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1.  How big is the burden of visual loss caused by age related macular degeneration in the United Kingdom? 
Aims: To predict the burden of blindness, partial sight, and visual impairment (binocular visual acuity 6/18 or less) due to late stage age related macular degeneration (AMD) in the ageing population of the United Kingdom.
Methods: A systematic review, followed by a request for data, was used to establish a pooled prevalence of AMD and corresponding visual loss. Prevalence figures were applied to the UK population. Using UK population trends, the future burden of AMD over the coming decade was established.
Results: Pooled data from six studies showed that the prevalence of visual loss caused by AMD increased exponentially from the age of 70–85 years of age, with 3.5% (95% CI 3.0 to 4.1) having visual impairment beyond the age of 75 years. The authors estimate that there are currently 214 000 (95% CI 151 000 to 310 000) with visual impairment caused by AMD (suitable for registration). This number is expected to increase to 239 000 (95% CI 168 000 to 346 000) by the year 2011. Currently there are 172 000 (95% CI 106 000 to 279 000) and 245 000 (95% CI 163 000 to 364 000) with geographical and neovascular AMD, respectively.
Conclusions: Estimates of visual impairment agree with official statistics for the number registered partially sighted or blind, caused by AMD, and are well below other figures often cited. Although these estimates are associated with wide confidence intervals (CI) and a number of caveats, they represent the best available data, which can be used to guide health and social care provision for older people in the UK setting. Implications for low vision services are outlined.
PMCID: PMC1771556  PMID: 12598445
age related macular degeneration; blindness; partial sight; prevalence
2.  Prevalence of Early and Late Age-Related Macular Degeneration in India: The INDEYE Study 
This large, two-center, population-based study provides estimates of the prevalence of age-related macular degeneration in India.
Purpose.
To estimate the prevalence of early and late age-related macular degeneration (AMD) in India.
Methods.
Of 7518 people aged 60 years and older identified from randomly sampled villages in North and South India, 5853 (78%) attended an eye examination including fundus photography. Fundus images were graded according to the Wisconsin Age-Related Maculopathy Grading System.
Results.
Fundus images were ungradable in 1587 people, mainly because of cataract. People 80 years of age and older were less likely to attend the eye examination and more likely to have ungradable images. For ages 60 to 79 years, the percent prevalence (95% confidence interval [CI]) were late AMD 1.2 (0.8–1.5); and early AMD: grade 1 (soft distinct drusen or pigmentary irregularities), 39.3 (37.2–41.5); grade 2 (soft distinct drusen with pigmentary irregularities or soft indistinct or reticular drusen), 6.7 (5.8–7.6); and grade 3 (soft indistinct or reticular drusen with pigmentary irregularities), 0.2 (0.1–0.4). For ages 80 and older, the respective percent prevalence was: late AMD, 2.5 (0.4–4.7); and early AMD: grade 1, 43.1(35.7–50.6); grade 2, 8.1 (4.3–12.0); and grade 3, 0.5 (0–1.5).
Conclusions.
The prevalence of early AMD (grades 1 and 2) is similar to that observed in Western populations, but grade 3 appears to be lower. The prevalence of late AMD is comparable to that in Western populations in the age group 60 to 79 years. It is likely that the prevalence in the 80 and older age group is underestimated.
doi:10.1167/iovs.09-4114
PMCID: PMC2868454  PMID: 19696177
3.  FOUR-YEAR INCIDENCE AND PROGRESSION OF AGE-RELATED MACULAR DEGENERATION: THE LOS ANGELES LATINO EYE STUDY 
American journal of ophthalmology  2010;149(5):741-751.
Purpose
To estimate 4-year incidence and progression of early and advanced age-related macular degeneration (AMD).
Design
Population-based cohort study.
Methods
A comprehensive ophthalmologic examination including stereoscopic fundus photography was performed on adult Latinos at baseline and follow-up. Photographs were graded using a modified Wisconsin Age-Related Maculopathy Grading System. For estimations of incidence and progression of AMD, the Age Related Eye Disease Study Scale was used. Main outcome measures are incidence and progression of early AMD (drusen type, drusen size, and retinal pigmentary abnormalities) and advanced AMD (exudative AMD and geographic atrophy).
Results
4,658/6100 (76%) completed the follow-up examination. The 4-year incidence of early AMD was 7.5% (95%CI:6.6,8.4) and advanced AMD was 0.2% (95%CI:0.1,0.4). Progression of any AMD occurred in 9.3% (95%CI:8.4,10.3) of at-risk participants. Incidence and progression increased with age. Incidence of early AMD in the second eye (10.8%) was higher than incidence in the first eye (6.9%). Baseline presence of soft indistinct large drusen≥250μm in diameter was more likely to predict the 4-year incidence of pigmentary abnormalities, geographic atrophy, and exudative AMD than smaller or hard or soft distinct drusen.
Conclusions
Age-specific incidence and progression of AMD in Latinos are lower than in non-Hispanic whites. While incident early AMD is more often unilateral, the risk of its development in the second is higher than in the first eye. Older persons and those with soft indistinct large drusen had a higher risk of developing advanced AMD compared to those who were younger and did not have soft indistinct large drusen.
doi:10.1016/j.ajo.2010.01.009
PMCID: PMC3138505  PMID: 20399926
4.  Kidney function, albuminuria and age-related macular degeneration in NHANES III 
Nephrology Dialysis Transplantation  2011;26(10):3159-3165.
Background. Age-related macular degeneration (AMD) and kidney disease may have shared risk factors, including cardiovascular disease risk factors; additionally AMD and dense deposit disease share a common causal link, with both associated with polymorphisms in the complement pathway. Accordingly, we explored a population-based cohort of US adults to examine if markers of kidney disease identify a higher risk population for prevalent AMD.
