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1.  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
2.  An Apolipoprotein E Variant may Protect against Age-Related Macular Degeneration through Cytokine Regulation 
Age-related macular degeneration (AMD) is the leading cause of visual impairment and blindness among the elderly in Western countries. Genetic factors, age, cigarette smoking, nutrition, and exposure to light have been identified as AMD risk factors. In this study, we investigated the association between ApoE C112R/R158C single nucleotide polymorphisms (which determine the E2, E3, and E4 isoforms) and age-related macular degeneration (AMD), and the mechanism underlying the association. Genomic DNA was extracted from 133 clinically screened controls, 94 volunteers with a younger mean age, 120 patients with advanced AMD, and 40 archived ocular AMD slides for single nucleotide polymorphism typing. The effects of recombinant ApoE isoforms on CCL2 (a chemokine), CX3CR1 (a chemokine receptor), and VEGF (a cytokine) expression in cultured human retinal pigment epithelium (RPE) cells were tested and serum cholesterol profiles of the clinically screened subjects were analyzed. ApoE112R (E4) distribution differed significantly between AMD patients and controls. ApoE112R allele frequency was 10.9% in the AMD group when compared with 16.5% in the younger controls and 18.8% in the clinically screened controls. The pathologically diagnosed archived AMD cases had the lowest allele frequency of 5%. No significant differences in ApoE158C (E2) distribution were observed among the groups. A meta-analysis of 8 cohorts including 4,289 subjects showed a strong association between AMD and 112R, but not 158C. In vitro studies found that recombinant ApoE suppresses CCL2 and VEGF expression in RPE cells. However, the E4 isoform showed more suppression than E3 in both cases. These results further confirm the association between ApoE112R and a decreased risk of AMD development. The underlying mechanisms may involve differential regulation of both CCL2 and VEGF by the ApoE isoforms.
doi:10.1002/em.20233
PMCID: PMC1899525  PMID: 16823865
age-related macular degeneration; apolipoprotein E, single nucleotide polymorphism; genetic susceptibility; cytokines
3.  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
4.  Five-year incidence, progression and risk factors for age-related macular degeneration: The Age, Gene/Environment Susceptibility Study 
Ophthalmology  2014;121(9):1766-1772.
Objective
To investigate the incidence and progression of age related m acular degeneration (AMD) and associated risk factors.
Design
Population-based prospective cohort study.
Participants
2868 participants from the Age Gene/Environment Susceptibility-Reykjavik Study with retinal data at baseline and five-year follow-up.
Methods
Digital macular photographs were graded for presence of AMD. Participants completed a questionnaire and extensive clinical battery. Biomarkers were assessed. Risk factors for AMD were analyzed using multivariate regression analysis with odds ratios (ORs) and 95% confidence intervals (CIs).
Main outcome measures
AMD, defined as early or late.
Results
Among 2196 participants free of AMD at baseline, 14.9% developed incident AMD. In multivariate models, incident AMD was significantly associated with age (OR per year 1.14 (95% CI 1.11, 1.17)), current smoking (OR 2.07 (1.38, 3.11)), former smoking (OR 1.36 (1.04, 1.79)), plasma high-density lipoprotein (HDL) cholesterol level (OR 1.62 per mmol/L (1.19, 2.22)), and body mass index (BMI) (OR 1.04 per kg/m2 (1.01, 1.07)). Among 563 participants with early AMD at baseline, 22.7% progressed to late AMD (11.0% pure geographic atrophy (GA) and 11.7% exudative AMD). In multivariate analyses, age was significantly associated with progression to GA (OR 1.14 (1.07, 1.21)) and exudative AMD (OR 1.08 (1.01, 1.14)). Adjusting for age, female sex was associated with exudative AMD (OR 2.10 (1.10, 3.98)) and plasma HDL cholesterol with GA (OR 2.03 per mmol/L (1.02, 4.05)).
Conclusion
By age 85 years, 57.4% of participants had signs of AMD. Age, smoking, plasma HDL cholesterol, BMI and female sex are associated with AMD. Elevated HDL cholesterol is associated with GA development.
doi:10.1016/j.ophtha.2014.03.013
PMCID: PMC4145014  PMID: 24768241
Age-related macular degeneration; risk; smoking; HDL cholesterol; gender; body mass index
5.  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
6.  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
7.  Does smoking influence the type of age related macular degeneration causing visual impairment? 
Aims
To assess the influence of smoking on the type of age related macular degeneration (AMD) lesion causing visual impairment in a large cohort of patients with AMD at a tertiary referral UK centre.
Methods
Prospective, observational, cross sectional study to analyse smoking data on 711 subjects, of western European origin, in relation to the type of AMD lesion present. Colour fundus photographs were graded according to a modified version of the international classification. Multiple logistic regression analysis was performed, adjusting for age and sex using the statistical package SPSS ver 9.0 for Windows. χ2 tests were also used to assess pack year and ex‐smoker data.
