Paul R. Healey

Prevalence of Open-angle Glaucoma in Australia: The Blue Mountains Eye Study

PURPOSE The purpose of this study was to determine the prevalence of open-angle glaucoma and ocular hypertension in an Australian community whose residents are 49 years of age or older. SUBJECTS There were 3654 persons, representing 82.4% of permanent residents from an area west of Sydney, Australia, who were examined. The population was identified by a door-to-door census of all dwellings and by closely matched findings from the national census. METHODS All participants received a detailed eye examination, including applanation tonometry, suprathreshold automated perimetry (Humphrey 76-point test), and Zeiss stereoscopic optic disc photography. Glaucoma suspects were asked to return for full threshold fields (Humphrey 30-2 test), gonioscopy, and repeat tonometry. RESULTS A 5-point hemifield difference on the 76-point test was found in 616 persons (19% of people tested). Humphrey 30-2 tests were performed on 336 glaucoma suspects (9.2% of population), of whom 125 had typical glaucomatous field defects. Two hundred three persons had enlarged or asymmetric cup-disc ratios (> or = 0.7 in 1 or both eyes or a cup-disc ratio difference of > or = 0.3). Open-angle glaucoma was diagnosed when glaucomatous defects on the 30-2 test matched the optic disc changes, without regard to the intraocular pressure level. This congruence was found in 87 participants (2.4%), whereas an additional 21 persons (0.6%) had clinical signs of open-angle glaucoma but incomplete examination findings. Open-angle glaucoma was thus found in 108 persons, a prevalence of 3.0% (95% confidence interval [CI], 2.5-3.6), of whom 49% were diagnosed previously. An exponential rise in prevalence was observed with increasing age. Ocular hypertension, defined as an intraocular pressure in either eye greater than 21 mmHg, without matching disc and field changes, was present in 3.7% of this population (95% CI, 3.1-4.3), but there was no significant age-related increase in prevalence. The prevalence of glaucoma was higher in women after adjusting for age (odds ratio, 1.5; CI, 1.0-2.2). There was no sex difference in the age-adjusted prevalence of ocular hypertension. CONCLUSIONS These data provide detailed age and sex-specific prevalence rates for open-angle glaucoma and ocular hypertension in an older Australian population.

Open-angle glaucoma and diabetes : The Blue Mountains Eye Study, Australia

PURPOSE The authors explore the relationship between diabetes and open-angle glaucoma in a defined older Australian population. METHODS Three thousand six hundred fifty-four people 49 to 96 years of age, living west of Sydney, underwent a detailed eye examination. This included automated perimetry, stereo optic disc photographs, and applanation tonometry; in addition, fasting plasma glucose levels were ascertained. Glaucoma was diagnosed if matching visual field and optic disc cupping were present, without reference to intraocular pressure (IOP) level. Ocular hypertension (OH) was diagnosed if IOP in either eye was > or = 22 mm and glaucomatous disc and visual field changes were absent. RESULTS Glaucoma prevalence was increased in people with diabetes, diagnosed from history or elevated fasting plasma glucose level (5.5%), compared with those without diabetes (2.8%; age-gender adjusted odds ratio [OR] 2.12, 95% confidence intervals [CI] 1.18-3.79). Ocular hypertension was also more common in people with diabetes (6.7%), compared with those without diabetes (3.5%; OR 1.86, CI 1.09-3.20). Diabetes was present in 13.0% of people with glaucoma, compared with 6.9% of those without glaucoma. This increase was highest for previously diagnosed glaucoma cases (16.7%; OR 2.82, CI 1.35-5.87). However, in 67% of such cases, glaucoma was diagnosed before the diabetes. For those not receiving glaucoma treatment, IOP was consistently slightly higher in people with diabetes, with the age-gender adjusted mean IOP 0.6 mm higher. CONCLUSIONS The significant and consistent association between diabetes and glaucoma found in our study, which appeared independent of the effect of diabetes on IOP, suggests that there is a real association between these two diseases.

