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1.  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
2.  Neovascular Age-Related Macular Degeneration Risk Based on CFH, LOC387715/HTRA1, and Smoking 
PLoS Medicine  2007;4(12):e355.
Background
Age-related macular degeneration (AMD) is the major cause of blindness in the elderly. Those with the neovascular end-stage of disease have irreversible loss of central vision. AMD is a complex disorder in which genetic and environmental factors play a role. Polymorphisms in the complement factor H (CFH) gene, LOC387715, and the HTRA1 promoter are strongly associated with AMD. Smoking also contributes to the etiology. We aimed to provide a model of disease risk based on these factors.
Methods and Findings
We genotyped polymorphisms in CFH and LOC387715/HTRA1 in a case–control study of 401 patients with neovascular AMD and 266 controls without signs of disease, and used the data to produce genetic risk scores for the European-descent population based on haplotypes at these loci and smoking history. CFH and LOC387715/HTRA1 haplotypes and smoking status exerted large effects on AMD susceptibility, enabling risk scores to be generated with appropriate weighting of these three factors. Five common haplotypes of CFH conferred a range of odds ratios (ORs) per copy from 1 to 4.17. Most of the effect of LOC387715/HTRA1 was mediated through one detrimental haplotype (carriage of one copy: OR 2.83; 95% confidence interval [CI] 1.91–4.20), with homozygotes being at particularly high risk (OR 32.83; 95% CI 12.53–86.07). Patients with neovascular macular degeneration had considerably higher scores than those without disease, and risk of blinding AMD rose to 15.5% in the tenth of the population with highest predicted risk.
Conclusions
An individual's risk of developing AMD in old age can be predicted by combining haplotype data with smoking status. Until there is effective treatment for AMD, encouragement to avoid smoking in those at high genetic risk may be the best option. We estimate that total absence of smoking would have reduced the prevalence of severe AMD by 33%. Unless smoking habits change or preventative treatment becomes available, the prevalence of AMD will rise as a consequence of the increasing longevity of the population.
Anne Hughes and colleagues show that an individual's risk of developing age-related macular degeneration in old age can be predicted by combining haplotype data with smoking status.
Editors' Summary
Background.
Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly. The macula is the 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. In the commonest form of AMD—“dry” AMD—the light-sensitive cells in the macula gradually die. In “wet” or “neovascular” AMD (one in 10 cases of AMD, but responsible for 90% of severe AMD-related blindness), abnormal blood vessels grow below the macula. Fluid leaking out of these vessels dislodges and damages the macula, after which loss of vision occurs rapidly. Both forms of AMD destroy the sharp central vision that is needed for reading and driving, leaving only dim, blurred images or a black hole at the center of vision. Neither form can be cured but with wet AMD the loss of vision can sometimes be slowed or halted if caught early by destroying the new blood vessels with laser surgery or a technique called photodynamic therapy or by blocking their formation by injecting special drugs into the eye.
Why Was This Study Done?
No-one knows what causes AMD but factors that increase a person's risk of developing the disease include increasing age, smoking, being white, and a family history of AMD. Recently, researchers have identified several “polymorphisms” (inherited DNA sequence variations that are common within populations) that are associated with AMD. These polymorphisms are in the complement factor H gene (the scientific symbol for this gene is CFH) and in a gene region called LOC387715/HTRA1. It would be useful to be able to use these risk factors to identify those people at the highest risk of developing neovascular AMD before the disease damages their vision. In this study, the researchers have investigated the association between AMD and polymorphisms in CFH and LOC387715/HTRA1 in more depth. They have then used this new information to build a model of AMD risk that should allow physicians to identify individuals at high risk of developing neovascular AMD.
What Did the Researchers Do and Find?
The researchers catalogued polymorphisms in CFH and LOC387715/HTRA1 in several hundred people with and without neovascular AMD. From these data, they identified three haplotypes (sets of polymorphisms that are inherited as a unit; everyone inherits two copies of each haplotype, one from each parent) in CFH that were more common in people with AMD than in those without and two that were associated with a decreased risk of developing AMD. In LOC387715/HTRA1 they identified one particularly detrimental haplotype. Compared to people without this haplotype, people with one copy of the deleterious haplotype were three times as likely to develop neovascular AMD; people with two copies were thirty times as likely to develop AMD. Smoking history also had a large effect on susceptibility to AMD. The researchers then developed a simple AMD risk scoring system based on CFH and LOC387715/HTRA1haplotypes and smoking status. From this, they calculated that people with the lowest risk scores have a minimal risk of developing AMD whereas about 15% of people with the highest risk scores are likely to develop AMD.
What Do These Findings Mean?
These findings indicate that it is possible to predict an individual's risk of developing AMD in old age by examining a small number of haplotypes and asking about their smoking status. The model developed by the researchers needs to be validated in other groups of people and may have to be modified if other gene variants that affect the risk of AMD are identified. For now, the results of this research provide physicians with a way to identify those individuals at the highest genetic risk of developing AMD so that they can step up their efforts to persuade these people to avoid smoking. In the future, when effective long-term treatments for AMD become available, the scoring system could also help doctors decide which of their elderly patients should be monitored most intensively for the early signs of AMD so that they can be treated before their vision is irreversibly damaged.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040355.
MedlinePlus provides links to information on macular degeneration and an encyclopedia page on macular degeneration (in English and Spanish)
Pages on the US National Institutes of Health NIH SeniorHealth site provides text and speech information about AMD
The US National Eye Institute and the UK Royal National Institute of Blind People also provide information about AMD
doi:10.1371/journal.pmed.0040355
PMCID: PMC2222948  PMID: 18162041
3.  Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype 
Background Variation in the complement factor H gene (CFH) is associated with risk of late age-related macular degeneration (AMD). Previous studies have been case–control studies in populations of European ancestry with little differentiation in AMD subtype, and insufficient power to confirm or refute effect modification by smoking.
Methods To precisely quantify the association of the single nucleotide polymorphism (SNP rs1061170, ‘Y402H’) with risk of AMD among studies with differing study designs, participant ancestry and AMD grade and to investigate effect modification by smoking, we report two unpublished genetic association studies (n = 2759) combined with data from 24 published studies (26 studies, 26 494 individuals, including 14 174 cases of AMD) of European ancestry, 10 of which provided individual-level data used to test gene–smoking interaction; and 16 published studies from non-European ancestry.