Methods. A cross-sectional nested case–control study matching on age, sex and race was performed using data on adult participants in the Third National Health and Nutrition Examination Survey. Predictor variables included urine albumin-to-creatinine ratio and estimated glomerular filtration rate (eGFR). Study outcomes included late AMD, defined as neovascular disease or geographic atrophy (5:1 matching), and a composite of both early AMD, defined as soft drusen or pigment irregularities with or without any drusen, and late AMD (1:1 matching).
Results. There were 51 participants with late AMD and 865 with any AMD. In conditional logistic regression adjusting for diabetes, hypertension and total cholesterol, lower eGFR was independently associated with late AMD [odds ratio (OR) = 3.05, 95% confidence interval (CI): 1.51–6.13], while albuminuria was not significant. For any AMD, neither albuminuria nor eGFR were significant in adjusted models. In sensitivity analyses excluding diabetics, albuminuria was associated with any AMD (OR = 1.56, 95% CI: 1.11–1.29 and 1.57, 95% CI: 0.61–3.69 for micro- and macroalbuminuria, respectively, P = 0.03).
Conclusions. Late AMD is more common among individuals with reduced kidney function. Whether this association reflects a common causal pathway or shared risk factors such as hypertension requires additional investigation.
doi:10.1093/ndt/gfr022
PMCID: PMC3247860  PMID: 21339308
age-related macular degeneration; albuminuria; chronic kidney disease; dense deposit disease; glomerular filtration rate
5.  Insights into the Genetic Architecture of Early Stage Age-Related Macular Degeneration: A Genome-Wide Association Study Meta-Analysis 
PLoS ONE  2013;8(1):e53830.
Genetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5×10−31) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3×10−24) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1×10−6) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9×10−6) and upstream of GLI2 (rs6721654; P = 6.5×10−6), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5×10−6), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.
doi:10.1371/journal.pone.0053830
PMCID: PMC3543264  PMID: 23326517
6.  The Complement Component 5 gene and Age-related Macular Degeneration 
Ophthalmology  2009;117(3):500-511.
Objective
To investigate the association between variants in the complement component 5 (C5) gene and age-related macular degeneration (AMD).
Design
Separate and combined data from three large AMD case-control studies and a prospective population-based study (The Rotterdam Study).
Participants
A total of 2599 AMD cases and 3458 ethnically matched controls.
Methods
Fifteen single nucleotide polymorphisms (SNPs) spanning the C5 gene were initially genotyped in 375 cases and 199 controls from the Netherlands (The AMRO-NL study population). Replication testing of selected SNPs was performed in the Rotterdam Study (NL) and study populations from Southampton, United Kingdom (UK) and New York, United States (US).
Main Outcome Measures
Early and late stages of prevalent and incident AMD, graded according to (a modification of) the international grading and classification system of AMD.
Results
Significant allelic or genotypic associations between eight C5 SNPs and AMD were found in the AMRO-NL study and this risk appeared independently of CFH Y402H, LOC387715 A69S, age and gender. None of these findings could be confirmed consistently in three replication populations.
Conclusions
Although the complement pathway, including C5, plays a crucial role in AMD, and the C5 protein is present in drusen, no consistent significant associations between C5 SNPs and AMD were found in all studies. The implications for genetic screening of AMD are discussed.
doi:10.1016/j.ophtha.2009.08.032
PMCID: PMC2830367  PMID: 20022638
7.  Age-related macular degeneration and long-term risk of stroke subtypes 
Background and Purpose
We examined the relationship of age-related macular degeneration (AMD) with incident stroke, including stroke subtypes of cerebral infarction and intracerebral haemorrhage (ICH).
Methods
We included 12,216 participants with retinal photographs taken at the third examination visit (1993–1995) from the Atherosclerosis Risk in Communities Study (ARIC), a population-based cohort study in middle-aged persons. Images were evaluated for AMD signs according to a standardized protocol. Incident events of stroke and its subtypes were identified and validated via case record review over time.
Results
AMD was diagnosed in 591 participants, of whom 576 had early and 15 late AMD. After a mean follow-up of 13.0 years (standard deviation: 3.3), 619 persons developed an incident stroke, including 548 cerebral infarction and 57 ICH. Participants with any AMD were at an increased risk of stroke (multi-variable adjusted hazard ratio [HR]: 1.51; 95% confidence interval [CI]: 1.11–2.06), with a stronger association for ICH (HR: 2.64; 95% CI: 1.18–5.87) than cerebral infarction (HR: 1.42; 95% CI: 1.01–1.99).
Conclusions
Persons with AMD are at an increased risk of both cerebral infarction and ICH. These data provide further insights into common pathophysiological processes between AMD and stroke subtypes.
doi:10.1161/STROKEAHA.112.654632
PMCID: PMC3361598  PMID: 22535267
retinal imaging; age-related macular degeneration; cerebral infarction; intra-cerebral hemorrhage
8.  Do Nutritional Supplements Have a Role in Age Macular Degeneration Prevention? 
Journal of Ophthalmology  2014;2014:901686.
Purpose. To review the proposed pathogenic mechanisms of age macular degeneration (AMD), as well as the role of antioxidants (AOX) and omega-3 fatty acids (ω-3) supplements in AMD prevention. Materials and Methods. Current knowledge on the cellular/molecular mechanisms of AMD and the epidemiologic/experimental studies on the effects of AOX and ω-3 were addressed all together with the scientific evidence and the personal opinion of professionals involved in the Retina Group of the OFTARED (Spain). Results. High dietary intakes of ω-3 and macular pigments lutein/zeaxanthin are associated with lower risk of prevalence and incidence in AMD. The Age-Related Eye Disease study (AREDS) showed a beneficial effect of high doses of vitamins C, E, beta-carotene, and zinc/copper in reducing the rate of progression to advanced AMD in patients with intermediate AMD or with one-sided late AMD. The AREDS-2 study has shown that lutein and zeaxanthin may substitute beta-carotene because of its potential relationship with increased lung cancer incidence. Conclusion. Research has proved that elder people with poor diets, especially with low AOX and ω-3 micronutrients intake and subsequently having low plasmatic levels, are more prone to developing AMD. Micronutrient supplementation enhances antioxidant defense and healthy eyes and might prevent/retard/modify AMD.
doi:10.1155/2014/901686
PMCID: PMC3941929  PMID: 24672708
9.  Dietary and lifestyle risk factors associated with age-related macular degeneration: A hospital based study 
Indian Journal of Ophthalmology  2013;61(12):722-727.
