2.1, 4.0] in participants <60 years; 3.2 [2.3, 4.4] 60-69 years; 4.5 [3.0, 6.6] 70-79 years; 4.0 [2.1, 8.2] 80+ years; Supplementary Table 2; Supplemental Material available at AJO.com). The association between positive FH and POAG risk was very similar between sexes, with an age-adjusted odds ratio of 3.7 (2.6, 5.1) for male subjects and 3.7 (2.9, 4.7) for female subjects (Supplementary Table 3; Supplemental Material available at AJO.com).

       Family History and Baseline Characteristics, Comorbidities, and Lifestyle Choices in Cases

      Table 3 shows the comparison of baseline characteristics, comorbidities, and lifestyle choices between POAG cases with vs without positive FH. Cases with positive FH were approximately 3 years younger (P < .001) and more likely to be female (66.6% vs 53.3%, age-adjusted P < .001) than cases without FH. Cases with positive FH were also more likely to have hypertension (82.3% vs 78.6%, age-adjusted P = .006) and to take medication for hypertension (80.3% vs 77.7%, age-adjusted P = .03). No relationship was detected between positive FH and lifestyle-related factors such as body mass index, smoking status, and alcohol use.
      Table 3Association of Family History of Glaucoma With Patient Characteristics Among Cases
      CharacteristicN (%)
      Unless otherwise specified.
      P Value
      Cases Without FH (N = 548)Cases With FH (N = 776)UnadjustedAge-adjusted
      Age, mean (SE)72.5 (0.49)69.8 (0.39)<.001<.001
      Sex
       Male256 (46.7%)259 (33.4%)<.001<.001
       Female292 (53.3%)517 (66.6%)
      BMI, mean (SE)29.2 (0.28)29.9 (0.25).10.54
      Hypertension
       No117 (21.4%)137 (17.7%).09.006
       Yes430 (78.6%)639 (82.3%)
      Taking hypertension medication
       No121 (22.3%)152 (19.7%).25.03
       Yes422 (77.7%)621 (80.3%)
      Diabetes
       No325 (59.5%)472 (60.9%).61.72
       Yes221 (40.5%)303 (39.1%)
      Taking diabetes medication
       No338 (62.1%)505 (65.5%).21.22
       Yes206 (37.9%)266 (34.5%)
      Smoking status
       Never smoker223 (44.3%)328 (44.8%).82.89
       Former smoker219 (43.5%)308 (42.1%)
       Current smoker61 (12.1%)96 (13.1%)
      History of alcohol use
       No334 (66.3%)478 (65.3%).72.62
       Yes170 (33.7%)254 (34.7%)
      Past retinal surgery
       No504 (92.0%)708 (91.2%).64.58
       Yes44 (8.0%)68 (8.8%)
      Taking nonglaucoma ocular medications
       No542 (98.9%)763 (98.3%).39.41
       Yes6 (1.1%)13 (1.7%)
      Any ocular comorbidities
       No30 (5.5%)48 (6.3%).55.52
       Yes513 (94.5%)712 (93.7%)
      Age-related macular degeneration
       No538 (99.1%)758 (99.7%).13.20
       Yes5 (0.9%)2 (0.3%)
      Blind (VA 20/200 or worse)
       No488 (89.9%)689 (90.7%).63.82
       Yes55 (10.1%)71 (9.3%)
      Cataract (nuclear sclerosis)
       No180 (33.1%)213 (28.0%).047.055
       Yes363 (66.9%)547 (72.0%)
      Pseudophakia
       No358 (65.3%)554 (71.4%).02.47
       Yes190 (34.7%)222 (28.6%)
      Diabetic retinopathy
       No499 (91.9%)702 (92.4%).75.89
       Yes44 (8.1%)58 (7.6%)
      Optic neuropathy
       No540 (99.4%)753 (99.1%).46.59
       Yes3 (0.6%)7 (0.9%)
      Glaucoma diagnosis
       Unilateral24 (4.4%)42 (5.5%).38.41
       Bilateral519 (95.6%)720 (94.5%)
      Normal (low) tension glaucoma
       No524 (96.5%)739 (97.2%).45.37
       Yes19 (3.5%)21 (2.8%)
      Mixed-mechanism glaucoma
       No526 (96.9%)744 (97.9%).25.27
       Yes17 (3.1%)16 (2.1%)
      Past glaucoma surgery
       No369 (67.3%)488 (62.9%).10.02
       Yes179 (32.7%)288 (37.1%)
      Taking glaucoma medications
       No190 (34.7%)248 (32.0%).30.26
       Yes358 (65.3%)528 (68.0%)
      BMI = body mass index; FH = family history; SE = standard error; VA = visual acuity.
      a Unless otherwise specified.