Results In individuals of European ancestry, there was a significant association between Y402H and late-AMD with a per-allele odds ratio (OR) of 2.27 [95% confidence interval (CI) 2.10–2.45; P = 1.1 x 10−161]. There was no evidence of effect modification by smoking (P = 0.75). The frequency of Y402H varied by ancestral origin and the association with AMD in non-Europeans was less clear, limited by paucity of studies.
Conclusion The Y402H variant confers a 2-fold higher risk of late-AMD per copy in individuals of European descent. This was stable to stratification by study design and AMD classification and not modified by smoking. The lack of association in non-Europeans requires further verification. These findings are of direct relevance for disease prediction. New research is needed to ascertain if differences in circulating levels, expression or activity of factor H protein explain the genetic association.
doi:10.1093/ije/dyr204
PMCID: PMC3304526  PMID: 22253316
Age-related macular degeneration (AMD); Complement factor H gene; meta-ananlysis
4.  Associations of Candidate Genes to Age-related Macular Degeneration Among Racial/Ethnic Groups in the Multi-Ethnic Study of Atherosclerosis 
American journal of ophthalmology  2013;156(5):10.1016/j.ajo.2013.06.004.
Purpose
To describe the relationships of selected candidate genes to the prevalence of early age-related macular degeneration (AMD) in a cohort of whites, blacks, Hispanics, and Chinese Americans.
Design
Cross-sectional study.
Methods
Setting
Multicenter study.
Study Population
2456 persons aged 45–84 years with genotype information and fundus photographs.
Procedures
Twelve of 2862 single nucleotide polymorphisms (SNPs) from 11 of 233 candidate genes for cardiovascular disease were selected for analysis based on screening with marginal unadjusted P value <0.001 within 1 or more racial/ethnic groups. Logistic regression models tested for association in case-control samples.
Main Outcome Measure
Prevalence of early AMD.
Results
Early AMD was present in 4.0% of the cohort and varied from 2.4% in blacks to 6.0% in whites. The odds ratio increased from 2.3 for one to 10.0 for four risk alleles in a joint effect analysis of Age-Related Maculopathy Susceptibility 2 rs10490924 and Complement Factor H Y402H (P for trend=4.2×10−7). Frequencies of each SNP varied among the racial/ethnic groups. Adjusting for age and other factors, few statistically significant associations of the 12 SNPs with AMD were consistent across all groups. In a multivariate model, most candidate genes did not attenuate the comparatively higher odds of AMD in whites. The higher frequency of risk alleles for several SNPs in Chinese Americans may partially explain their AMD frequency approaching that of whites.
Conclusions
The relationships of 11 candidate genes to early AMD varied among 4 racial/ethnic groups, and partially explained the observed variations in early AMD prevalence among them.
doi:10.1016/j.ajo.2013.06.004
PMCID: PMC3812928  PMID: 23938121
5.  Variation in genetic admixture and population structure among Latinos: the Los Angeles Latino eye study (LALES) 
BMC Genetics  2009;10:71.
Background
Population structure and admixture have strong confounding effects on genetic association studies. Discordant frequencies for age-related macular degeneration (AMD) risk alleles and for AMD incidence and prevalence rates are reported across different ethnic groups. We examined the genomic ancestry characterizing 538 Latinos drawn from the Los Angeles Latino Eye Study [LALES] as part of an ongoing AMD-association study. To help assess the degree of Native American ancestry inherited by Latino populations we sampled 25 Mayans and 5 Mexican Indians collected through Coriell's Institute. Levels of European, Asian, and African descent in Latinos were inferred through the USC Multiethnic Panel (USC MEP), formed from a sample from the Multiethnic Cohort (MEC) study, the Yoruba African samples from HapMap II, the Singapore Chinese Health Study, and a prospective cohort from Shanghai, China. A total of 233 ancestry informative markers were genotyped for 538 LALES Latinos, 30 Native Americans, and 355 USC MEP individuals (African Americans, Japanese, Chinese, European Americans, Latinos, and Native Hawaiians). Sensitivity of ancestry estimates to relative sample size was considered.
Results
We detected strong evidence for recent population admixture in LALES Latinos. Gradients of increasing Native American background and of correspondingly decreasing European ancestry were observed as a function of birth origin from North to South. The strongest excess of homozygosity, a reflection of recent population admixture, was observed in non-US born Latinos that recently populated the US. A set of 42 SNPs especially informative for distinguishing between Native Americans and Europeans were identified.
Conclusion
These findings reflect the historic migration patterns of Native Americans and suggest that while the 'Latino' label is used to categorize the entire population, there exists a strong degree of heterogeneity within that population, and that it will be important to assess this heterogeneity within future association studies on Latino populations. Our study raises awareness of the diversity within "Latinos" and the necessity to assess appropriate risk and treatment management.
doi:10.1186/1471-2156-10-71
PMCID: PMC3087512  PMID: 19903357
6.  Routine Eye Examinations for Persons 20-64 Years of Age 
Executive Summary
Objective
The objective of this analysis was to determine the strength of association between age, gender, ethnicity, family history of disease and refractive error and the risk of developing glaucoma or ARM?
Clinical Need
A routine eye exam serves a primary, secondary, and tertiary care role. In a primary care role, it allows contact with a doctor who can provide advice about eye care, which may reduce the incidence of eye disease and injury. In a secondary care role, it can via a case finding approach, diagnose persons with degenerative eye diseases such as glaucoma and or AMD, and lead to earlier treatment to slow the progression of the disease. Finally in a tertiary care role, it provides ongoing monitoring and treatment to those with diseases associated with vision loss.