Aim:
To establish the frequency, associations and risk factors for age-related macular degeneration (AMD) in hospital population of South India.
Materials and Methods:
In this cross-sectional hospital based study, 3549 subjects (2090 men and 1459 women) above 45 years of age were screened randomly for AMD. Participants underwent ocular evaluation and were interviewed for lifestyle variables and dietary intake of carotenoids by structured food frequency questionnaire. AMD was defined according to the international classifications and grading system.
Results:
Either form of AMD was detected in 77 (2.2%) participants. Of which, early and late AMD was present in 63 (1.8%) and 14 (0.4%) subjects, respectively. Binary logistic analysis showed that the incidence of AMD was significantly higher with increasing age (Odds ratio [OR] 1.17; 95% CI 1.13-1.22) and diabetes (OR 3.97; 95% CI 2.11-7.46). However, AMD was significant among heavy cigarette smokers (OR 5.58; 95% CI 0.88-7.51) and alcoholics (OR 4.85; 95% CI 2.45-12.22). Dietary lutein/zeaxanthin (L/Z) and β-carotene intake were associated (P < 0.001) with the reduction in risk for AMD, with an OR of 0.38 and 0.65, respectively.
Conclusions:
Higher dietary intake of carotenoids, especially L/Z, was associated with lower risk for AMD. Risk of AMD is higher with increasing age and was prevalent among subjects with diabetes. Cessation of smoking and alcohol may reduce the risk of AMD in this population.
doi:10.4103/0301-4738.120218
PMCID: PMC3917390  PMID: 24178404
Age-related macular degeneration; carotenoids; cross-sectional studies; lutein
10.  Association between complementary factor H Y402H polymorphisms and age-related macular degeneration in Chinese: Systematic review and meta-analysis 
AIM
Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world and complement factor H (CFH) polymorphism has been found to associate with the AMD. To investigate whether the Y402H variant in CFH is associated with AMD in Chinese populations, a systematic review and meta-analysis were performed to estimate the magnitude of the gene effect and the possible mode of action.
METHODS
A meta-analysis was performed using data available from ten case-control studies assessing association between the CFH Y402H polymorphism and AMD in Chinese populations involving 1538 AMD. Data extraction and study quality assessment were performed in duplicate. Summary odds ratios (ORs) and 95% confidence intervals (CIs) an allele contrast and genotype contrast were estimated using fixed- effects models. The Q-statistic test was used to assess heterogeneity, and Funnel plot was used to evaluate publication bias.
RESULTS
Seven of ten case-control studies were neovascular AMD, and few studies came from west and north of China. There was strong evidence for association between CFH and AMD in Chinese population, with those having risk allele C 2.35 times more likely to have AMD than subjects with T allele. Evidence of publication bias was not observed in our meta-analysis.
CONCLUTION
This meta-analysis summarizes the strong evidence for an association between CFH and AMD in Chinese and indicates each C allele increasing the odds of AMD by 2.33-fold.But more evidences about the relation between CFH polymorphism and different type of Chinese AMD from various district were needed.
doi:10.3980/j.issn.2222-3959.2012.02.25
PMCID: PMC3359047  PMID: 22762059
age-related macular degeneration; complement factor H polymorphism; meta-analysis; Chinese population
11.  Prevalence of Age-Related Macular Degeneration in Nakuru, Kenya: A Cross-Sectional Population-Based Study 
PLoS Medicine  2013;10(2):e1001393.
Using digital retinal photography and slit lamp examination in a population-based sample in the Nakuru District of Kenya, Andrew Bastawrous and colleagues determined the prevalence of age-related macular degeneration in adults 50 years and older.
Background
Diseases of the posterior segment of the eye, including age-related macular degeneration (AMD), have recently been recognised as the leading or second leading cause of blindness in several African countries. However, prevalence of AMD alone has not been assessed. We hypothesized that AMD is an important cause of visual impairment among elderly people in Nakuru, Kenya, and therefore sought to assess the prevalence and predictors of AMD in a diverse adult Kenyan population.
Methods and Findings
In a population-based cross-sectional survey in the Nakuru District of Kenya, 100 clusters of 50 people 50 y of age or older were selected by probability-proportional-to-size sampling between 26 January 2007 and 11 November 2008. Households within clusters were selected through compact segment sampling.
All participants underwent a standardised interview and comprehensive eye examination, including dilated slit lamp examination by an ophthalmologist and digital retinal photography. Images were graded for the presence and severity of AMD lesions following a modified version of the International Classification and Grading System for Age-Related Maculopathy. Comparison was made between slit lamp biomicroscopy (SLB) and photographic grading.
Of 4,381 participants, fundus photographs were gradable for 3,304 persons (75.4%), and SLB was completed for 4,312 (98%). Early and late AMD prevalence were 11.2% and 1.2%, respectively, among participants graded on images. Prevalence of AMD by SLB was 6.7% and 0.7% for early and late AMD, respectively. SLB underdiagnosed AMD relative to photographic grading by a factor of 1.7.
After controlling for age, women had a higher prevalence of early AMD than men (odds ratio 1.5; 95% CI, 1.2–1.9). Overall prevalence rose significantly with each decade of age. We estimate that, in Kenya, 283,900 to 362,800 people 50 y and older have early AMD and 25,200 to 50,500 have late AMD, based on population estimates in 2007.
