We report a genome-wide association study for open-angle glaucoma (OAG) blindness using a discovery cohort of 590 individuals with severe visual field loss (cases) and 3,956 controls. We identified ...associated loci at TMCO1 (rs4656461G odds ratio (OR) = 1.68, P = 6.1 × 10(-10)) and CDKN2B-AS1 (rs4977756A OR = 1.50, P = 4.7 × 10(-9)). We replicated these associations in an independent cohort of cases with advanced OAG (rs4656461 P = 0.010; rs4977756 P = 0.042) and two additional cohorts of less severe OAG (rs4656461 combined discovery and replication P = 6.00 × 10(-14), OR = 1.51, 95% CI 1.35-1.68; rs4977756 combined P = 1.35 × 10(-14), OR = 1.39, 95% CI 1.28-1.51). We show retinal expression of genes at both loci in human ocular tissues. We also show that CDKN2A and CDKN2B are upregulated in the retina of a rat model of glaucoma.
To assess the association between hearing impairment and health-related quality of life (HRQOL) in an older population, using the self-administered 36-item Short-Form Health Survey (SF-36).
...Participants of the Blue Mountains Hearing Study (BMHS, N = 2956) attended a comprehensive interview and hearing examination in which both self-reported and measured hearing impairments were assessed. Hearing impairment was defined as the pure-tone average of air-conduction hearing thresholds >25 decibels hearing level (dB HL) for the four frequencies (0.5 to 4.0 kHz) in the better ear.
Of the 2431 participants with complete data (mean age, 67.0 yr), 1347 (55.4%) did not have measured hearing loss, whereas 324 (13.3%) had unilateral (285 mild, 22 moderate, 17 severe) and 760 (31.3%) had bilateral hearing impairment (478 mild, 207 moderate, 75 severe). After adjusting for demographic and medical confounders, bilateral hearing impairment was associated with poorer SF-36 scores in both physical and mental domains (fall in physical component score, PCS of 1.4 points, p = 0.025; fall in mental component score, MCS of 1.0 point, p = 0.13), with poorer scores associated with more severe levels of impairment (PCS p(trend) = 0.04, MCS p(trend) = 0.003). Participants with bilateral hearing impairment who habitually used hearing aids had a slightly better PCS (mean, 43.1; standard error SE, 0.9) than those with the same impairment who did not have hearing aids or who only used them occasionally (mean, 41.2; SE 0.5), although this finding was not statistically significant (p = 0.055). Persons with self-reported hearing loss had significantly poorer HRQOL than corresponding persons without, but persons with unilateral or high-frequency hearing loss did not have significantly different HRQOL scores than their corresponding counterparts.
This study quantifies the associated disease burden of age-related hearing impairment on health-related quality of life in a population-based cohort of older persons.
Purpose To assess whether hearing loss predicts an increased risk of mortality. Methods The Blue Mountains Hearing Study examined 2956 persons (49+ years) during 1997 to 2000. The Australian National ...Death Index was used to identify deaths until 2005. Hearing loss was defined as the pure-tone average (0.5−4 kHz) of air-conduction hearing thresholds greater than 25 dB HL. Associations between hearing loss and mortality risk were estimated using Cox regression and structural equation modeling (SEM). Results When we used Cox regression, we discovered that hearing loss was associated with increased risk of cardiovascular (hazard ratio HR 1.36, 95% confidence interval CI 1.08−1.84) and all-cause (AC) mortality (HR 1.39, 95% CI 1.11−1.79) after adjustment for age and sex but not after multivariable adjustment. SEM pathway analysis, however, revealed a greater AC mortality risk (HR 2.58, 95% CI 1.64−4.05) in persons with hearing loss, which was mediated: cognitive impairment (HR 1.45, 95% CI 1.08−1.94) and walking disability (HR 1.63, 95% CI 1.24−2.15). These variables increased mortality both directly and indirectly through effects on self-rated health. Conclusions Hearing loss was associated with increased AC mortality via three mediating variables: disability in walking, cognitive impairment, and self-rated health. It is important to recognize that persons with combined disabilities are at increased risk of cardiovascular and AC mortality.
To examine effect modification between genetic susceptibility to age-related macular degeneration (AMD) and dietary antioxidant or fish consumption on AMD risk.
Pooled data analysis of ...population-based cohorts.
Participants from the Blue Mountains Eye Study (BMES) and Rotterdam Study (RS).
Dietary intakes of antioxidants (lutein/zeaxanthin LZ, β-carotene, and vitamin C), long-chain omega-3 polyunsaturated fatty acids, and zinc were estimated from food frequency questionnaires. The AMD genetic risk was classified according to the number of risk alleles of CFH (rs1061170) or ARMS2 (rs10490924) as low (no or 1 risk allele) or high (≥ 2 risk alleles). Interactions between dietary intake and genetic risk levels were assessed. Associations between dietary intake and AMD risk were assessed comparing the highest with the 2 lower intake tertiles by genetic risk subgroups using discrete logistic regression, conducted in each study separately and then using pooled data. Participants without AMD lesions at any visit were controls. We adjusted for age and sex in analyses of each cohort sample and for smoking status and study site in pooled-data analyses.