Glaucoma is a progressive degenerative disease of the optic nerve, which causes gradual loss of peripheral (side) vision, and in advanced disease states loss of central vision. Blindness may results if glaucoma is not diagnosed and managed. The prevalence of primary open angle glaucoma (POAG) ranges from 1.1% to 3.0% in Western populations, and from 4.2% to 8.8% in populations of African descent. It is estimated up to 50% of people with glaucoma are aware that they have the disease. In Canada, glaucoma disease is the second leading cause of blindness in people aged 50 years and older. Tonometry, inspection of the optic disc and perimetry are used concurrently by physicians and optometrists to make the diagnosis of glaucoma. In general, the evidence shows that treating people with increased IOP only, increased IOP and clinical signs of early glaucoma or with normal-tension glaucoma can reduce the progression of disease.
Age-related maculopathy (ARM) is a degenerative disease of the macula, which is a part of the retina. Damage to the macula causes loss of central vision affecting the ability to read, recognize faces and to move about freely. ARM can be divided into an early- stage (early ARM) and a late-stage (AMD). AMD is the leading cause of blindness in developed countries. The prevalence of AMD increases with increasing age. It is estimated that 1% of people 55 years of age, 5% aged 75 to 84 years and 15% 80 years of age and older have AMD. ARM can be diagnosed during fundoscopy (ophthalmoscopy) which is a visual inspection of the retina by a physician or optometrist, or from a photograph of the retina. There is no cure or prevention for ARM. Likewise, there is currently no treatment to restore vision lost due to AMD. However, there are treatments to delay the progression of the disease and further loss of vision.
The Technology
A periodic oculo-visual assessment is defined “as an examination of the eye and vision system rendered primarily to determine if a patient has a simple refractive error (visual acuity assessment) including myopia, hypermetropia, presbyopia, anisometropia or astigmatism.” This service includes a history of the presenting complaint, past medical history, visual acuity examination, ocular mobility examination, slit lamp examination of the anterior segment, ophthalmoscopy, and tonometry (measurement of IOP) and is completed by either a physician or an optometrist.
Review Strategy
The Medical Advisory Secretariat conducted a computerized search of the literature in the following databases: OVID MEDLINE, MEDLINE, In-Process & Other Non-Indexed Citations, EMBASE, INAHTA and the Cochrane Library. The search was limited to English-language articles with human subjects, published from January 2000 to March 2006. In addition, a search was conducted for published guidelines, health technology assessments, and policy decisions. Bibliographies of references of relevant papers were searched for additional references that may have been missed in the computerized database search. Studies including participants 20 years and older, population-based prospective cohort studies, population-based cross-sectional studies when prospective cohort studies were unavailable or insufficient and studies determining and reporting the strength of association or risk- specific prevalence or incidence rates of either age, gender, ethnicity, refractive error or family history of disease and the risk of developing glaucoma or AMD were included in the review. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to summarize the overall quality of the body of evidence.
Summary of Findings
A total of 498 citations for the period January 2000 through February 2006 were retrieved and an additional 313 were identified when the search was expanded to include articles published between 1990 and 1999. An additional 6 articles were obtained from bibliographies of relevant articles. Of these, 36 articles were retrieved for further evaluation. Upon review, 1 meta-analysis and 15 population-based epidemiological studies were accepted for this review
Primary Open Angle Glaucoma
Age
Six cross-sectional studies and 1 prospective cohort study contributed data on the association between age and PAOG. From the data it can be concluded that the prevalence and 4-year incidence of POAG increases with increasing age. The odds of having POAG are statistically significantly greater for people 50 years of age and older relative to those 40 to 49 years of age. There is an estimated 7% per year incremental odds of having POAG in persons 40 years of age and older, and 10% per year in persons 49 years of age and older. POAG is undiagnosed in up to 50% of the population. The quality of the evidence is moderate.
Gender
Five cross-sectional studies evaluated the association between gender and POAG. Consistency in estimates is lacking among studies and because of this the association between gender and prevalent POAG is inconclusive. The quality of the evidence is very low.
Ethnicity
Only 1 cross-sectional study compared the prevalence rates of POAG between black and white participants. These data suggest that prevalent glaucoma is statistically significantly greater in a black population 50 years of age and older compared with a white population of similar age. There is an overall 4-fold increase in prevalent POAG in a black population compared with a white population. This increase may be due to a confounding variable not accounted for in the analysis. The quality of the evidence is low.
Refractive Error
Four cross-sectional studies assessed the association of myopia and POAG. These data suggest an association between myopia defined as a spherical equivalent of -1.00D or worse and prevalent POAG. However, there is inconsistency in results regarding the statistical significance of the association between myopia when defined as a spherical equivalent of -0.5D. The quality of the evidence is very low.
Family History of POAG
Three cross-sectional studies investigated the association between family history of glaucoma and prevalent POAG. These data suggest a 2.5 to 3.0 fold increase in the odds having POAG in persons with a family history (any first-degree relative) of POAG. The quality of the evidence is moderate.
Age-Related Maculopathy
Age
Four cohort studies evaluated the association between age and early ARM and AMD. After 55 years of age, the incidence of both early ARM and AMD increases with increasing age. Progression to AMD occurs in up to 12% of persons with early ARM. The quality of the evidence is low
Gender
Four cohort studies evaluated the association between gender and early ARM and AMD. Gender differences in incident early ARM and incident AMD are not supported from these data. The quality of the evidence is lows.
Ethnicity
One meta-analysis and 2 cross-sectional studies reported the ethnic-specific prevalence rates of ARM. The data suggests that the prevalence of early ARM is higher in a white population compared with a black population. The data suggest that the ethnic-specific differences in the prevalence of AMD remain inconclusive.
Refractive Error
Two cohort studies investigated the association between refractive error and the development of incident early ARM and AMD. The quality of the evidence is very low.
Family History
Two cross-sectional studies evaluated the association of family history and early ARM and AMD. Data from one study supports an association between a positive family history of AMD and having AMD. The results of the study indicate an almost 4-fold increase in the odds of any AMD in a person with a family history of AMD. The quality of the evidence, as based on the GRADE criteria is moderate.
Economic Analysis
The prevalence of glaucoma is estimated at 1 to 3% for a Caucasian population and 4.2 to 8.8% for a black population. The incidence of glaucoma is estimated at 0.5 to 2.5% per year in the literature. The percentage of people who go blind per year as a result of glaucoma is approximately 0.55%.