Conclusions
AMD is an important cause of visual impairment and blindness in Kenya. Greater availability of low vision services and ophthalmologist training in diagnosis and treatment of AMD would be appropriate next steps.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, 39 million people are blind, and 246 million people (mainly living in developing countries) have moderate or severe visual impairment. The third leading global cause of blindness (after cataracts and glaucoma) is age-related macular degeneration (AMD). This group of conditions is characterized by lesions in the macular (central) region of the retina, the tissue at the back of the eye that converts light into electrical messages and sends them to the brain. AMD, which affects older people, destroys the sharp central vision that is needed for reading or driving, leaving only dim, blurred images or a black hole at the center of vision. AMD can be diagnosed by examining digital photographs of the retina or by examining the retina directly using a special magnifying lens (slit lamp biomicroscopy). There is no cure for AMD, although injections into the eye of certain drugs, such as bevacizumab, that block the activity of vascular endothelial growth factor can slow the rate of vision loss caused by some forms of AMD.
Why Was This Study Done?
Most investigations of the prevalence (the proportion of a population with a disease) of AMD and of risk factors for AMD have studied people with European or Asian ancestry. Very little is known about AMD in African populations, and the data that are available mainly come from African populations living outside Africa. It is important to know whether AMD is an important cause of visual impairment and blindness in Africa, so that informed decisions can be made about the need for AMD programs in African countries. In this cross-sectional population-based study, the researchers investigate the prevalence of AMD among people aged 50 years or older living in Nakuru District (an ethnically diverse region of Kenya) and look for predictors of AMD in this population. In a cross-sectional population-based study, researchers observe a representative subset of a population at a single time point.
What Did the Researchers Do and Find?
The researchers randomly selected 100 clusters of 50 people aged 50 years or older for their study. Between January 2007 and November 2008, study participants had a comprehensive eye examination and completed a standardized interview that included questions about their age, gender, other demographic details, medical history, and exposure to possible risk factors for AMD. Based on digital retinal images, the prevalences of early and late AMD among the study population were 11.2% and 1.2%, respectively. The prevalences of early and late AMD judged by slit lamp biomicroscopy were 6.7% and 0.7%, respectively. After controlling for age, women had a higher prevalence of both early and late AMD than men. The overall prevalence of AMD rose with age: compared to the youngest age group, the oldest age group had a three-fold higher risk of developing late AMD. Of the people with any grade of AMD, 25.6% had some visual impairment and 2.5% were blind. Overall, 9.9% of the blindness seen in the study was attributable to AMD.
What Do These Findings Mean?
These findings identify AMD as an important cause of visual impairment and blindness in Nakuru District, Kenya. Extrapolation of these findings to the whole of Kenya suggests that 283,900 to 362,800 Kenyans had early AMD and 25,200 to 50,500 had late AMD in 2007. The accuracy of these findings is limited by the inability to obtain digital retinal images from all the participants (often because of electricity failures) and by other aspects of the study design. Moreover, because the methodology used in this study differed from some other studies of AMD, the prevalence of AMD reported here cannot be compared directly to those found in other studies. Nevertheless, these findings have several important implications. In particular, although recent evidence suggests that bevacizumab is likely to be both effective and affordable in Africa, the infrastructure required to deliver an adequate AMD service is currently prohibitively expensive in most African countries. Thus, these findings suggest that it is essential that research is undertaken to support the development of AMD treatment programs that are affordable and deliverable in Africa, and that low vision resources are provided for individuals with vision impairment.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001393.
The US National Eye Institute provides detailed information about age-related macular degeneration
The UK National Health Service Choices website also provides information about age-related macular degeneration, including personal stories about the condition
The UK Royal National Institute of Blind People has information on age-related macular degeneration, including a video of a person describing their experiences of the condition
AMD Alliance International provides written and audio information in several languages about age-related macular degeneration, including a large selection of personal stories; the Macular Degeneration Partnership also provides information about age-related macular degeneration, including a simulation of the condition
MedlinePlus has links to additional resources about age-related macular degeneration (in English and Spanish)
doi:10.1371/journal.pmed.1001393
PMCID: PMC3576379  PMID: 23431274
12.  Prevalence and Risks factors of Age-Related Macular Degeneration in Oklahoma Indians: The Vision Keepers Study 
Ophthalmology  2011;118(7):1380-1385.
Objective
To determine the prevalence of age-related macular degeneration (AMD) and indentify its risk factors in an Oklahoma Indian population.
Design
Cross sectional study design
Participants
A total of 1019 Oklahoma Indians who participated in baseline and second examinations of the Oklahoma Strong Heart Study were enrolled in Vision Keepers.
Methods
Retinal photographs of at least one eye were taken and graded for AMD by the University of Wisconsin Ocular Epidemiology Reading Center using the Wisconsin Age-Related Maculopathy Grading System. Retinal photographs of 986 participants were considered gradable and included in the study.
Main Outcome Measures
Age-related macular degeneration (early & late).
Results
The overall prevalence of any AMD in the Vision Keepers study was 35.2% including a prevalence of 0.81% for late AMD. The prevalence of early AMD increased from 30.6% in those aged 48–59 years to 46.1% in age group 70–82 years. When potential risk factor was considered individually in the univariate analyses, men with hypertension had significantly higher prevalence of AMD (p=0.02) than those without hypertension. In women high density lipoprotein-cholesterol and sun exposure were positively associated with the prevalence of AMD (p=0.01) while a history of using multivitamins was associated with lower AMD prevalence (p= 0.005). When multiple risk factors were considered simultaneously in the logistic regression analyses, only age showed significant association with AMD in both men (p=0.02) and women (p <0.0001) and was the only significant risk factor in men. In women, multivitamin use and total cholesterol had significant inverse association with AMD while sun exposure and high density lipoprotein cholesterol had positive association. When men and women are combined, age and high density lipoproteincholesterol had significant positive association while total cholesterol and multivitamin use and current alcohol use showed a significant inverse association with AMD.