All 15-year incident late AMD cases were confirmed by chief investigators of the Beaver Dam Eye Study, BMES, and RS. Intergrader reproducibility was assessed in an early AMD subsample, with 86.4% agreement between BMES and RS graders, allowing for a 1-step difference on a 5-step AMD severity scale.
In pooled data analyses, we found significant interaction between AMD genetic risk status and LZ intake (P=0.0009) but nonsignificant interactions between genetic risk status and weekly fish consumption (P=0.05) for risk of any AMD. Among participants with high genetic risk, the highest intake tertile of LZ was associated with a >20% reduced risk of early AMD, and weekly consumption of fish was associated with a 40% reduced risk of late AMD. No similar association was evident among participants with low genetic risk. No interaction was detected between β-carotene or vitamin C and genetic risk status.
Protection against AMD from greater LZ and fish consumption in persons with high genetic risk based on 2 major AMD genes raises the possibility of personalized preventive interventions.
Summary Background Lacunar stroke accounts for a quarter of cases of acute ischaemic stroke; however, its underlying pathophysiology remains unclear. Our aim was to establish whether there is an ...association between changes in the retinal microvasculature and lacunar stroke that might provide clues to the pathology of cerebral small vessel disease. Methods In this cross-sectional study, we recruited patients who presented with acute stroke at three centres in two countries (Sydney and Melbourne, Australia, and Singapore). Each patient had standardised clinical assessments, retinal photography, and CT or MRI of the brain. Changes in the retinal microvasculature were assessed from retinal photographs by graders who were masked to the patients' clinical details. Lacunar stroke was diagnosed according to a modified version of the TOAST criteria (Treatment of Acute Stroke Trial) or the OCSP criteria (Oxfordshire Community Stroke Project) and by MRI findings. Findings We recruited 1321 patients aged 19 to 94 years with acute ischaemic stroke; 410 (31%) had lacunar stroke. Patients with acute lacunar stroke were no more likely to have hypertension (p=0·12), diabetes (p=0·51), or hypercholesterolaemia (p=0·91) than were patients with other types of ischaemic stroke. However, patients with lacunar stroke were more likely to have retinal microvessel signs, particularly when stroke subtype was confirmed using diffusion-weighted MRI, than were patients with other stroke subtypes. After adjustment for age, sex, study site, smoking history, hypertension, and diabetes, the patients with lacunar stroke were more likely than those with other stroke subtypes to have microvessel signs, and when stroke subtype was confirmed by diffusion-weighted MRI the odds ratios were: 3·55 (95% CI 1·77–7·12) for focal arteriolar narrowing; 1·96 (1·19–3·24) for arteriovenous nipping; 2·32 (1·42–3·79) for enhanced light reflex of the arteriolar wall; 1·33 (0·74–2·41) for generalised retinal arteriolar narrowing; 1·45 (0·84–2·51) for small retinal arteriole:venule ratio; and 1·35 (0·80–2·26) for retinal venular widening. Interpretation Our findings suggest that acute lacunar stroke is a manifestation of non-atherothrombotic occlusive small vessel disease, which might have implications for the prevention and treatment of this stroke subtype. Funding National Health and Medical Research Council of Australia; National Medical Research Council of Singapore; Scottish Funding Council; New South Wales Health.
Longitudinal associations between inhaled and oral corticosteroid use and 10-year incident cataract were examined.
Population-based cohort study.
The Blue Mountains Eye Study examined 3654 ...Australians aged 49 years or older (1992-1994); 2335 were re-examined after 5 years and 1952 were re-examined after 10 years (75.1%, 75.6% of survivors, respectively).
Questionnaires were used to assess inhaled and oral corticosteroid use at baseline. Past users were participants who had used these medications for at least 1 month in the past but were not using them at baseline. Current users were those who were using these medications at baseline and had been doing so for at least 1 month. Ever users combined past and current users.
Lens photographs were obtained at each examination and graded for nuclear, cortical, and posterior subcapsular (PSC) cataracts following the Wisconsin Cataract Grading System. Participants without a specific subtype of cataract in either eye at baseline were considered to be at risk of that type of cataract developing over the 10-year follow-up. Incidence of each cataract subtype in this report refers to person-specific, first-eye incidence.
At baseline, 103 participants were current and 120 past users of inhaled corticosteroids, and 31 were current and 147 were past users of oral corticosteroids. Current users had a greater risk of developing PSC cataract after adjustment for age and gender (inhaled: odds ratio OR 2.50, 95% confidence interval CI 1.33-4.69; oral: OR 4.11; 95% CI 1.67-10.08) and nuclear cataract (inhaled: OR 2.04, 95% CI 1.21-3.43; oral: OR 3.45, 95% CI 1.26-9.43) but not cortical cataract. Interaction between inhaled and oral corticosteroid use was significant for PSC (P = 0.01) and nuclear (P = 0.02) cataract incidence. In subgroup analyses, only individuals who used both inhaled and oral steroids were at increased risk of PSC cataract (after adjusting for age, sex, smoking, hypertension, diabetes, and education levels; OR 4.76, 95% CI 2.59-8.74), comparing ever users of both with users of neither.