       Family History and Ocular Characteristics in Cases

      Ocular characteristics including VA, CDR, maximum IOP, CCT, RNFL, and MD were compared between POAG cases with vs without positive FH, as shown in Table 4. Cases with positive FH were more likely to have an IOP > 30 mm Hg (19.7% vs 17.5%, age-adjusted P = .055) and an overall RNFL thickness > 80 μm (32.2% vs 23.7%, age-adjusted = .03). VA, CDR, CCT, and MD did not differ significantly between POAG cases with and without FH of glaucoma.
      Table 4Association of Family History of Glaucoma With Ocular Characteristics Among Cases
      Ocular CharacteristicsLevelN (%)
      Unless otherwise specified.
      P Value
      Cases Without FH (N = 1060 Eyes)Cases With FH (N = 1480 Eyes)UnadjustedAge-adjusted
      logMAR visual acuity20/20 or better218 (27.2%)424 (36.5%).002.12
      Worse than 20/20, 20/40 or better348 (43.4%)466 (40.1%)
      Worse than 20/40, better than 20/200154 (19.2%)166 (14.3%)
      20/200 or worse82 (10.2%)106 (9.1%)
      Mean (SE)0.36 (0.020)0.31 (0.017).13.50
      Cup-to-disc ratio<0.5106 (11.6%)113 (8.6%).18.19
      0.5 to 0.8557 (60.9%)819 (62.1%)
      >0.8252 (27.5%)387 (29.3%)
      Mean (SE)0.71 (0.0060)0.72 (0.0048).44.39
      Max intraocular pressure (mm Hg)<21404 (38.2%)476 (32.5%).07.055
      21 to 30469 (44.3%)701 (47.8%)
      >30185 (17.5%)289 (19.7%)
      Mean (SE)24.6 (0.26)25.2 (0.22).17.20
      Central corneal thickness (μm)<500182 (19.3%)278 (21.2%).40.19
      500 to 540391 (41.5%)567 (43.2%)
      >540370 (39.2%)467 (35.6%)
      Mean (SE)531 (1.29)529 (1.10).49.29
      Retinal nerve fiber layer thickness (μm)<60130 (21.2%)180 (19.5%).007.03
      60 to 80338 (55.1%)446 (48.3%)
      >80145 (23.7%)297 (32.2%)
      Mean (SE)71.0 (0.54)73.4 (0.50).01.08
      Mean deviation (dB)<−10210 (33.3%)235 (27.4%).17.41
      −10 to −3186 (29.5%)269 (31.4%)
      >−3 to <0174 (27.6%)248 (28.9%)
      ≥060 (9.5%)106 (12.4%)
      Mean (SE)71.0 (0.54)73.4 (0.50).22.39
      Max = maximum; SE = standard error.
      a Unless otherwise specified.