The total population of Ontarians aged 50 to 64 years is estimated at 2.6 million based on the April 2006 Ontario Ministry of Finance population estimates. The range of utilization for a major eye examination in 2006/07 for this age group is estimated at 567,690 to 669,125, were coverage for major eye exams extended to this age group. This would represent a net increase in utilization of approximately 440,116 to 541,551.
The percentage of Ontario population categorized as black and/or those with a family history of glaucoma was approximately 20%. Therefore, the estimated range of utilization for a major eye examination in 2006/07 for this sub-population is estimated at 113,538 - 138,727 (20% of the estimated range of utilization in total population of 50-64 year olds in Ontario), were coverage for major eye exams extended to this sub-group. This would represent a net increase in utilization of approximately 88,023 to 108,310 within this sub-group.
Costs
The total cost of a major eye examination by a physician is $42.15, as per the 2006 Schedule of Benefits for Physician Services.(1) The total difference between the treatments of early-stage versus late-stage glaucoma was estimated at $167. The total cost per recipient was estimated at $891/person.
Current Ontario Policy
As of November 1, 2004 persons between 20 years and 64 years of age are eligible for an insured eye examination once every year if they have any of the following medical conditions: diabetes mellitus type 1 or 2, glaucoma, cataract(s), retinal disease, amblyopia, visual field defects, corneal disease, or strabismus. Persons between 20 to 64 years of age who do not have diabetes mellitus, glaucoma, cataract(s), retinal disease, amblyopia, visual field defects, corneal disease, or strabismus may be eligible for an annual eye examination if they have a valid “request for major eye examination” form completed by a physician (other than that who completed the eye exam) or a nurse practitioner working in a collaborative practice. Persons 20-64 years of age who are in receipt of social assistance and who do not have one of the 8 medical conditions listed above are eligible to receive an eye exam once every 2 years as a non-OHIP government funded service. Persons 19 years of age or younger and 65 years of age or older may receive an insured eye exam once every year.
Considerations for Policy Development
As of July 17, 2006 there were 1,402 practicing optometrists in Ontario. As of December 31, 2005 there were 404 practicing ophthalmologists in Ontario. It is unknown how many third party payers now cover routine eye exams for person between the ages of 20 and 64 years of age in Ontario.
PMCID: PMC3379534  PMID: 23074485
7.  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
8.  Three Major Loci Involved in Age-Related Macular Degeneration are also Associated with Polypoidal Choroidal Vasculopathy 
Ophthalmology  2010;117(8):1567-1570.
Purpose
To investigate the frequency of variants in three major age-related macular degeneration (AMD)-associated loci in patients with polypoidal choroidal vasculopathy (PCV) of European-American descent.
Design
Cross-sectional case-control association study.
Participants
Fifty-five patients with PCV, 368 patients with advanced AMD and 368 age- and ethnically-matched unaffected controls of European-American descent.
Methods
Association analysis of allele and genotype frequencies, determined by TaqMan assays, was performed for the following haplotype-tagging single nucleotide polymorphisms (htSNPs): risk alleles in the complement factor H (CFH) gene (Y402H and IVS14) in the ARMS2/HTRA1 locus on 10q26 (A69S) and protective alleles in CFH (IVS1 and IVS6) and in the complement factor B/complement component C2 (CFB/C2) locus (IVS10 and H9L).
Main Outcome Measures
Allele and genotype frequencies of the htSNPs in the CFH, CFB/C2, and ARMS2/HTRA1 loci.
Results
Four AMD-associated haplotype-tagging alleles (rs547154, rs1061170, rs1410996, rs10490924) in the three major loci, CFH, CFB/C2 and ARMS2/HTRA1, were statistically significantly associated also with the PCV phenotype (P<0.05). Three other alleles from the same loci (rs4151667, rs529825, rs3766404) showed a trend towards association (P<0.2), but did not reach statistical significance possibly because of the combined effects of a relatively small sample size and low minor allele frequency in the screened populations.
Conclusion
The PCV phenotype in Caucasian patients is associated with the major alleles/genotypes in the AMD-associated loci, suggesting that PCV and AMD are genetically similar in the tested loci.
doi:10.1016/j.ophtha.2009.12.018
PMCID: PMC2901561  PMID: 20378180
9.  Protective Effect of Paraoxonase 1 Gene Variant Gln192Arg in Age-Related Macular Degeneration 
American journal of ophthalmology  2009;149(3):513-522.
Purpose
Age-related macular degeneration (AMD) is the leading cause of blindness among older adults, in which oxidative damage may play a pivotal role. Paraoxonase 1 (PON1) protects against oxidative damage and has been evaluated for its involvement in aging diseases including AMD. This study investigated whether PON1 gene polymorphisms associate with AMD.
Design
Case-control association study.
Methods
We studied 1037 individuals with AMD subcategorized using AREDS criteria and 370 control subjects without retinal disease. Participants were primarily Caucasian of European descent. All exons of PON1 were evaluated by single strand conformation polymorphism and direct sequence analysis.
Results
Six missense changes (Leu55Met, Met127Arg, His155Arg, Gln192Arg, Gln192Glu, Ala252Gly) were identified in PON1. We observed a weak association of Leu55Met with an increased risk of wet AMD (P = 0.02), but not with dry AMD or when combining all patient categories. A significantly higher allele frequency for Gln192Arg was detected in controls than in the combined AMD patient population (P < 0.0001), and when category 2, 3 and 4 patients were separately considered (P = 0.004, P = 0.002 and P < 0.0001, respectively). For category 4 AMD, the Arg192 allele was significantly less prevalent in the wet form (P < 0.0001) but not in the dry form (P = 0.377).
Conclusion
We report a weak association of PON1 Leu55Met with an increased risk of wet AMD, replicating previous reports. Our findings indicate a protective role for Gln192Arg, particularly for patients with the wet form. Gln192Glu warrants consideration, as this variant alters the same amino acid as Gln192Arg and was identified only in Category 4 AMD patients. We believe that Met127Arg, His155Arg and Ala252Gly play minor roles in AMD susceptibility due to their limited frequency and/or location within the PON1 gene. The functional and biological mechanism by which Gln192Arg is acting to decrease AMD susceptibility remains to be determined.
doi:10.1016/j.ajo.2009.09.024
PMCID: PMC3026437  PMID: 20042177
age-related macular degeneration; paraoxonase; oxidative damage; genetics; mutation
10.  Inflammation, Complement Factor H, and Age-Related Macular Degeneration: The Multi-Ethnic Study of Atherosclerosis 
Ophthalmology  2008;115(10):1742-1749.
