January 2004
Volume 45, Issue 1
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Clinical and Epidemiologic Research  |   January 2004
Heritability of Risk Factors for Primary Open-Angle Glaucoma: The Beaver Dam Eye Study
Author Affiliations
  • Barbara E. K. Klein
    From the Department of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, Madison, Wisconsin.
  • Ronald Klein
    From the Department of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, Madison, Wisconsin.
  • Kristine E. Lee
    From the Department of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, Madison, Wisconsin.
Investigative Ophthalmology & Visual Science January 2004, Vol.45, 59-62. doi:10.1167/iovs.03-0516
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      Barbara E. K. Klein, Ronald Klein, Kristine E. Lee; Heritability of Risk Factors for Primary Open-Angle Glaucoma: The Beaver Dam Eye Study. Invest. Ophthalmol. Vis. Sci. 2004;45(1):59-62. doi: 10.1167/iovs.03-0516.

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purpose. To investigate the family aggregation and heritability of risk indicators of primary open-angle glaucoma.

methods. During the baseline examination of the Beaver Dam Eye Study, standardized measurements of intraocular pressure were performed with a Goldmann applanation tonometer. Stereoscopic photographs of the optic discs were taken of both eyes of each study participant. The eyes were graded for the size of the optic disc and cup according to a standardized protocol, with graders masked to other subject characteristics. Family members who had participated in the examination phase were identified.

results. Correlations in sibling pairs (n = 1136), parent–child pairs (n = 514), and cousin pairs (n = 1807) for intraocular pressure were 0.17, 0.18, and 0.12, respectively and were all statistically significant, whereas the spouse pair correlation was not. Correlations for sibling, parent–child, and avuncular pairs were higher for vertical optic disc, vertical optic cup, and vertical cup-to-disc ratio than for intraocular pressure. Heritability estimates were 0.36, 0.55, 0.57, and 0.48 for intraocular pressure, optic cup diameter, optic disc diameter, and cup-to-disc ratio, respectively. Correlations for the optic disc parameters were compatible with the amount of gene sharing in relative pairs of different degrees.

conclusions. Risk indicators of open-angle glaucoma correlate highly in families, and the patterns are consistent with the hypothesis of genetic determinants of these factors.