      Discussion

       Family History and Primary Open-Angle Glaucoma Risk

      More than 35% of POAAGG subjects reported a positive FH of glaucoma in a first-degree relative. In contrast, the Baltimore Eye Survey and Barbados Eye Study reported that only 16.1%
      • Tielsch J.M.
      • Katz J.
      • Sommer A.
      • Quigley H.A.
      • Javitt J.C.
      Family history and risk of primary open angle glaucoma. The Baltimore Eye Survey.
      and 17%
      • Leske M.C.
      • Connell A.M.
      • Wu S.Y.
      • Hyman L.G.
      • Schachat A.P.
      Risk factors for open-angle glaucoma. The Barbados Eye Study.
      of cases had positive FH of glaucoma in a first-degree relative, respectively. The Ocular Hypertension Treatment Study, on the other hand, showed that 42% of participants reported a positive FH of glaucoma in any relative.
      • Gordon M.O.B.J.
      • Brandt J.D.
      • et al.
      The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma.
      We believe that our higher rate of reported FH may be owing to the unusually high prevalence of POAG in African Americans, especially among older individuals.
      Positive FH in a first-degree relative was associated with a 3.4 odds ratio of having POAG. The Baltimore Eye Survey and the Barbados Eye Study reported slightly lower odds ratios (3.1 [1.9, 5.2]; 2.4 [1.4, 4.2]),
      • Tielsch J.M.
      • Katz J.
      • Sommer A.
      • Quigley H.A.
      • Javitt J.C.
      Family history and risk of primary open angle glaucoma. The Baltimore Eye Survey.
      • Leske M.C.
      • Wu S.-Y.
      • Hennis A.
      • Honkanen R.
      • Nemesure B.
      BESs Study Group. Risk factors for incident open-angle glaucoma: the Barbados Eye Studies.
      while other studies, such as a case-control study in the Congo, found that positive FH conferred up to an 18-fold higher risk of POAG.
      • Kaimbo D.K.
      • Buntinx F.
      • Missotten L.
      Risk factors for open-angle glaucoma: a case-control study.
      These studies had much smaller cohorts (POAAGG, 2365; Congo, 144) with potentially different ancestry, and used slightly different definitions of OAG, possibly accounting for these differences in risk. The POAAGG definition of glaucoma was particularly stringent, requiring diagnosis by a glaucoma specialist of a characteristic optic nerve appearance and a corresponding visual field defect.
      Age-adjusted associations of POAG with FH were highest in siblings, which is consistent with the findings of the Baltimore Eye Survey and Barbados Eye Study.
      • Tielsch J.M.
      • Katz J.
      • Sommer A.
      • Quigley H.A.
      • Javitt J.C.
      Family history and risk of primary open angle glaucoma. The Baltimore Eye Survey.
      • Leske M.C.
      • Wu S.-Y.
      • Hennis A.
      • Honkanen R.
      • Nemesure B.
      BESs Study Group. Risk factors for incident open-angle glaucoma: the Barbados Eye Studies.
      Interestingly, paternal FH had a higher association with POAG than maternal FH (3.3 [2.3, 4.7] vs 2.3 [1.8, 2.9]), conflicting with many reports in literature.
      • Mitchell P.
      • Rochtchina E.
      • Lee A.J.
      • Wang J.J.
      Bias in self-reported family history and relationship to glaucoma: the Blue Mountains Eye Study.
      • Nemesure B.
      • Leske M.C.
      • He Q.
      • Mendell N.
      Analyses of reported family history of glaucoma: a preliminary investigation. The Barbados Eye Study Group.
      • Charliat G.
      • Jolly D.
      • Blanchard F.
      Genetic risk factor in primary open-angle glaucoma: a case-control study.
      • Shin D.H.
      • Becker B.
      • Kolker A.E.
      Family history in primary open-angle glaucoma.
      Evaluating FH can introduce many biases, specifically recall bias, as subjects have a tendency to know maternal lineage better than paternal lineage.
      • Wormald R.P.
      • Basauri E.
      • Wright L.A.
      • Evans J.R.
      The African Caribbean Eye Survey: risk factors for glaucoma in a sample of African Caribbean people living in London.
      We did not observe this commonly cited recall bias.