Objective
To describe the relationship of systemic inflammatory disease, complement factor H (CFH) Y402H (1277T→C) genotype status and age-related macular degeneration (AMD) prevalence in a multiethnic population of whites, blacks, Hispanics, and Chinese.
Design
Population-based, cross-sectional study.
Participants
We included 5887 persons aged 45 to 84 years with gradable AMD.
Methods
Digital fundus photographs were used to measure AMD. Two years earlier, biomarkers of inflammation were measured and history of inflammatory disease and use of antiinflammatory agents obtained.
Main Outcome Measure
Prevalence of AMD.
Results
While controlling for age, gender, race/ethnicity, and study site, there were no associations between systemic inflammatory factors and AMD severity. Higher levels of high-sensitivity C-reactive protein (odds ratio [OR] per standard deviation [SD] increase in natural log [ln] units, 2.34; 95% confidence interval [CI], 1.33–4.13) and interleukin-6 (OR per SD in ln, 2.06; 95% CI, 1.21–3.49) were associated with geographic atrophy but not other AMD end points. History of periodontal disease (OR, 1.68; 95% CI, 1.14–2.47) was related to increased retinal pigment. A history of arthritis was associated with soft distinct drusen (OR, 1.24; 95% CI, 1.06–1.46). A history of oral steroid use was related to large drusen (OR, 2.13; 95% CI, 1.14–3.97) and soft distinct drusen (OR, 1.76; 95% CI, 1.00–3.10) and history of cyclooxygenase 2 inhibitor use were associated with large drusen (OR, 1.50; 95% CI, 1.10–2.04), soft indistinct drusen (OR, 1.84; 95% CI, 1.09–3.10), and large drusen area (OR, 1.66; 95% CI, 1.02–2.71). Whites, blacks, and Hispanics with CFH Y402H CC variant genotype had the highest frequency of early AMD compared with those with wild TT genotype. The frequency of CFH did explain some of the difference in AMD prevalence between Chinese and Hispanics compared with whites, but did not explain the difference in prevalence between whites and blacks.
Conclusions
This study confirmed associations of the Y402H CFH gene variant with AMD in nonwhite populations, but neither explained the lack of association between inflammatory factors and AMD in the cohort nor the basis for the observed differences in AMD prevalence across ethnic groups.
doi:10.1016/j.ophtha.2008.03.021
PMCID: PMC2936447  PMID: 18538409
11.  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
12.  Polymorphism p.402Y>H in the complement factor H protein is a risk factor for age related macular degeneration in an Italian population 
The British Journal of Ophthalmology  2006;90(9):1142-1145.
Aims
To evaluate the complement factor H (CFH) p.402Y>H polymorphism as a risk factor in age related macular degeneration (AMD) in an Italian population.
Methods
104 unrelated Italian AMD patients and 131 unrelated controls were screened for the CFH polymorphism p.402Y>H (c.1277 T>C), which has been associated with AMD. Retinography was obtained for patients and controls; the AMD diagnosis was confirmed by fluorescein angiograms. The c.1277 T>C polymorphism was genotyped with the TaqMan real time polymerase chain reaction single nucleotide polymorphism assay.
Results
The frequency of c.1277C allele was higher in AMD patients than in controls (57.2% v 39.3%; p<0.001). The odds ratio (OR; logistic regression analysis) for AMD was 3.9 (95% confidence interval (CI): 1.9 to 8.2) for CC homozygotes. The CC genotype conferred a higher risk for sporadic (OR 4.6; CI: 2.0 to 10.5) than for familial AMD (OR 2.9; CI: 1.0 to 8.4). Genotypes were not related to either age at AMD diagnosis or to AMD phenotype. However, geographic atrophy and choroidal neovascularisation were more frequent in sporadic than in familial AMD (p = 0.027). Overall, the percentage of population attributable risk for the CC genotype was 28% (95% CI:18% to 33%).
Conclusion
The association between the p.402Y>H (c.1277T>C) polymorphism and AMD applies to the Italian population and the CC genotype is more frequent in sporadic than in familial AMD cases.
doi:10.1136/bjo.2006.096487
PMCID: PMC1857371  PMID: 16774956
age related macular degeneration; polymorphisms; complement factor H; Italy
13.  Prediction of Age-related Macular Degeneration in the General Population 
Ophthalmology  2013;120(12):2644-2655.
Purpose
Prediction models for age-related macular degeneration (AMD) based on case-control studies have a tendency to overestimate risks. The aim of this study is to develop a prediction model for late AMD based on data from population-based studies.
Design
Three population-based studies: the Rotterdam Study (RS), the Beaver Dam Eye Study (BDES), and the Blue Mountains Eye Study (BMES) from the Three Continent AMD Consortium (3CC).
Participants
People (n = 10106) with gradable fundus photographs, genotype data, and follow-up data without late AMD at baseline.
Methods
Features of AMD were graded on fundus photographs using the 3CC AMD severity scale. Associations with known genetic and environmental AMD risk factors were tested using Cox proportional hazard analysis. In the RS, the prediction of AMD was estimated for multivariate models by area under receiver operating characteristic curves (AUCs). The best model was validated in the BDES and BMES, and associations of variables were re-estimated in the pooled data set. Beta coefficients were used to construct a risk score, and risk of incident late AMD was calculated using Cox proportional hazard analysis. Cumulative incident risks were estimated using Kaplan–Meier product-limit analysis.
Main Outcome Measures
Incident late AMD determined per visit during a median follow-up period of 11.1 years with a total of 4 to 5 visits.