Conclusion
This study was the first to report detailed prevalence of AMD in Oklahoma Indians and its risk factors. The prevalence appeared to be relatively high as compared to other ethnic groups. Some of the modifiable risk factors identified confirmed previous findings and can be used to design preventive programs to reduce the burden of AMD, though longitudinal data are still needed.
doi:10.1016/j.ophtha.2010.11.007
PMCID: PMC3129490  PMID: 21310490
13.  Potential Public Health Impact of Age-Related Eye Disease Study Results 
Archives of ophthalmology  2003;121(11):1621-1624.
Objective
To estimate the potential public health impact of the findings of the Age-Related Eye Disease Study (AREDS) on reducing the number of persons developing advanced age-related macular degeneration (AMD) during the next 5 years in the United States.
Methods
The AREDS clinical trial provides estimates of AMD progression rates and of reduction in risk of developing advanced AMD when a high-dose nutritional supplement of antioxidants and zinc is used. These results are applied to estimates of the US population at risk, to estimate the number of people who would potentially avoid advanced AMD during 5 years if those at risk were to take a supplement such as that used in AREDS.
Results
An estimated 8 million persons at least 55 years old in the United States have monocular or binocular intermediate AMD or monocular advanced AMD. They are considered to be at high risk for advanced AMD and are those for whom the AREDS formulation should be considered. Of these people, 1.3 million would develop advanced AMD if no treatment were given to reduce their risk. If all of these people at risk received supplements such as those used in AREDS, more than 300 000 (95% confidence interval, 158 000–487 000) of them would avoid advanced AMD and any associated vision loss during the next 5 years.
Conclusion
If people at high risk for advanced AMD received supplements such as those suggested by AREDS results, the potential impact on public health in the United States would be considerable during the next 5 years.
doi:10.1001/archopht.121.11.1621
PMCID: PMC1473209  PMID: 14609922
14.  The Relationship of Cataract and Cataract Extraction to Age-related Macular Degeneration: The Beaver Dam Eye Study 
Ophthalmology  2012;119(8):1628-1633.
Objective
To examine the associations of cataract and cataract surgery with early and late age-related macular degeneration (AMD) over a 20-year interval.
Design
Longitudinal population-based study of age-related eye diseases. Participants: Beaver Dam Eye Study participants.
Methods
All persons 43-84 years of age were recruited in 1987-1988. Participants were followed up at five year intervals after the baseline examination in 1988-1990. Examinations consisted of ocular examination with lens and fundus photography, medical history, measurements of blood pressure, height, and weight. Values of risk variables were updated, and incidences of early and late AMD were calculated for each 5-year interval. Odds ratios were computed using discrete linear logistic regression modeling with generalized estimating equation methods to account for correlation between the eyes and multiple intervals.
Main Outcome Measures
AMD.
Results
After controlling for age and sex, neither cataract nor cataract surgery was associated with increased odds for developing early AMD. Further controlling for high risk gene alleles (CFH and ARMS2) and other possible risk factors did not materially affect the odds ratio (OR). However, cataract surgery was associated with incidence of late AMD (OR 1.93; 95% CI 1.28, 2.90). This OR was not materially altered by further controlling for high risk alleles (CFH Y402H, ARMS2) or for other risk factors. The OR for late AMD was higher for cataract surgery performed 5 or more years prior as compared to less than 5 years prior.
Conclusions
These data strongly support the past findings of an association of cataract surgery with late AMD independent of other risk factors including high risk genetic status, and suggest the importance of considering these findings when counseling patients regarding cataract surgery. These findings should provide further impetus for the search for measures to prevent or delay the development of age-related cataract.
doi:10.1016/j.ophtha.2012.01.050
PMCID: PMC3411928  PMID: 22578823
15.  Long Term Use of Aspirin and Age-Related Macular Degeneration 
Context
Aspirin is widely used for relief of pain and for cardio-protective effects. Its use is of concern to ophthalmologists when ocular surgery is being considered and also in the presence of age-related macular degeneration (AMD).
Objective
To examine the association of regular aspirin use with incidence of AMD.
Design, Setting, and Participants
A longitudinal population-based study of age-related eye diseases in Beaver Dam, Wisconsin. Examinations were performed every 5 years over a 20-year period (1988–1990 through 2008–2010). Participants were aged 43–86 years at the baseline examination. At subsequent examinations, study participants were asked if they had regularly used aspirin at least twice a week for more than 3 months.
Main Outcome Measure
The incidence of early AMD, late AMD, and 2 subtypes of late AMD (neovascular AMD and pure geographic atrophy) were assessed in retinal photographs according to the Wisconsin Age-Related Maculopathy Grading System.
Results
The mean duration of follow-up was 14.8 years. There were 512 incident cases of early (of 6243 person-visits at risk) and 117 incident cases of late AMD (of 8675 person-visits at risk) over the course of the study. Regular aspirin use 10 years prior to retinal examination was associated with late AMD (hazard ratio 1.63; 95% CI 1.01–2.63; P=0.05) with estimated incidence of 1.76% (1.17–2.64) in regular users and 1.03% (0.70–1.51) in non-users. For subtypes of late AMD, regular aspirin use 10 years prior to retinal examination was significantly associated with neovascular AMD (reported as hazard ratio 2.20; 95% CI 1.20–4.15; P=0.01) but not pure geographic atrophy (0.66; 0.25–1.95; P=0.45). Aspirin use 5 (0.86; 0.71–1.05; P=0.13) or 10 years prior (0.86; 0.65–1.13; P=0.28) to retinal examination was not associated with incident early AMD.