       Family History and Characteristics in Cases

      Subjects with positive FH were younger than those without FH, suggesting that FH may contribute to earlier onset of POAG. It is interesting that female subjects were more likely to report positive FH of POAG, whereas male subjects were more likely to develop the disease.
      • Kehoe R.
      • Wu S.Y.
      • Leske M.C.
      • Chylack L.T.
      Comparing self-reported and physician-reported medical history.
      African-American women play an important role as conduits and recorders of family health information, perhaps leading to better knowledge and higher reporting rates of FH information.
      • Williams K.
      Kin keeper: a family-focused cancer prevention model for African-American women.
      Although those with positive FH were more likely to have hypertension or take medications for hypertension, the majority of previous studies found no relationship between hypertension and POAG.
      • Leske M.C.
      • Connell A.M.
      • Wu S.Y.
      • Hyman L.G.
      • Schachat A.P.
      Risk factors for open-angle glaucoma. The Barbados Eye Study.
      • Wormald R.P.
      • Basauri E.
      • Wright L.A.
      • Evans J.R.
      The African Caribbean Eye Survey: risk factors for glaucoma in a sample of African Caribbean people living in London.
      • Tielsch J.M.
      • Katz J.
      • Sommer A.
      • Quigley H.A.
      • Javitt J.C.
      Hypertension, perfusion pressure, and primary open-angle glaucoma. A population-based assessment.
      Maximum IOP was higher in cases with positive FH, as were rates of past glaucoma surgery. These findings may well be correlated. Patients presenting with higher maximum IOP may be considered at an earlier stage for surgical as opposed to pharmacologic intervention. The younger age, higher maximum IOP, and greater rates of past glaucoma surgery all point toward a more severe form of POAG in cases with positive FH.
      RNFL thickness measured by OCT is useful in detecting early RNFL damage and monitoring glaucomatous changes over time.
      • Kanamori A.
      • Nakamura M.
      • Escano M.F.
      • Seya R.
      • Maeda H.
      • Negi A.
      Evaluation of the glaucomatous damage on retinal nerve fiber layer thickness measured by optical coherence tomography.
      This study found that cases with positive FH were more likely to have a RNFL value > 80 μm. This is a surprising result, as other data (younger age, higher maximum IOP, more glaucoma surgeries) suggest more severe disease in this group, which is typically associated with thinner RNFL.
      • Bowd C.
      • Weinreb R.N.
      • Williams J.M.
      • Zangwill L.M.
      The retinal nerve fiber layer thickness in ocular hypertensive, normal, and glaucomatous eyes with optical coherence tomography.
      It is possible that patients with a known positive FH of POAG are more likely to actively seek preventative care, which could detect disease prior to significant RNFL loss. Additionally, thicker RNFL may be a characteristic of a glaucoma sub-type existing within our study population. Groups have previously found that RNFL thickness is determined by genetic effects,
      • van Koolwijk L.M.E.
      • Despriet D.D.G.
      • van Duijn C.M.
      • et al.
      Genetic contributions to glaucoma: heritability of intraocular pressure, retinal nerve fiber layer thickness, and optic disc morphology.
      so it is possible that some cases with positive FH demonstrate the phenotypes associated with different genetic variants underlying their disease. Future research will explore this possibility, as well as the other nuclear and mitochondrial variants underlying POAG in African Americans. Genome-wide association studies and whole exome sequencing are currently in progress.