Results
Overall, 363 participants developed incident late AMD, 3378 participants developed early AMD, and 6365 participants remained free of any AMD. The highest AUC was achieved with a model including age, sex, 26 single nucleotide polymorphisms in AMD risk genes, smoking, body mass index, and baseline AMD phenotype. The AUC of this model was 0.88 in the RS, 0.85 in the BDES and BMES at validation, and 0.87 in the pooled analysis. Individuals with low-risk scores had a hazard ratio (HR) of 0.02 (95% confidence interval [CI], 0.01–0.04) to develop late AMD, and individuals with high-risk scores had an HR of 22.0 (95% CI, 15.2–31.8). Cumulative risk of incident late AMD ranged from virtually 0 to more than 65% for those with the highest risk scores.
Conclusions
Our prediction model is robust and distinguishes well between those who will develop late AMD and those who will not. Estimated risks were lower in these population-based studies than in previous case-control studies.
doi:10.1016/j.ophtha.2013.07.053
PMCID: PMC3986722  PMID: 24120328
14.  Association of CFH, LOC387715, and HTRA1 polymorphisms with exudative age-related macular degeneration in a northern Chinese population 
Molecular Vision  2008;14:1373-1381.
Purpose
Variants in complement factor H (CFH), the hypothetical LOC387715, and the high-temperature requirement A-1 (HTRA1) genes have been reported to be associated with age-related macular degeneration (AMD). The purpose of this study was to investigate the association of reported common single-nucleotide polymorphisms (SNPs) in CFH, LOC387715, and HTRA1 with exudative AMD in a northern Chinese population.
Methods
A cohort of 121 unrelated patients with exudative AMD and 132 control subjects were enrolled in this study. Genomic DNA was extracted from blood leukocytes. Genotyping for SNPs rs1061170:T>C in CFH (Y402H), rs10490924:G>T in LOC387715 (A69S), and rs11200638:G>A in the promoter of HTRA1 was performed using a polymerase chain reaction (PCR) method followed by allele-specific restriction enzyme digestion and direct sequencing.
Results
The Y402H variant in CFH was not associated with exudative AMD in our study population. Frequencies of Y402H was 10.3% in AMD cases and 8.0% in controls (p=0.353). Significant associations were detected for exudative AMD with SNPs rs10490924:G>T in LOC387715 (A69S), and rs11200638:G>A in the promoter of HTRA1. The risk T-allele frequency of rs10490924 in LOC387715 was 64.9% in cases versus 43.2% in controls (p<0.001). The odds ratio for risk of AMD was 1.56 (95% CI; 0.80–3.03) for the GT genotype and 5.45 (95% CI; 2.59–11.49) for the TT genotype. The A allele frequency of rs11200638 in the HTRA1 promoter was 67.8% in cases versus 42.4% in controls (p<0.001). The odds ratio was 2.75 (95% CI; 1.34–5.64) for the GA genotype and 7.90 (95% CI; 3.61–17.26) for the AA genotype. An odds ratio of 7.94 (95% CI; 3.49–18.04) was obtained for carriers with both TT genotype in LOC387715 and AA genotype in the HTRA1 promoter.
Conclusions
Our data suggest that the LOC387715 and HTRA1 polymorphisms are associated with a higher risk of exudative AMD in northern Chinese. We found no association of CFH Y402H with exudative AMD. The low frequency of CFH Y402H variant was further confirmed in this study population.
PMCID: PMC2493029  PMID: 18682812
15.  A prospective study of common variants in the CX3CR1 gene and risk of macular degeneration: pooled analysis from five long-term studies 
JAMA ophthalmology  2014;132(1):84-95.
Context
The CX3CR1 gene is implicated as a candidate gene for age-related macular degeneration (AMD) through several lines of evidence. There is uncertainty, however, as to whether common genetic variants in CX3CR1 alter risk of AMD, since prior studies have been inconsistent and mostly limited to evaluation of two non-synonymous variants, T280M (rs3732378) and V249I (rs3732379).
Objective
We aimed to determine if common variants in CX3CR1 predict future risk of AMD.
Design
Prospective nested case-control study within five large study populations with long-term follow-up.
Participants
We measured genotypes for T280M, V249I and 13 other common single-nucleotide polymorphisms (SNPs) of the CX3CR1 gene among people who developed AMD (N=1110, including N=369 with neovascular AMD) and 2532 age- and sex-matched controls.
Main outcome measures
We determined the incidence rate ratios (RR) and 95% confidence intervals (CI) for incidence of AMD for each variant, and examined interactions with other AMD-associated variants and modifiable risk factors.
Results
In additive genetic models, we identified non-significant associations with AMD for T280M (RR=0.87, P=0.074) and three other SNPs, rs2853707 (RR=0.88, P=0.069), rs12636547 (RR=0.85, P=0.098), and rs1877563 (RR=0.84, P=0.056), one of which, rs2853707, is positioned in the CX3CR1 promoter region and was associated with neovascular AMD (RR=0.75, P=0.028). We observed that a recessive model was a better fit to the data for some SNPs, with associations between rs11715522 and AMD (RR=1.27, P=0.034), and between rs2669845 (RR=3.10, P=0.035), rs2853707 (RR=0.48, P=0.050) and rs9868689 (RR=0.31, P=0.017) and neovascular AMD. Moreover, in exploratory analyses we identified a number of possible interactions including between V249I and rs2669845 and dietary intake of omega-3 fatty acids (P=0.004, and P=0.009, respectively) for AMD; between rs2669845 and obesity (P=0.031) for neovascular AMD; between T280M and complement component 3 (C3) R102G for AMD (P=0.027); between rs2669845 and Y402H in complement factor H (CFH) for AMD (P=0.037); and between rs2669845, rs2853707, and V249I and C3 R102G for neovascular AMD (P=0.008, 0.039 and 0.002, respectively).
Conclusion
This study failed to identify significant associations between common CX3CR1 variants and AMD after considering the number of SNPs analyzed and multiple comparisons. However, we observed evidence consistent with recessive modes of association, and that an effect of CX3CR1 variants may depend on other factors including dietary intake of omega-3 fatty acids, obesity, and genotypes at CFH Y402H and C3 R102G. If replicated in other populations, these findings would support a role for CX3CR1 in AMD, but also suggest that its role may involve mechanisms that are independent of the T280M/V249I variations.
doi:10.1001/jamaophthalmol.2013.5506
PMCID: PMC4170669  PMID: 24287500
16.  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
17.  The ERCC6 Gene and Age-Related Macular Degeneration 
PLoS ONE  2010;5(11):e13786.