Primary open-angle glaucoma is a diagnosis that is often made after damage extensive enough to cause functional deficit, as manifest by a visual field defect. By this time, it is likely that many optic nerve fibers have been lost. 1 Based on incidence data, 2 3 4 5 overt glaucoma is more likely to develop in those with higher baseline intraocular pressures than in those with lower pressures. The relationship appears to be monotonic, with no evidence of a threshold of increased risk at any particular pressure. The risk rose acutely from approximately 1% in those with pressures below 16 mm Hg to as high as 40% in those with pressures greater than 30 mm Hg in the Ocular Hypertension Treatment Study (OHTS). 6 The most persuasive data in support of the importance of intraocular pressure as a risk factor for primary open-angle glaucoma are from the OHTS which demonstrated that lowering the intraocular pressure by medical treatment resulted in a hazard ratio of 0.40 (95% confidence interval, 0.27–0.59) for open-angle glaucoma at 60 months after treatment was begun. 6 Cup-to-disc ratios, both vertical and horizontal, as well as other ocular factors that may be associated with risk of glaucoma were also evaluated in that trial. Although larger ratios have been considered to be caused by glaucoma, the Ocular Hypertension Treatment Study found that relatively larger ratios preceded the diagnosis of glaucoma, with the hazard ratio being slightly greater for the vertical than for the horizontal ratio. 
Family studies of primary open-angle glaucoma, 7 8 9 a study of individuals with the disease, 10 and large epidemiologic studies 11 12 13 are all consistent with the notion of genetic determinants of this condition. Twin studies 14 15 as well as other family studies 16 17 support the hypothesis of genetic determinants of intraocular pressure. There are few data in the literature concerning family similarity of optic disc morphology, but there are data indicating that there are genetic determinants of the number of retinal ganglion cells in mice, 18 19 which would be likely to affect optic disc morphology in that species. 
The clinical diagnosis of glaucoma is not made according to a uniform set of guidelines. The lack of uniformity may lead to phenotypic heterogeneity. This may hamper the search for determinants of this condition, both environmental and genetic. Also, it is likely that identifying affected individuals early in the disease is hard to do with certainty. Waiting for the appearance of late-stage unequivocal disease may impede the search for causes, because the number of persons with overt disease may be small relative to the number with early-onset disease. Therefore, the search for either early markers or strong risk factors may facilitate understanding the genetic mechanisms underlying this disease as it occurs in populations. We sought to investigate the heritability of intraocular pressure and vertical cup and disc diameters in a large, population-based study. 
Methods
Methods used to identify the population and description of participants and nonparticipants appear in previous reports. 20 21 Briefly, a private census of the population of Beaver Dam, Wisconsin, was performed from fall 1987 through spring 1988. All 5924 persons 43 to 84 years of age were eligible to participate in a baseline examination that took place from March 1988 to September 1, 1990. Tenets of the Declaration of Helsinki were observed and institutional review board approval was obtained. The baseline examination included measurements of intraocular pressure in each eye according to the following protocol: A drop of fluorescein sodium (Fluress; Armour, Kankakee, IL) was instilled in each eye. The tonometer was set at 10. The measurement was taken as the examiner viewed the mires through the prism. When the end point was reached, the examiner moved the slit lamp away from the eye and read and recorded the reading. The procedure was repeated for the other eye. The time of the measurement was recorded. The pupils were dilated and photographs of the ocular fundus including stereoscopic images of the optic discs of both eyes were taken. Grading of optic disc and cup dimensions was performed according to a specified protocol. 22 In brief, the stereoscopic pairs of photographs of each optic disc were examined, and both vertical and horizontal disc and cup diameters were measured with a template of grade circles of increasing sizes (in fractions of an inch). Vertical cup and disc measurements were used in analyses in this study, because they have been shown to be slightly more commonly associated with incident glaucoma than have horizontal dimensions. 6  
Persons with one or more siblings who were identified during the initial census of Beaver Dam were grouped into families. The families were expanded to include cousin and avuncular relationships by telephone interviews and obituaries. Family relationships were confirmed by interview and extended pedigrees constructed. There were 2783 persons in these families. There were additional spouses without other relatives in the population. 
Statistical analyses were accomplished using FCOR, a procedure for estimating multivariate family correlations, in the SAGE software. 23 Logistic regression was used to assess the odds of a person being affected given that a family member was affected, adjusting for age and sex. Generalized estimating equations (GEE) were used to adjust for contributions from multiple family members. 24  
Results
There were no consistent systematic differences between the eyes in the measurements of intraocular pressure or optic disc. Data for these continuous variables are given for the eye with the higher intraocular pressure and larger cup-to-disc ratio. The mean intraocular pressure was 16.3 ± 3.3 mm Hg in women and 15.9 ± 3.5 mm Hg in men (Table 1) . Intraocular pressure increased with each decade of current age. Mean vertical optic cup diameters were 0.069 ± 0.025 inches in women and 0.069 ± 0.025 inches in men. Mean vertical optic disc diameters were 0.172 ± 0.018 inches in women and 0.172 ± 0.018 inches in men. Both increased with age. The average vertical cup-to-disc ratio was 0.403 ± 0.128 for women and 0.404 ± 0.123 for men. There was an increase with age. 
Because of the effects of age on all measures and on sex for intraocular pressure, the following correlation analyses were adjusted for these two variables (Table 2) . The correlation of intraocular pressure in siblings was 0.17, in parents and children, 0.18; in avunculars, 0.02; in cousins, 0.12; and in spouses, 0.06. Heritability (h2) derived from the parent–child correlation was 0.36. The correlation of vertical cup-to-disc ratio in siblings was 0.25; in parents and children, 0.24; in avunculars, 0.14; in cousins, 0.04; and in spouses, 0.01. Heritability was 0.48. The correlations and heritability for optic disc and cup separately were higher than for the cup-to-disc ratio. 
Discussion
These analyses support the hypothesis of strong familial effects on risk indicators of glaucoma. Especially noteworthy was the consistent and strong quantitative relationship of intraocular pressures and (vertical) optic cup dimensions in siblings and in parents and children and the lack of correlation of these parameters in spouses. The pattern for optic disc parameters is compatible with the amount of gene-sharing in relative pairs of different degrees. 
The correlations for intraocular pressure between family members was lower than for the optic disc and cup measures. This may be a reflection of the quantity and variability of correlates of intraocular pressure which include not only age and sex, but medical intervention by drops or surgery, time of day of measurement (diurnal variation) as well as systolic blood pressure, body mass index, refractive error, serum cholesterol, hematocrit, month of measurement, pulse rate, severity of nuclear sclerosis, diastolic blood pressure, and glycolsylated hemoglobin. 25  
We present data for the eye with the higher value, because data on glaucoma reflect these values and data from other studies do indicate that genetic factors are important in this disease. We did not find a consistent difference in the patterns of correlations when we analyzed data from like-side eyes (data not shown). 
We note that primary open-angle glaucoma occurs in approximately 2% of many adult white 22 26 27 28 populations, but the frequency is probably more than twice that in black populations. 26 29 It would be of interest to know whether there is a familial tendency to intraocular pressure and to larger cup-to-disc ratios in diverse black populations and whether the correlations are of the same magnitude that we found in whites. It would also be of interest to determine whether the same genes are related to these characteristics across ethnic groups. 
Table 1.
 
