Jie Jin Wang

Global prevalence and major risk factors of diabetic retinopathy

OBJECTIVE To examine the global prevalence and major risk factors for diabetic retinopathy (DR) and vision-threatening diabetic retinopathy (VTDR) among people with diabetes. RESEARCH DESIGN AND METHODS A pooled analysis using individual participant data from population-based studies around the world was performed. A systematic literature review was conducted to identify all population-based studies in general populations or individuals with diabetes who had ascertained DR from retinal photographs. Studies provided data for DR end points, including any DR, proliferative DR, diabetic macular edema, and VTDR, and also major systemic risk factors. Pooled prevalence estimates were directly age-standardized to the 2010 World Diabetes Population aged 20–79 years. RESULTS A total of 35 studies (1980–2008) provided data from 22,896 individuals with diabetes. The overall prevalence was 34.6% (95% CI 34.5–34.8) for any DR, 6.96% (6.87–7.04) for proliferative DR, 6.81% (6.74–6.89) for diabetic macular edema, and 10.2% (10.1–10.3) for VTDR. All DR prevalence end points increased with diabetes duration, hemoglobin A1c, and blood pressure levels and were higher in people with type 1 compared with type 2 diabetes. CONCLUSIONS There are approximately 93 million people with DR, 17 million with proliferative DR, 21 million with diabetic macular edema, and 28 million with VTDR worldwide. Longer diabetes duration and poorer glycemic and blood pressure control are strongly associated with DR. These data highlight the substantial worldwide public health burden of DR and the importance of modifiable risk factors in its occurrence. This study is limited by data pooled from studies at different time points, with different methodologies and population characteristics.

Prevalence of Age-related Maculopathy in Australia: The Blue Mountains Eye Study

PURPOSE To examine the prevalence of age-related maculopathy (drusen and retinal pigmentary abnormalities) and end-stage age-related macular degeneration lesions (neovascular maculopathy or geographic atrophy) in a defined older Australian urban population. SUBJECTS All noninstitutionalized residents 49 years of age or older who were identified in a door-to-door census of two postcode areas west of Sydney, Australia. METHODS All participants received a detailed eye examination, including stereoscopic photographs of each macula. Two trained graders used the Wisconsin Age-related Maculopathy Grading System to assess the presence and severity of typical lesions. RESULTS A marked age-related increase in all typical lesions of age-related maculopathy and macular degeneration was observed. End-stage age-related macular degeneration was present in 1.9% of the population, rising from 0% among people younger than 55 years of age to 18.5% among those 85 years of age or older. Soft drusen were found in 13.3% of people, with distinct drusen more frequent than indistinct soft drusen. Retinal pigmentary abnormalities were found in 12.6% of people. For end-stage lesions and soft drusen, females had higher age-specific prevalence rates than males, whereas retinal pigmentary abnormalities were more frequent in males, although most of these differences were not significant. Prevalence rates for all lesions were lower (statistically significant for retinal pigmentary abnormalities and soft drusen) than for the United States Beaver Dam Eye Study which examined a similar population. CONCLUSIONS These data provide detailed prevalence rates for most components of ARM in an Australian population and reinforce the Beaver Dam Eye Study findings for the relative age-specific frequency of age-related macular degeneration components.

Risk factors for age-related macular degeneration: Pooled findings from three continents.

OBJECTIVE To assess the prevalence and potential risk factors for late age-related macular degeneration (AMD) in three racially similar populations from North America, Europe, and AUSTRALIA: DESIGN Combined analysis of population-based eye disease prevalence data. PARTICIPANTS There were 14,752 participants with gradable photographs from the Beaver Dam Eye Study (n = 4756), Rotterdam Study (n = 6411), and Blue Mountains Eye Study (n = 3585). MAIN OUTCOME MEASURES AMD diagnosis was made from masked grading of stereo macular photographs. Final classification of AMD cases was agreed by consensus between study investigators. RESULTS AMD prevalence was strongly age related. Overall, AMD was present in 0.2% of the combined population aged 55 to 64 years, rising to 13% of the population older than 85 years. Prevalence of neovascular AMD (NV) increased from 0.17% among subjects aged 55 to 64 years to 5.8% for those older than 85 years. Prevalence of pure geographic atrophy (GA) increased from 0.04% to 4.2% for these age groups. There were no significant gender differences in the prevalence of NV or GA. Subjects in the Rotterdam population had a significantly lower age-adjusted and smoking-adjusted risk of NV than subjects in the Beaver Dam and Blue Mountains populations. Apart from age, tobacco smoking was the only risk factor consistently associated with any form of AMD in all sites separately and in pooled analyses over the three sites. CONCLUSIONS These combined data from racially similar communities across three continents provide strong and consistent evidence that tobacco smoking is the principal known preventable exposure associated with any form of AMD.

The relationship between glaucoma and myopia: the Blue Mountains Eye Study.