Optic disc hemorrhages in a population with and without signs of glaucoma

OBJECTIVE This study aimed to determine the prevalence and associations of optic disc hemorrhage in a well-defined older Australian population. DESIGN The study design was a population-based, cross-sectional study. PARTICIPANTS A total of 3654 persons 49 years of age or older, representing 88% of permanent residents from an area west of Sydney, participated in the study. MAIN OUTCOME MEASURES Participants underwent a detailed eye examination. The diagnosis of optic disc hemorrhage was made from masked photographic grading; disc hemorrhages were subclassified as flame or blot in shape. Open-angle glaucoma was diagnosed from matching visual field loss and optic disc rim thinning. RESULTS The overall prevalence of disc hemorrhage in either or both eyes was 1.4%. Disc hemorrhage prevalence was higher in women (odds radios [OR], 1.9; confidence interval [CI], 1.0-3.5) and increased with age (OR, 2.2 per decade; CI, 1.7-2.8 per decade). The overall prevalence in subjects with open-angle glaucoma was 13.8% (8% in high-pressure glaucoma and 25% in low-pressure glaucoma) and 1.5% in subjects with ocular hypertension. Disc hemorrhages were associated with increasing intraocular pressure (OR, 1.7 per 5 mmHg; CI, 1.3-2.3 per 5 mmHg), pseudoexfoliation (OR, 3.5; CI, 1.1-11.8), diabetes (OR, 2.9; CI, 1.4-6.3), and increasing systolic blood pressure (OR, 1.1 per 10 mmHg; CI, 1.0-1.3) after adjusting for age and gender. Among subjects without open-angle glaucoma, disc hemorrhages were more frequent in eyes with larger vertical cup-disc ratios and in subjects with a history of typical migraine headache (OR, 2.2; CI, 1.1-4.6). No associations were found among subjects with a history of vascular events, smoking, regular aspirin use, or myopia. CONCLUSIONS Disc hemorrhage prevalence in this population is higher than that in the two previous population-based reports. Although the strong association of disc hemorrhage with open-angle glaucoma was confirmed (particularly low-pressure glaucoma), most disc hemorrhages (70%) were found in participants without definite signs of glaucoma.

Common genetic variants near the Brittle Cornea Syndrome locus ZNF469 influence the blinding disease risk factor central corneal thickness.

Central corneal thickness (CCT), one of the most highly heritable human traits (h2 typically>0.9), is important for the diagnosis of glaucoma and a potential risk factor for glaucoma susceptibility. We conducted genome-wide association studies in five cohorts from Australia and the United Kingdom (total N = 5058). Three cohorts were based on individually genotyped twin collections, with the remaining two cohorts genotyped on pooled samples from singletons with extreme trait values. The pooled sample findings were validated by individual genotyping the pooled samples together with additional samples also within extreme quantiles. We describe methods for efficient combined analysis of the results from these different study designs. We have identified and replicated quantitative trait loci on chromosomes 13 and 16 for association with CCT. The locus on chromosome 13 (nearest gene FOXO1) had an overall meta-analysis p-value for all the individually genotyped samples of 4.6×10−10. The locus on chromosome 16 was associated with CCT with p = 8.95×10−11. The nearest gene to the associated chromosome 16 SNPs was ZNF469, a locus recently implicated in Brittle Cornea Syndrome (BCS), a very rare disorder characterized by abnormal thin corneas. Our findings suggest that in addition to rare variants in ZNF469 underlying CCT variation in BCS patients, more common variants near this gene may contribute to CCT variation in the general population.

Assessing quality of life in patients with glaucoma using the Glaucoma Quality of Life-15 (GQL-15) questionnaire.