Age and Sex Distributions of Mean Intraocular Pressure and Optic Disc Characteristics in Family Members
Table 1.
 
Age and Sex Distributions of Mean Intraocular Pressure and Optic Disc Characteristics in Family Members
Sex Age (y) n Mean SD
Intraocular pressure (mm Hg)
 Women 43–54 319 15.8 3.0
55–64 293 16.1 3.1
65–74 390 16.8 3.4
75+ 307 16.6 3.7
  Total 1309 16.3 3.3
 Men 43–54 321 15.5 3.4
55–64 291 16.1 3.2
65–74 268 16.1 3.5
75+ 153 16.1 4.0
  Total 1033 15.9 3.5
 Women vs. men P = 0.002; age P < 0.0001
Vertical optic cup diameter (inches)
 Women 43–54 317 0.066 0.023
55–64 290 0.068 0.025
65–74 385 0.067 0.025
75+ 273 0.074 0.026
  Total 1265 0.069 0.025
 Men 43–54 319 0.066 0.023
55–64 290 0.069 0.023
65–74 261 0.071 0.027
75+ 140 0.073 0.027
  Total 1010 0.069 0.025
 Women vs. men P > 0.5; age P < 0.0001
Vertical optic disc diameter (inches)
 Women 43–54 317 0.169 0.017
55–64 291 0.171 0.018
65–74 387 0.173 0.018
75+ 283 0.177 0.019
  Total 1278 0.172 0.018
 Men 43–54 319 0.168 0.017
55–64 290 0.172 0.018
65–74 262 0.176 0.019
75+ 144 0.177 0.020
  Total 1015 0.172 0.018
 Women vs. men P > 0.9; age P < 0.0001
Vertical cup to disc ratio
 Women 43–54 317 0.395 0.114
55–64 290 0.403 0.133
65–74 384 0.395 0.128
75+ 272 0.424 0.138
  Total 1263 0.403 0.128
 Men 43–54 319 0.396 0.117
55–64 290 0.405 0.115
65–74 261 0.407 0.132
75+ 140 0.418 0.132
  Total 1010 0.404 0.123
 Women vs. men P > 0.9; age P = 0.006
Table 2.
 
Adjusted Family Correlations for Risk Factors for Primary Glaucoma
Table 2.
 
Adjusted Family Correlations for Risk Factors for Primary Glaucoma
Trait n Corr. 95% CI H*
Sibling
 IOP 1136 0.17 (0.10–0.24)
 Vertical cup 1091 0.28 (0.21–0.36)
 Vertical disc 1105 0.38 (0.31–0.45)
 Cup–disc ratio 1091 0.25 (0.18–0.32)
Parent-Child
 IOP 514 0.18 (0.09–0.27) 0.36
 Vertical cup 472 0.27 (0.18–0.36) 0.55
 Vertical disc 482 0.29 (0.20–0.37) 0.57
 Cup–disc ratio 469 0.24 (0.15–0.33) 0.48
Avuncular
 IOP 748 0.02 (−0.07–0.11)
 Vertical cup 710 0.17 (0.07–0.27)
 Vertical disc 721 0.19 (0.09–0.30)
 Cup–disc ratio 708 0.14 (0.04–0.23)
Cousin
 IOP 1807 0.12 (0.06–0.18)
 Vertical cup 1764 0.05 (−0.02–0.11)
 Vertical disc 1782 0.10 (0.03–0.18)
 Cup–disc ratio 1764 0.04 (−0.02–0.10)
Spouse
 IOP 1154 0.06 (0.00–0.12)
 Vertical cup 1125 0.03 (−0.03–0.09)
 Vertical disc 1142 0.03 (−0.03–0.09)
 Cup–disc ratio 1124 0.01 (−0.05–0.06)
 
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