OBJECTIVE To quantify the relationship between myopia and open-angle glaucoma, ocular hypertension (OH), and intraocular pressure (IOP) in a representative older population. DESIGN Cross-sectional population-based study of 3654 Australians 49 to 97 years of age. METHODS Subjects with any myopia (> or =-1.0 diopter [D]) were identified by a standardized subjective refraction and categorized into low myopia (> or =-1.0 D to <-3.0 D) or moderate-to-high myopia (> or =-3.0 D). Glaucoma was diagnosed from characteristic visual field loss, combined with optic disc cupping and rim thinning, without reference to IOP. Ocular hypertension was diagnosed when applanation IOP was greater than 21 mmHg in either eye in the absence of glaucomatous visual field and optic disc changes. MAIN OUTCOME MEASURE General estimating equation models were used to assess associations between eyes with myopia and either glaucoma or OH. RESULTS Glaucoma was present in 4.2% of eyes with low myopia and 4.4% of eyes with moderate-to-high myopia compared to 1.5% of eyes without myopia. The relationship between glaucoma and myopia was maintained after adjusting for known glaucoma risk factors, odds ratio (OR) of 2.3, and 95% confidence intervals (CI) of 1.3 to 4.1 for low myopia. It was stronger for eyes with moderate-to-high myopia (OR, 3.3; CI, 1.7-6.4). Only a borderline relationship was found with OH, OR of 1.8 (CI, 1.2-2.9) for low myopia, and OR of 0.9 (CI, 0.4-2.0) for moderate-to-high myopia. Mean IOP was approximately 0.5 mmHg higher in myopic eyes compared to nonmyopic eyes. CONCLUSIONS This study has confirmed a strong relationship between myopia and glaucoma. Myopic subjects had a twofold to threefold increased risk of glaucoma compared with that of nonmyopic subjects. The risk was independent of other glaucoma risk factors and IOP.

Assessment of polygenic effects links primary open-angle glaucoma and age-related macular degeneration.

Primary open-angle glaucoma (POAG) and age-related macular degeneration (AMD) are leading causes of irreversible blindness. Several loci have been mapped using genome-wide association studies. Until very recently, there was no recognized overlap in the genetic contribution to AMD and POAG. At genome-wide significance level, only ABCA1 harbors associations to both diseases. Here, we investigated the genetic architecture of POAG and AMD using genome-wide array data. We estimated the heritability for POAG (h2g = 0.42 ± 0.09) and AMD (h2g = 0.71 ± 0.08). Removing known loci for POAG and AMD decreased the h2g estimates to 0.36 and 0.24, respectively. There was evidence for a positive genetic correlation between POAG and AMD (rg = 0.47 ± 0.25) which remained after removing known loci (rg = 0.64 ± 0.31). We also found that the genetic correlation between sexes for POAG was likely to be less than 1 (rg = 0.33 ± 0.24), suggesting that differences of prevalence among genders may be partly due to heritable factors.

Genetic loci for retinal arteriolar microcirculation

Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10−8. This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10−12 in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.

Natural history of central retinal vein occlusion: an evidence-based systematic review.

OBJECTIVE To describe the natural history of central retinal vein occlusion (CRVO) based on the best available evidence from the literature. CLINICAL RELEVANCE Central retinal vein occlusion is a common sight-threatening retinal vascular disease. Despite the introduction of new interventions, the natural history of CRVO is unclear. METHODS Systemic review of all English language articles retrieved using a keyword search of MEDLINE, EMBASE, Current Contents, and the Cochrane Library to November 13, 2008. This was supplemented by hand-searching references of review articles published within the last 5 years. Two investigators independently identified all relevant observational studies evaluating the natural history of RVO and all clinical trials evaluating interventions for CRVO; an untreated control arm was included. RESULTS Of 5966 citations retrieved, 53 studies were reviewed, providing 3271 eyes with CRVO for analysis of its natural history. Visual acuity (VA) was generally poor at baseline (<20/40) and decreased further over time. Although 6 studies reported an improvement in VA, none of these improvements resulted in VA better than 20/40. Up to 34% of eyes with nonischemic CRVO converted to ischemic CRVO over a 3-year period. In ischemic CRVO cases, neovascular glaucoma developed in at least 23% of eyes within 15 months. In nonischemic CRVO cases, macular edema resolved in approximately 30% of eyes over time, and subsequent neovascular glaucoma was rare. CONCLUSIONS Untreated eyes with CRVO generally had poor VA, which declined further over time. One quarter of eyes with nonischemic CRVO converted to ischemic CRVO.

Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1

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 (rs4656461[G] odds ratio (OR) = 1.68, P = 6.1 × 10−10) and CDKN2B-AS1 (rs4977756[A] 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.

Hearing impairment and health-related quality of life : The blue mountains hearing study

Objectives: 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). Design: 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. Results: 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 ptrend = 0.04, MCS ptrend = 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. Conclusions: 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.

Retinal vascular caliber: systemic, environmental, and genetic associations

Quantitative studies of retinal vascular caliber using new computer-assisted retinal imaging systems have allowed physicians and researchers to understand the influence of systemic, environmental, and genetic factors on retinal vascular caliber. Retinal vascular caliber changes reflect cumulative response to aging, cardiovascular risk factors, inflammation, nitric oxide-dependent endothelial dysfunction, and other processes. Recent epidemiological studies have shown that changes in retinal arteriolar and venular caliber size may reflect the differential effects of a range of systemic, environmental, and genetic risk factors. Narrower retinal arteriolar caliber and smaller arteriovenous ratio are associated with older age; higher levels of past, current, and future blood pressure and obesity; and predict the incidence of diabetes and coronary heart disease. Wider retinal venular caliber, in contrast, is associated with younger age; impaired fasting glucose and diabetes; dyslipidemia; obesity; systemic marker of inflammation, endothelial dysfunction, and cigarette smoking; and predicts the risk of stroke and coronary heart disease. New data from family and twin studies indicate a significant genetic contribution to retinal vascular caliber, an area that is under investigation. Elucidating the complete range of systemic, environmental, and genetic factors linked with retinal vascular caliber changes may provide critical insight into the etiology, pathogenesis, and natural history of early vascular disease not only in the eye but elsewhere in the body.