PurposeTo measure and compare quality of life in patients with and without glaucoma using the Glaucoma Quality of Life-15 Questionnaire, and to determine the association between glaucoma-related quality of life and clinical indices of glaucoma. Patients and MethodsUsing a prospective, cross-sectional study, we collected demographic information via interviews and administered the questionnaire to assess glaucoma-related quality of life in 121 patients with glaucoma and 31 subjects without glaucoma. Visual function was measured objectively by clinical examination. Group differences and the association between questionnaire scores and clinical indices were evaluated using nonparametric analysis of variance and correlation coefficients, respectively. The relationship between the likelihood of reporting vision-related dysfunction and glaucoma severity was examined using logistic regression. ResultsPatients with glaucoma had significantly poorer glaucoma-related quality of life than controls (P<0.001). Summary scores differed significantly among patients with mild, moderate, and severe glaucoma demonstrating a trend of poorer quality of life with increasing disease severity. Activities involving glare and dark adaptation were most problematic for all, but patients with glaucoma felt significantly more compromised in central and near vision, peripheral vision, and outdoor mobility (all P<0.001). Glaucoma-related quality of life scores correlated moderately and significantly with visual acuity, disease severity, and visual field measurements, but only severe glaucoma was a significant predictor of self-perceived deficits in glaucoma-related quality of life (P=0.038). ConclusionsThe Glaucoma Quality of Life-15 Questionnaire correlated well with objective measures of visual function and discriminated between quality of life in patients with glaucoma and subjects without glaucoma.

The effect of optic disc diameter on vertical cup to disc ratio percentiles in a population based cohort: the Blue Mountains Eye Study

Objective: The 97.5th percentile for vertical cup to disc ratio (VCDR) has been proposed as a useful tool to assist in the diagnosis of glaucoma in population studies. Previous reports of VCDR percentiles have either not been adjusted for disc size or have been calculated by regression analysis from small hospital based cohorts. The authors’ aim was to generate VCDR percentiles in a large, population based sample. Methods: Data were collected from 3654 individuals, aged 49 years or older, living in the Blue Mountains, west of Sydney. Vertical disc diameter and VCDR were determined by planimetry from stereo optic disc photographs. The distribution of VCDR and percentiles (95th, 97.5th, 99th) were calculated. Results: 6678 eyes were included in the analysis. Median cup to disc ratio, 95th, 97.5th, and 99th percentile increased with vertical optic disc diameter in a linear fashion. An increase of 0.2 in median VCDR (0.35 to 0.55) was observed between small (1.1–1.3 mm) and large (1.8–2.0 mm) optic discs. An equivalent increase of 0.2 (0.59 to 0.74) was observed for the 97.5th percentile from small to large discs. Conclusion: VCDR percentiles for a “normal” population, adjusted for vertical optic disc diameter are presented. One quarter of all discs fell within the small or large disc categories highlighting the importance for estimating optic disc size. These data may assist in the diagnosis of glaucoma in clinical practice as well as providing a normative database. Sole use of VCDR percentile cut offs in defining glaucoma cases in population surveys requires further validation.

Common variants near ABCA1 , AFAP1 and GMDS confer risk of primary open-angle glaucoma

Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 cases with advanced POAG and 1,992 controls. We investigated the association of the top SNPs from the discovery stage in two Australian replication cohorts (932 cases and 6,862 controls total) and two US replication cohorts (2,616 cases and 2,634 controls total). Meta-analysis of all cohorts identified three loci newly associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493[G], odds ratio (OR) = 1.31, P = 2.1 × 10−19), within AFAP1 (rs4619890[G], OR = 1.20, P = 7.0 × 10−10) and within GMDS (rs11969985[G], OR = 1.31, P = 7.7 × 10−10). Using RT-PCR and immunolabeling, we show that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells.

Optic disk size in open-angle glaucoma : The Blue Mountains Eye Study

PURPOSE To compare optic disk size in eyes of subjects classified as normal with the eyes of subjects with open-angle glaucoma, ocular hypertension, or pseudoexfoliation syndrome in an older population-based sample. METHODS The Blue Mountains Eye Study examined 3,654 subjects. Vertical disk diameter was measured from stereoscopic disk photographs, and we used spherical equivalent refraction to correct for magnification. Analyses used all eyes in a general estimating equation model. RESULTS Mean disk diameter was 1.556 mm in glaucomatous eyes, significantly different (P <.05) than normal eyes (1.506 mm) and eyes with ocular hypertension (1.494 mm) or pseudoexfoliation (1.501 mm). CONCLUSIONS Patients with glaucoma have slightly larger optic disks than nonglaucomatous subjects.