High long-term risks of PSC and nuclear cataract development were found for users of combined inhaled and oral corticosteroids.
BACKGROUND: Identification of modifiable risk factors that could prevent or slow the development of age-related hearing loss (presbycusis) would be valuable. Dietary polyunsaturated fatty acid (PUFA) ...intake may be related to age-related hearing loss. OBJECTIVE: We aimed to determine the association between dietary intakes of omega-3 (n-3) PUFAs and fish and the risk of presbycusis. DESIGN: The Blue Mountains Hearing Study is a population-based survey of age-related hearing loss (1997-1999 to 2002-2004). We collected dietary data by using a semiquantitative food-frequency questionnaire and calculated PUFA and fish intakes. In 2956 participants (aged ≥50 y), we measured presbycusis, which we defined as the pure-tone average of frequencies 0.5, 1.0, 2.0, and 4.0 kHz >25 decibels of hearing loss. RESULTS: There was an inverse association between total n-3 PUFA intake and prevalent hearing loss odds ratio (OR) per SD increase in energy-adjusted n-3 PUFAs: 0.89; 95% CI: 0.81, 0.99. There was an inverse association between long-chain n-3 PUFAs and incident hearing loss (OR per SD increase in long-chain n-3 PUFAs: 0.76; 95% CI: 0.60, 0.97). Participants who had ≥2 servings of fish/wk compared with participants who had <1 serving of fish/wk had a significantly reduced risk (42%) of developing presbycusis at follow-up (multivariate-adjusted OR: 0.58; 95% CI: 0.35, 0.95). There was an association between consumption of ≥1 to <2 servings/wk of fish and a reduced risk of a progression of hearing loss (OR: 0.53; 95% CI: 0.32, 0.88). CONCLUSIONS: There was an inverse association between higher intakes of long-chain n-3 PUFAs and regular weekly consumption of fish and hearing loss. Dietary intervention with n-3 PUFAs could prevent or delay the development of age-related hearing loss.
The influence of hematological indices such as complete blood count on microcirculation is poorly understood. Retinal microvasculature can be directly visualized and vessel calibers are associated ...with a range of ocular and systemic diseases. We examined the association of complete blood count with retinal vessel calibers.
Cross-sectional population-based Blue Mountains Eye Study, n = 3009, aged 49+ years. Complete blood count was measured from fasting blood samples taken at baseline examination, 1992-4. Retinal arteriolar and venular calibers were measured from digitized retinal photographs using a validated semi-automated computer program.
All analyses adjusted for age, sex, systolic blood pressure, diabetes, smoking and fellow vessel caliber. Higher hematocrit, white cell count and platelet count were associated with narrower arteriolar caliber (p = 0.02, 0.03 and 0.001 respectively), while higher hemoglobin, hematocrit, red cell count, white cell count and platelet count were associated with wider venular caliber (p<0.0001 for all). Each quintile increase in hematocrit, white cell count and platelet count was associated with approximately 0.5 µm narrower arteriolar caliber; whereas each quintile increase in all of the complete blood count components was associated with approximately 1-2 µm wider venular caliber.
These associations show that elevated levels of hematological indices can have adverse effects on the microcirculation.
Intravitreal injections of anti-vascular endothelial growth factor agents, such as ranibizumab, have significantly improved the management of neovascular age-related macular degeneration. This study ...used patient-level simulation modelling to estimate the number of individuals in Australia who would have been likely to avoid legal blindness or visual impairment due to neovascular age-related macular degeneration over a 2-year period as a result of intravitreal ranibizumab injections. The modelling approach used existing data for the incidence of neovascular age-related macular degeneration in Australia and outcomes from ranibizumab trials. Blindness and visual impairment were defined as visual acuity in the better-seeing eye of worse than 6/60 or 6/12, respectively. In 2010, 14,634 individuals in Australia were estimated to develop neovascular age-related macular degeneration who would be eligible for ranibizumab therapy. Without treatment, 2246 individuals would become legally blind over 2 years. Monthly 0.5 mg intravitreal ranibizumab would reduce incident blindness by 72% (95% simulation interval, 70-74%). Ranibizumab given as needed would reduce incident blindness by 68% (64-71%). Without treatment, 4846 individuals would become visually impaired over 2 years; this proportion would be reduced by 37% (34-39%) with monthly intravitreal ranibizumab, and by 28% (23-33%) with ranibizumab given as needed. These data suggest that intravitreal injections of ranibizumab, given either monthly or as needed, can substantially lower the number of cases of blindness and visual impairment over 2 years after the diagnosis of neovascular age-related macular degeneration.
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