Background
Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in the developed countries and is caused by both environmental and genetic factors. A recent study (Tuo et al., PNAS) reported an association between AMD and a single nucleotide polymorphism (SNP) (rs3793784) in the ERCC6 (NM_000124) gene. The risk allele also increased ERCC6 expression. ERCC6 is involved in DNA repair and mutations in ERCC6 cause Cockayne syndrome (CS). Amongst others, photosensitivity and pigmentary retinopathy are hallmarks of CS.
Methodology/Principal Findings
Separate and combined data from three large AMD case-control studies and a prospective population-based study (The Rotterdam Study) were used to analyse the genetic association between ERCC6 and AMD (2682 AMD cases and 3152 controls). We also measured ERCC6 mRNA levels in retinal pigment epithelium (RPE) cells of healthy and early AMD affected human donor eyes. Rs3793784 conferred a small increase in risk for late AMD in the Dutch population (The Rotterdam and AMRO-NL study), but this was not replicated in two non-European studies (AREDS, Columbia University). In addition, the AMRO-NL study revealed no significant association for 9 other variants spanning ERCC6. Finally, we determined that ERCC6 expression in the human RPE did not depend on rs3793784 genotype, but, interestingly, on AMD status: Early AMD-affected donor eyes had a 50% lower ERCC6 expression than healthy donor eyes (P = 0.018).
Conclusions/Significance
Our meta-analysis of four Caucasian cohorts does not replicate the reported association between SNPs in ERCC6 and AMD. Nevertheless, our findings on ERCC6 expression in the RPE suggest that ERCC6 may be functionally involved in AMD. Combining our data with those of the literature, we hypothesize that the AMD-related reduced transcriptional activity of ERCC6 may be caused by diverse, small and heterogeneous genetic and/or environmental determinants.
doi:10.1371/journal.pone.0013786
PMCID: PMC2967476  PMID: 21072178
18.  Elevated High-Density Lipoprotein Cholesterol and Age-Related Macular Degeneration: The Alienor Study 
PLoS ONE  2014;9(3):e90973.
Background
Lipid metabolism and particularly high-density lipoprotein (HDL) may be involved in the pathogenic mechanism of age-related macular degeneration (AMD). However, conflicting results have been reported in the associations of AMD with plasma HDL and other lipids, which may be confounded by the recently reported associations of AMD with HDL-related genes. We explored the association of AMD with plasma lipid levels and lipid-lowering medication use, taking into account most of HDL-related genes associated with AMD.
Methods
The Alienor study is a population-based study on age-related eye diseases performed in 963 elderly residents of Bordeaux (France). AMD was graded from non mydriatic color retinal photographs in three exclusive stages: no AMD (n = 430 subjects, 938 eyes); large soft distinct drusen and/or large soft indistinct drusen and/or reticular drusen and/or pigmentary abnormalities (early AMD, n = 176, 247); late AMD (n = 40, 61). Associations of AMD with plasma lipids (HDL, total cholesterol (TC), Low-density lipoprotein (LDL), and triglycerides (TG)) were estimated using Generalized Estimating Equation logistic regressions. Statistical analyses included 646 subjects with complete data.
Results
After multivariate adjustment for age, sex, educational level, smoking, BMI, lipid-lowering medication use, cardiovascular disease and diabetes, and for all relevant genetic polymorphisms (ApoE2, ApoE4, CFH Y402H, ARMS2 A69S, LIPC rs10468017, LIPC rs493258, LPL rs12678919, ABCA1 rs1883025 and CETP rs3764261), higher HDL was significantly associated with an increased risk of early (OR = 2.45, 95%CI: 1.54–3.90; P = 0.0002) and any AMD (OR = 2.29, 95%CI: 1.46–3.59; P = 0.0003). Association with late AMD was far from statistical significance (OR = 1.58, 95%CI: 0.48–5.17; p = 0.45). No associations were found for any stage of AMD with TC, LDL and TG levels, statin or fibrate drug use.
Conclusions
This study suggests that elderly patients with high HDL concentration may be at increased risk for AMD and, further, that HDL dysfunction might be implicated in AMD pathogenesis.
doi:10.1371/journal.pone.0090973
PMCID: PMC3946623  PMID: 24608419
19.  Complement Factor H 402H Variant and Reticular Macular Disease 
Archives of ophthalmology  2011;129(8):1061-1066.
Objective
To determine the association of high-risk alleles in the complement factor H (CFH; Y402H, rs1061170) and age-related maculopathy susceptibility (ARMS2; A69S, rs10490924) genes with reticular macular disease (RMD), a major clinical subphenotype of age-related macular degeneration (AMD).
Methods
Using retinal images from the Columbia Macular Genetics Study, we identified 67 subject individuals with RMD. A comparison group of 64 subjects with AMD without RMD was matched by ethnicity, age, sex, and AMD clinical stage.
Results
In the RMD group, 53 of 67 subjects (79.1%) were female, the mean age was 83 years, and 47 of 67 (70.1%) had late AMD, with closely matched values in the non-RMD group. The frequencies of the CFH 402H allele were 39.6% in the RMD group (53 of 134 individuals) and 58.6% in the non-RMD group (75 of 128 individuals) (χ2=8.8; P=.003; odds ratio, 0.46 [95% confidence interval, 0.28–0.76]). The corresponding frequencies of the risk allele for ARMS2 were 44.0% (40 of 128 individuals) and 31.3% (40 of 128 individuals), respectively (χ2=4.0; P=.045; odds ratio, 1.73 [95% confidence interval, 1.04–2.90]). Homozygosity for 402Hwas particularly associated with the absence of RMD, occurring in 8 of 67 subjects (11.9%) with RMD vs 24 of 64 subjects (37.5%) without RMD(P χ.001). Retinal macular disease also was associated with hypertension among male patients.
Conclusions
The AMD-associated CFH 402H risk variant is significantly associated with the absence of RMD but enhanced risk for RMD is conferred by the ARMS2 69S AMD risk allele. These results are consistent with the hypothesis that 402H may confer a survival benefit against certain infections, some of which may cause RMD.