Conclusions
Among persons aged 43 years and older followed for 20 years, aspirin use 5 years prior to observed incidence was not associated with incident early or late AMD. However, regular aspirin use 10 years prior was associated with a small but statistically significant increase in the risk of incident late and neovascular AMD.
doi:10.1001/jama.2012.65406
PMCID: PMC3630794  PMID: 23288416
aspirin; age-related macular degeneration; epidemiology
16.  Bevasiranib for the Treatment of Wet, Age-Related Macular Degeneration 
Age- related Macular Degeneration (AMD) is the leading cause of severe visual impairment in people 65 years and older in industrialized nations. Exudative, or “wet”, AMD is a late form of AMD (as distinguished from atrophic, so-called dry, AMD) and is responsible for over 60% of all cases of blindness due to AMD. It is widely accepted that vascular endothelial growth factor (VEGF) is a key component in the pathogenesis of choroidal neo-vascularization (CNV), which is a precursor to wet AMD. The current gold-standard for treating wet AMD is the monoclonal antibody fragment ranibizumab (trade name Lucentis), which targets VEGF. Other agents used to treat wet AMD include pegaptanib (Macugen), bevacizumab (Avastin; off-label use), and several other experimental agents. The advent of small interfering RNA (siRNA) has presented a whole new approach to inhibiting VEGF. This article reviews the status of a novel siRNA-based therapeutic, bevasiranib, for the treatment of wet AMD. Bevasiranib is believed to work by down regulating VEGF production in the retina. Studies in human cell-lines and animal models have shown that VEGF siRNAs are effective in inhibiting VEGF production. Although there is a lack of sufficient published data on human studies supporting the use of bevasiranib for wet AMD, available data indicates that due to its unique mechanism of action, bevasiranib might hold some promise as a primary or adjunct treatment for wet AMD.
doi:10.4137/OED.S4878
PMCID: PMC3661434  PMID: 23861616
age-related macular degeneration; vascular endothelial growth factor; bevasiranib
17.  Polymorphisms in ARMS2/HTRA1 and Complement Genes and Age-Related Macular Degeneration in India: Findings from the INDEYE Study 
Purpose.
Association between genetic variants in complement factor H (CFH), factor B (CFB), component 2 (C2), and in the ARMS2/HTRA1 region with age-related macular degeneration (AMD) comes mainly from studies of European ancestry and case-control studies of late-stage disease. We investigated associations of both early and late AMD with these variants in a population-based study of people aged 60 years and older in India.
Methods.
Fundus images were graded using the Wisconsin Age-Related Maculopathy Grading System and participants assigned to one of four mutually exclusive stages based on the worse affected eye (0 = no AMD, 1–3 = early AMD, 4 = late AMD). Multinomial logistic regression was used to derive risk ratios (RR) accounting for sampling method and adjusting for age, sex, and study center.
Results.
Of 3569 participants, 53.2% had no signs of AMD, 45.6% had features of early AMD, and 1.2% had late AMD. CFH (rs1061170), C2 (rs547154), or CFB (rs438999) was not associated with early or late AMD. In the ARMS2 locus, rs10490924 was associated with both early (adjusted RR 1.22, 95% confidence interval [CI]: 1.13–1.33, P < 0.0001) and late AMD (adjusted RR 1.81, 95% CI: 1.15–2.86; P = 0.01); rs2672598 was associated only with early AMD (adjusted RR 1.12, 95% CI: 1.02–1.23; P = 0.02); rs10490923 was not associated with early or late AMD.
Conclusions.
Two variants in ARMS2/HTRA1 were associated with increased risk of early AMD, and for one of these, the increased risk was also evident for late AMD. The study provides new insights into the role of these variants in early stages of AMD in India.
We report results from a genetic association study of early AMD in an Indian population. Two variants in the ARMS/HTRA1 region were associated with early AMD but variants in C2, CFH, and CFB were not.
doi:10.1167/iovs.12-10073
PMCID: PMC3490538  PMID: 23060141
18.  Nutritional supplements for age-related macular degeneration 
Current opinion in ophthalmology  2010;21(3):184-189.
Purpose of review
Age-related macular degeneration, a leading cause of visual loss in older adults, has limited therapeutic options. This review describes the current literature on the role of nutritional supplementation in primary and secondary prevention of AMD.
Recent findings
Many observational studies have explored the association between diet, nutrient intake, and AMD. In particular, high dietary intakes of omega 3 fatty acids, and macular xanthophylls lutein and zeaxanthin have been associated with a lower risk of prevalent and incident AMD. However, the Age-Related Eye Disease Study (AREDS) is the only large-scale randomized controlled clinical trial to show a 25% beneficial effect of nutritional supplementation in reducing the risk progression to advanced AMD in patients with intermediate AMD or with advanced AMD in one eye at 5 years of follow-up. Based on the results of AREDS, these patients are recommended to take AREDS formulation of vitamins C, E, beta-carotene, and zinc with copper.
Summary
At the present time, there is insufficient evidence in the literature to recommend routine nutritional supplementation in healthy adults for primary prevention of AMD. However, patients with intermediate risk of AMD or advanced AMD in one eye should consider taking AREDS-type supplements. Observational studies have also suggested benefit from increased dietary intake of macular xanthophylls and omega-3 fatty acids. These are currently being evaluated prospectively in a randomized controlled clinical trial, the Age-Related Eye Disease Study 2 (AREDS2).
doi:10.1097/ICU.0b013e32833866ee
PMCID: PMC2909501  PMID: 20216418
age-related macular degeneration; antioxidant vitamins; omega-3 fatty acids; lutein; zeaxanthin
19.  Apolipoprotein E gene and age-related macular degeneration in a Chinese population 
Molecular Vision  2011;17:997-1002.
Purpose
To examine the association between apolipoprotein E (APOE) polymorphisms and age-related macular degeneration (AMD) in a Chinese population.
Methods
The study consisted of 712 subjects, including 201 controls, 363 cases with early AMD, and 148 cases with exudative AMD. Genomic DNA was extracted from venous blood leukocytes. Common allelic variants of APOE (ε2, ε3, and ε4) were analyzed by PCR and direct sequencing.