Female reproductive factors and open angle glaucoma: the Blue Mountains Eye Study

Aims: To determine whether endogenous oestrogen exposures are associated with open angle glaucoma (OAG). Methods: The Blue Mountains Eye Study examined 2072 women aged 49–97 years during 1992–4. Questions about female reproductive factors included age at menarche and menopause, parity, and use of hormone replacement therapy. Applanation tonometry, visual field tests, and stereo-optic disc photographs were performed. OAG was diagnosed when glaucomatous visual fields matched optic disc changes. Ocular hypertension (OH) was defined in the absence of glaucoma, but with intraocular pressure ⩾22 mm Hg. Results: A significantly increased OAG risk with later (>13 years) compared with earlier (⩽12 years) age of menarche was found, odds ratio (OR) = 2.0; 95% confidence interval (CI) 1.0 to 3.9, p for trend = 0.01, after adjustment for multiple confounders. Non-significant increased odds for OAG were found for early natural menopause (<45 years) compared with the reference group (⩾50 years), adjusted OR = 1.7; CI: 0.7 to 3.8, and for shorter duration of endogenous oestrogen exposure (<30 years), adjusted OR = 1.8; CI: 0.6 to 5.3. Increasing parity was associated with an increased risk of OAG (p = 0.03) and decreased risk of OH (p = 0.03). Conclusion: The modest associations found in relation to late menarche and increased parity do not allow the exclusion of a possible role for endogenous female hormones in the pathogenesis of OAG.

Glaucoma risk alleles at CDKN2B-AS1 are associated with lower intraocular pressure, normal-tension glaucoma, and advanced glaucoma.

PURPOSE Genetic variation at the 9p21 locus encompassing the CDKN2B-AS1, CDKN2A, and CDKN2B genes has been associated with primary open-angle glaucoma (POAG) in several independent studies. This study aimed to dissect the association further and to determine genotype-phenotype correlations between genetic variation at this locus and a range of glaucoma-related traits in a large cohort of POAG patients. DESIGN Comparative case series and case-control study. PARTICIPANTS One thousand four hundred thirty-two POAG patients and 595 unaffected controls recruited from 2 population-based and 2 cross-sectional studies. METHODS Each patient was genotyped at 9 single nucleotide polymorphisms (SNPs) previously associated with POAG at the 9p21 locus. Each SNP was assessed for association with each outcome measure using linear regression under an additive genetic model. Associated traits were explored further including adjustment for relevant covariates. Highest recorded intraocular pressure (IOP) also was analyzed both with and without correction for central corneal thickness (CCT) and was dichotomized into high-tension glaucoma and normal-tension glaucoma (NTG). MAIN OUTCOME MEASURES Intraocular pressure and vertical cup-to-disc ratio (VCDR). RESULTS Glaucoma risk alleles at 9p21, particularly, rs7049105 and rs10120688, were associated with the presence of both NTG and advanced POAG. The SNP rs10120688 was associated with greater VCDR after adjustment for covariates (P = 0.003; β = 0.016; standard error, 0.006). In addition, multiple SNPs in the region were associated with reduced IOP, before and after adjustment for CCT. The SNP most significantly associated with IOP was also rs10120688 (P = 0.001; β = -2.135; standard error, 0.634) after adjustment for covariates under an additive model. In a comparison of high-tension versus low-tension glaucoma, this SNP was also the most significantly associated, particularly when IOP was corrected for CCT before classification of the type of glaucoma (P = 0.0009; odds ratio, 0.63; 95% confidence interval, 0.48-0.83). CONCLUSIONS Patients with POAG carrying the glaucoma risk alleles at the 9p21 locus have larger VCDR and lower IOP than POAG patients without these alleles. Carriers of these alleles seem to be predisposed to POAG developing at lower IOP levels and exhibit stronger associations with NTG and advanced glaucoma phenotypes. This may be of relevance when setting target pressures in patients carrying these risk alleles.