Clinical Relevance
Reticular macular disease may be genetically distinct from the rest of AMD.
doi:10.1001/archophthalmol.2011.212
PMCID: PMC3767386  PMID: 21825189
20.  Assessment of the contribution of CFH and chromosome 10q26 AMD susceptibility loci in a Russian population isolate 
Background/aims
A strong association has been confirmed between age‐related macular degeneration (AMD) and variants at two independent loci including Tyr402His in the complement factor H (CFH) on 1q32 and Ser69Ala at LOC387715, a hypothetical gene on chromosome 10q26. The contribution of both loci to AMD was investigated in an isolated north‐west Russian population.
Methods
Together with a PLEKHA1 variant at 10q26, the CFH Tyr402His and LOC387715 Ser69Ala polymorphisms were genotyped in 155 patients with AMD and 151 age‐matched controls. χ2 and Mantel–Haenszel (M–H) score tests were used to test for association. Sex‐adjusted ORs were calculated.
Results
The frequency of the Tyr402His C allele was significantly higher in patients with AMD compared with controls (pM–H = 0.0035). The increased risk observed in patients homozygous for the C allele (ORHOM = 2.71, 95% CI 1.25 to 5.90) in this indigenous Russian population was considerably lower than that observed in previous western Caucasian populations. A significant increase in the frequency of the LOC387715 variant was observed in patients with late‐stage AMD compared with controls (pM–H = 0.007), with a homozygous OR of 3.47 (95% CI 1.01 to 11.9), although this association was not seen with early‐stage AMD.
Conclusion
The CFH gene contributes to AMD in this Russian population, although the risk conferred is considerably lower in this population than that found in other Western populations. A contribution of LOC387715 to disease in this population is also likely to be of weak effect.
doi:10.1136/bjo.2006.105577
PMCID: PMC1954757  PMID: 17050575
21.  A Common Complement C3 Variant Is Associated with Protection against Wet Age-Related Macular Degeneration in a Japanese Population 
PLoS ONE  2011;6(12):e28847.
Background
Genetic variants in the complement component 3 gene (C3) have been shown to be associated with age-related macular degeneration (AMD) in Caucasian populations of European descent. In particular, a nonsynonymous coding variant, rs2230199 (R102G), is presumed to be the most likely causal variant in the C3 locus based on strong statistical evidence for disease association and mechanistic functional evidence. However, the risk allele is absent or rare (<1%) in Japanese and Chinese populations, and the association of R102G with AMD has not been reported in Asian populations. Genetic heterogeneity of disease-associated variants among different ethnicities is common in complex diseases. Here, we sought to examine whether other common variants in C3 are associated with wet AMD, a common advanced-stage manifestation of AMD, in a Japanese population.
Methodology/Principal Findings
We genotyped 13 tag single nucleotide polymorphisms (SNPs) that capture the majority of common variations in the C3 locus and tested for associations between these SNPs and wet AMD in a Japanese population comprising 420 case subjects and 197 controls. A noncoding variant in C3 (rs2241394) exhibited statistically significant evidence of association (allelic P = 8.32×10−4; odds ratio = 0.48 [95% CI = 0.31–0.74] for the rs2241394 C allele). Multilocus logistic regression analysis confirmed that the effect of rs2241394 was independent of the previously described loci at ARMS2 and CFH, and that the model including variants in ARMS2 and CFH plus C3 rs2241394 provided a better fit than the model without rs2241394. We found no evidence of epistasis between variants in C3 and CFH, despite the fact that they are involved in the same biological pathway.
Conclusions
Our study provides evidence that C3 is a common AMD-associated locus that transcends racial boundaries and provides an impetus for more detailed genetic characterization of the C3 locus in Asian populations.
doi:10.1371/journal.pone.0028847
PMCID: PMC3236234  PMID: 22174912
22.  Association Assessment of Copy Number Polymorphism and Risk of Age-Related Macular Degeneration 
Ophthalmology  2011;118(12):2442-2446.
Purpose
We previously identified a genetic copy number polymorphism (CNP147) that was statistically associated with age-related macular degeneration (AMD), and which resides downstream of the complement factor H (CFH) gene. Factor H protein is polymorphic at amino acid 402 in which the resulting histidine containing moiety has been established to impart significant risk of AMD. Here we present a method to precisely determine the exact copy number of CNP147 and examine in more detail the association with AMD.
Design
Case-control Study
Participants
421 AREDS (Age-related Eye Disease cohort Study) subjects of whom approximately 35% were diagnosed with neovascular disease, 19% with geographic atrophy, 16% with both, 30% with large drusen and 215 controls.
Methods
Using copy number assays available from Applied Biosystems Inc., we examined four loci spanning CNP147 and neighboring CNP148 in an AREDS matched case-control sample set. We analyzed these data by copy number while controlling for two high-risk CFH variants, rs1061170 (Y402H) and rs1410996. We phased the high risk CFH variants with CNP147 and analyzed haplotype frequencies in cases and controls. To further validate copy numbers, six Utah CEPH families (Centre D’etude du Polymorphism Humaine) were typed for CNP147 and the segregation assessed.
Main Outcome Measures
Increased or decreased risk of AMD from genetic loci.
Results
Having fewer than 2 copies of CNP147 is associated with an estimated 43% reduction in odds of having AMD in this sample set (adjusted odds ratio=0.57, P=0.006). CNP148 variation is rare in Caucasians and it was not statistically significant. Common haplotypes reveal that the risk alleles for rs1061170 and rs1410996 most frequently segregate with higher copy numbers for CNP147; but not exclusively, and that one haplotype that carried a deletion of CNP147 was highly protective (odds ratio=0.25 P=1.3×10−13) when compared to the reference.
Conclusions
In this matched subset of AREDS subjects, after adjusting for two known risk variants in CFH, CNP147 deletion statistically associates with diminished risk for AMD.
doi:10.1016/j.ophtha.2011.05.027
PMCID: PMC3223559  PMID: 21856016
Copy number polymorphism; age-related macular degeneration; HapMap 3; TaqMan Copy Number Assays; qPCR
23.  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
24.  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
25.  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

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