Results
APOE ε3ε3 was the most frequent genotype, with a frequency of 72.6% in controls, 72.5% in early AMD, and 70.3% in exudative AMD. Frequency of the ε2 allele was 6.7% in controls, 7.4% in early AMD, and 8.8% in exudative AMD. Frequency of the ε4 allele was 8.7% in controls, 7.7% in early AMD, and 7.8% in exudative AMD. No statistically significant difference in APOE genotype and allele frequency distribution was observed among controls, cases with early AMD, and cases with exudative AMD. For ε2 allele carriers, the odds ratio was 1.12 (95% confidence interval [CI], 0.65–1.93) for early AMD and 1.06 (95% CI, 0.53–2.10) for exudative AMD. For ε4 allele carriers, the odds ratio was 1.04 (95% CI, 0.61–1.75) for early AMD and 0.83 (95% CI, 0.42–1.62) for exudative AMD.
Conclusions
Our data provide no evidence to support an association of APOE polymorphisms with early or exudative AMD, suggesting that APOE is less likely to be a major AMD susceptibility gene in the Chinese population.
PMCID: PMC3084239  PMID: 21541275
20.  C-Reactive Protein and the Incidence of Macular Degeneration – Pooled Analysis of 5 Cohorts 
JAMA ophthalmology  2013;131(4):507-513.
Objectives
To investigate the relationship between high-sensitivity C-reactive protein (hsCRP) and future risk of age-related macular degeneration (AMD) in US men and women.
Methods
We measured hsCRP in baseline blood samples from participants in five ongoing cohort studies. Patients were initially free of AMD. We prospectively identified 647 incident cases of AMD and selected age- and sex-matched controls for each AMD case (2 controls for each case with dry AMD, or 3 controls for each case of neovascular AMD). We used conditional logistic regression models to examine the relationship between hsCRP and AMD, and pooled findings using meta-analytic techniques.
Results
After adjusting for cigarette smoking status, participants with high (> 3 mg/L) compared with low (< 1 mg/L) hsCRP levels, had cohort-specific odds ratios (OR) for incident AMD ranging from 0.94 (95% CI 0.58-1.51) in the Physicians’ Health Study to 2.59 (95% CI 0.58-11.67) in the Women’s Antioxidant and Folic Acid Cardiovascular Study. After testing for heterogeneity between studies (Q=5.61, p=0.23), we pooled findings across cohorts, and observed a significantly increased risk of incident AMD for high versus low hsCRP levels (OR=1.49, 95% CI 1.06-2.08). Risk of neovascular AMD was also increased among those with high hsCRP levels (OR=1.84, 95% CI 1.14-2.98).
Conclusion
Overall these pooled findings from 5 prospective cohorts add further evidence that elevated levels of hsCRP predict greater future risk of AMD. This information might shed light on underlying mechanisms, and could be of clinical utility in the identification of persons at high risk of AMD who may benefit from increased adherence to lifestyle recommendations, eye examination schedules, and therapeutic protocols.
doi:10.1001/jamaophthalmol.2013.2303
PMCID: PMC3625501  PMID: 23392454
21.  Long-term effectiveness of ranibizumab for age-related macular degeneration and diabetic macular edema 
Neovascular age-related macular degeneration (AMD) and diabetic macular edema (DME) are major causes of visual impairment in the elderly population worldwide. With the aging population, the prevalence of neovascular AMD and DME has increased substantially over the recent years. Vascular endothelial growth factor (VEGF) has been implicated as playing an important role in the pathogenesis of both neovascular AMD and DME. Since its introduction in 2006, ranibizumab, a recombinant, humanized, monoclonal antibody fragment against all isoforms of VEGF-A, has revolutionized the treatment of neovascular AMD and DME. The efficacy and safety of ranibizumab in neovascular AMD has been demonstrated in the ANCHOR and MARINA trials. Further studies including the PIER, PrONTO, and SUSTAIN trials have also evaluated the optimal dosing regimen of ranibizumab in neovascular AMD. The CATT and IVAN trials compared the safety and efficacy of ranibizumab with off-label use of bevacizumab. Studies such as SUSTAIN and HORIZON have shown that ranibizumab has a good safety profile and is well tolerated for over 4 years with very few serious ocular and systemic adverse events. For DME, Phase II RESOLVE study and Phase III RISE and RIDE studies have demonstrated superiority of ranibizumab treatment in improving vision over placebo controls. Phase II READ and Phase III RESOLVE and REVEAL studies have shown that ranibizumab is more effective both as monotherapy and in combination with laser compared with laser monotherapy. The 3-year results from the DRCRnet protocol I study found that ranibizumab with deferred laser resulted in better long-term visual outcome compared with ranibizumab with prompt laser. This review summarizes various important clinical trials on the long-term efficacy and safety of ranibizumab in the treatment of neovascular AMD and DME. The pharmacological properties of ranibizumab, its cost effectiveness, and impact on quality of life will also be discussed.
doi:10.2147/CIA.S36811
PMCID: PMC3677930  PMID: 23766636
ranibizumab; anti-VEGF therapy; age-related macular degeneration; diabetic macular edema; safety; diabetic retinopathy; cost-effectiveness
22.  Age-Period-Cohort Effect on the Incidence of Age-Related Macular Degeneration: The Beaver Dam Eye Study 
Ophthalmology  2008;115(9):1460-1467.
Objective
To examine relationships of age, period, and birth cohort to the 5-year incidence of age-related macular degeneration (AMD).
Design
Population-based cohort study with 4 examination visits 5 years apart in 1988–1990, 1993–1995, 1998–2000, and 2003–2005.
Participants
2,968 persons (6,603 participant visits) and 3,588 persons (8,184 participant visits) 43–86 years of age at baseline contributing to the incidence of early and late AMD, respectively.
Methods
Grading of stereoscopic fundus photographs using the Wisconsin Age-Related Maculopathy Grading System.
Main Outcome Measures
5-year incidence of early AMD.
Results
While controlling for age, there was a lower 5-year incidence of early AMD in later than earlier birth cohorts (odds ratio per increasing category, 0.70; 95% confidence interval, 0.62–0.78; P < 0.001). This remained while controlling for smoking, blood pressure, and other related factors. There was no evidence for a period or birth cohort effect with late AMD.