       Study Limitations

      One potential flaw in this study's design is the reliance on self-reporting in data collection, which can be subject to recall bias. The Baltimore Eye Survey showed that previously diagnosed individuals reported FH of glaucoma significantly more often than newly diagnosed individuals.
      • Tielsch J.M.
      • Katz J.
      • Sommer A.
      • Quigley H.A.
      • Javitt J.C.
      Family history and risk of primary open angle glaucoma. The Baltimore Eye Survey.
      Because FH was captured at time of enrollment, subjects with newly diagnosed POAG may have incomplete FH information. Nevertheless, other large epidemiologic studies have shown that self-reporting is accurate among various ethnic groups
      • Kehoe R.
      • Wu S.Y.
      • Leske M.C.
      • Chylack L.T.
      Comparing self-reported and physician-reported medical history.
      and correlates well with medical records
      • Reijneveld S.A.
      • Stronks K.
      The validity of self-reported use of health care across socioeconomic strata: a comparison of survey and registration data.
      for a number of comorbidities
      • Kehoe R.
      • Wu S.Y.
      • Leske M.C.
      • Chylack L.T.
      Comparing self-reported and physician-reported medical history.
      and health care utilization rates.
      • Ritter P.L.
      • Stewart A.L.
      • Kaymaz H.
      • Sobel D.S.
      • Block D.A.
      • Lorig K.R.
      Self-reports of health care utilization compared to provider records.
      Additionally, the clinic-based method of enrollment of the POAAGG study could introduce some bias. It is possible that positive FH served as an impetus for some glaucoma patients to make an eye appointment (more so than controls), contributing to this group's higher rates of reported FH. The POAAGG study has obtained additional grants for a van and a complete suite of glaucoma equipment, which provides outreach to senior centers in Philadelphia.
      Furthermore, it is possible that the rate of reported FH is inflated in this study owing to subjects incorrectly identifying family members as having glaucoma. Some family members may actually be glaucoma suspects or have ocular hypertension without damage. In the literature, one study showed that FH reporting had 77% sensitivity in identifying relatives with coronary heart disease,
      • Hunt S.C.
      • Williams R.R.
      • Barlow G.K.
      A comparison of positive family history definitions for defining risk of future disease.
      while another study showed complete agreement between reported information and diabetes status among relatives.
      • Kahn L.B.
      • Marshall J.A.
      • Baxter J.
      • Shetterly S.M.
      • Hamman R.F.
      Accuracy of reported family history of diabetes mellitus. Results from San Luis Valley Diabetes Study.
      Diseases involving some stigma (such as alcoholism or schizophrenia) may be reported less reliably.
      • Yoon P.W.
      • Scheuner M.T.
      • Peterson-Oehlke K.L.
      • Gwinn M.
      • Faucett A.
      • Khoury M.J.
      Can family history be used as a tool for public health and preventive medicine?.
      Thus, we acknowledge that the rates of FH may be elevated owing to this bias, but we believe these studies show that the results can still be reported.
      Lastly, the transition in data collection from CRFs to REDCap over the study period may have impacted results, as data collected before November 2012 were obtained from a less detailed survey. We supplemented these data by consulting electronic medical records, recontacting patients, and verifying data accuracy through our random sampling of 200 patients.
      Funding/Support: This work was supported by the National Eye Institute, Bethesda, Maryland (grant #1RO1EY023557-01) and the Department of Ophthalmology at the Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Funds also come from the F.M. Kirby Foundation, Research to Prevent Blindness, The UPenn Hospital Board of Women Visitors, The Paul and Evanina Bell Mackall Foundation Trust, and the National Eye Institute, National Institutes of Health, Department of Health and Human Services, under eyeGENETM and contract nos. HHSN260220700001C and HHSN263201200001C. The sponsor or funding organization had no role in the design or conduct of this research.
      Financial Disclosures: The following authors have no financial disclosures: Joan M. O'Brien, Rebecca J. Salowe, Raymond Fertig, Julia Salinas, Maxwell Pistilli, Prithvi S. Sankar, Eydie Miller-Ellis, Amanda Lehman, Windell H.A. Murphy, Melissa Homsher, Katelyn Gordon, and Gui-shuang Ying. All authors attest that they meet the current ICMJE criteria for authorship.

      Supplemental Data

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