Conclusions
Lower incidence of early AMD in more recent birth cohorts is likely due to unmeasured risk factors for early AMD. Further study of possible unmeasured risk factors that may have caused this cohort effect may help identify new modifiable risk factors for AMD. Diminishing incidence of early AMD in later birth cohorts would be expected to result in lower long-term estimates of future incidence of AMD than current estimates that do not take this effect into account.
doi:10.1016/j.ophtha.2008.01.026
PMCID: PMC2577776  PMID: 18762073
23.  The Association of Smoking and Alcohol Use with Age-Related Macular Degeneration in the Oldest Old: the Study of Osteoporotic Fractures 
American journal of ophthalmology  2009;149(1):160-169.
Purpose
To estimate the incidence of age-related macular degeneration (AMD) and the association of smoking and alcohol in a population of older women.
Design
Prospective cohort study.
Methods
Subjects were women who attended the Study of Osteoporotic Fractures year 10 and year 15 follow-up clinic visits and had fundus photographs taken at both visits (n=1958; 245 Blacks and 1713 Whites. Mean age at year 10 visit=78.2 years). Forty-five degree stereoscopic fundus photographs were graded for AMD. Logistic regression was used to test whether risk factors were associated with incident AMD.
Results
The overall 5-year AMD inci dence was 24.1% (95% confidence interval [CI]: 21.7–26.6) for early and 5.7% (95% CI: 4.6–6.8) for late. Early AMD incidence in Whites ranged from 21.9% in those 74–79 years to 33.2% in those 80–84 years, but was observed at the slightly lower rate of 29.0% in subjects ≥85 years (trend p<0.0001). After confounder adjustment, alcohol consumption was significantly associated with an elevated risk of incident early AMD (odds ratio [OR] = 1.57; 95% CI: 1.18–2.11). There was an increased risk of early AMD among subjects aged 80 years or older who were smoking compared to those younger than 80 years who were not smoking (OR=5.49; 95% CI: 1.57–19.20; p for interaction=0.026).
Conclusions
The magnitude of the greater-than-additive effect of smoking on the age-adjusted risk of AMD reinforces recommendations to quit smoking even for older individuals.
doi:10.1016/j.ajo.2009.07.025
PMCID: PMC3068844  PMID: 19796757
older women; age-related macular degeneration; incidence; smoking and alcohol consumption
24.  Refractive Error and Risk of Early or Late Age-Related Macular Degeneration: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(3):e90897.
Objective
To summarize relevant evidence investigating the associations between refractive error and age-related macular degeneration (AMD).
Design
Systematic review and meta-analysis.
Methods
We searched Medline, Web of Science, and Cochrane databases as well as the reference lists of retrieved articles to identify studies that met the inclusion criteria. Extracted data were combined using a random-effects meta-analysis. Studies that were pertinent to our topic but did not meet the criteria for quantitative analysis were reported in a systematic review instead.
Main outcome measures
Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between refractive error (hyperopia, myopia, per-diopter increase in spherical equivalent [SE] toward hyperopia, per-millimeter increase in axial length [AL]) and AMD (early and late, prevalent and incident).
Results
Fourteen studies comprising over 5800 patients were eligible. Significant associations were found between hyperopia, myopia, per-diopter increase in SE, per-millimeter increase in AL, and prevalent early AMD. The pooled ORs and 95% CIs were 1.13 (1.06–1.20), 0.75 (0.56–0.94), 1.10 (1.07–1.14), and 0.79 (0.73–0.85), respectively. The per-diopter increase in SE was also significantly associated with early AMD incidence (OR, 1.06; 95% CI, 1.02–1.10). However, no significant association was found between hyperopia or myopia and early AMD incidence. Furthermore, neither prevalent nor incident late AMD was associated with refractive error. Considerable heterogeneity was found among studies investigating the association between myopia and prevalent early AMD (P = 0.001, I2 = 72.2%). Geographic location might play a role; the heterogeneity became non-significant after stratifying these studies into Asian and non-Asian subgroups.
Conclusion
Refractive error is associated with early AMD but not with late AMD. More large-scale longitudinal studies are needed to further investigate such associations.
doi:10.1371/journal.pone.0090897
PMCID: PMC3946285  PMID: 24603619
25.  Risk Alleles in CFH and ARMS2 and the Long Term Natural History of Age-Related Macular Degeneration. The Beaver Dam Eye Study 
JAMA ophthalmology  2013;131(3):383-392.
Objective
To describe relationships of risk alleles in complement factor H (CFH, rs1061170) and Age-Related Maculopathy susceptibility 2 (ARMS2, rs10490924) to the incidence and progression of age-related macular degeneration (AMD) over a 20-year period.
Methods
There were 4282 persons aged 43–86 years at the baseline examination in 1988–1990 enrolled in a population-based cohort study who participated in at least 1 pair of examinations spaced 5 years apart over a 20-year period and had gradable fundus photographs for AMD and genotype information on CFH and ARMS2. Low, intermediate, and high genetic risk for AMD was defined by the presence of 0–1, 2, or 3–4 risk alleles for CFH and ARMS2, respectively. Multi-state models (MSMs) were used to estimate progression of AMD over the entire age range.
Results
There were 2820 (66%), 1129 (26%), and 333 persons (8%) with low, intermediate, and high genetic risk for AMD, respectively. The 5-year incidences of early and late AMD were 9.1% and 1.6%, respectively, and increased with age but did not differ by sex. Using the MSM, of persons aged 45 years with no AMD in the low, intermediate, and high AMD genetic risk groups, 33.0%, 39.9%, and 46.5%, respectively were estimated to develop early AMD, and 1.4%, 5.2%, and 15.3%, respectively were estimated to develop late AMD by age 80 years.
Conclusions
These population-based data provide estimates of the long-term risk of the incidence and progression of AMD and its lesions by age and genetic risk alleles for CFH and ARMS2.
doi:10.1001/jamaophthalmol.2013.713
PMCID: PMC3602927  PMID: 23494043
age-related macular degeneration; ARMS2; CFH; epidemiology

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