Results
578 subjects were graded with neovascular AMD and 133 with non‐neovascular AMD. There was no statistically significant association found between smoking status or increasing number of pack years and type of AMD lesion. The odds of “current smokers” compared to “non‐smokers” developing neovascular rather than non‐neovascular AMD when adjusted for age and sex was 1.88 (95% CI: 0.91 to 3.89; p = 0.09).
Conclusions
Smoking is known to be a risk factor for AMD and this study suggests that smokers are at no more risk of developing neovascular than atrophic lesions.
doi:10.1136/bjo.2005.086355
PMCID: PMC1860217  PMID: 16597668
age related macular degeneration; smoking; neovascular
8.  Evaluation of New and Established Age-Related Macular Degeneration Susceptibility Genes in the Women’s Health Initiative Sight Exam (WHI-SE) Study 
American journal of ophthalmology  2011;152(6):1005-1013.e1.
PURPOSE
To assess whether established and newly reported genetic variants, independent of known lifestyle factors, are associated with the risk of age-related macular degeneration (AMD) among women participating in the Women’s Health Initiative Sight Exam (WHI-SE) Genetic Ancillary Study.
DESIGN
Multicenter case-control study.
METHODS
One hundred and forty-six women with intermediate and late stages of AMD and 1269 subjects without AMD underwent ocular examinations and fundus photography to determine stage of AMD. Fourteen polymorphisms at or near 11 genes, including previously confirmed genes CFH, ARMS2/HTRA1, C2, C3, and CFI; recently reported AMD genes in the high-density lipoprotein cholesterol (HDL) pathway LIPC, ABCA1, CETP, and LPL; TIMP3/SYN3, a known ocular gene recently linked with AMD; and APOE, were assessed using logistic regression analysis.
RESULTS
After adjustment for demographic, behavioral, and other genetic factors, a protective effect was detected among TT carriers compared with non-carriers for the HDL pathway gene, LIPC rs493258, for intermediate and late AMD (OR [95% confidence interval]: 0.3 [0.2–-0.7], P = .003). Variants in CFH rs1410996, ARMS2/HTRA1 A69S, and C3 R102G were significantly associated with an increased risk of AMD. Individuals with the homozygous CFI rs10033900 TT genotype had a 2.9 [1.2–7.2]-fold increased risk, and those with the CFH Y402H GG genotype had a 2.2 [1.0–4.8]-fold higher risk of developing AMD compared with non-carriers. APOE4 carriers may have a reduced risk of intermediate/late AMD (OR = 0.5 [0.3–0.9], P = .015. Suggestive associations were seen between AMD and the HDL pathway genes CETP and LPL.
CONCLUSION
In this unique national cohort of women, we found associations with established AMD-related genetic factors and the recently reported LIPC gene in the HDL pathway. These findings may help develop novel therapeutic targets to treat or delay the onset of the disease.
doi:10.1016/j.ajo.2011.05.016
PMCID: PMC4446967  PMID: 21906714
9.  Cross Sectional and Longitudinal Associations between Cardiovascular Risk Factors and Age Related Macular Degeneration in the EPIC-Norfolk Eye Study 
PLoS ONE  2015;10(7):e0132565.
Purpose
To examine the cross sectional and longitudinal relationship between cardiovascular risk factors and age-related macular degeneration (AMD) in a large British cohort study.
Methods
The EPIC Norfolk Eye study is nested in a larger prospective cohort study. Data on cardiovascular risk factors were collected at baseline (1993-1997) and follow up (2006-2011) via clinical examination, validated lifestyle questionnaires and serum blood samples. AMD was ascertained using standardised grading of fundus photographs at the follow up. Logistic regression was used to examine associations between baseline and follow up risk factors with AMD.
Results
5,344 pairs (62.0% of total 8623) of fundus photographs were of sufficient quality for grading of AMD in participants with mean age of 67.4 years old (range 44-91) at diagnosis. There were 28 cases of late AMD (0.5%, 95% confidence interval (CI)=0.3-0.8%) and 645 cases of early AMD (12.1%, 95%CI=11.2-13.0.%). In multivariable analysis, older people with higher levels of baseline high density lipoprotein- cholesterol (HDL-C ) and C-reactive protein (CRP) were more likely to have any signs of AMD, after adjusting for sex, education, smoking, and systolic blood pressure. In cross sectional analysis, only older age and higher HDL were significantly associated with AMD.
Conclusions
We have found that older age and higher levels of CRP and HDL-C were associated with increased odds of AMD in this population in the longitudinal analysis, but older age and HDL-C, not CRP was significantly associated with AMD in the cross sectional analysis. The prevalence of AMD in this cohort was low compared to other cohorts in Europe, the US and Australia, and probably reflects the some selection biases in follow up participation as well as the low rate of smoking among our healthy participants.
doi:10.1371/journal.pone.0132565
PMCID: PMC4503731  PMID: 26176222
10.  Association of Variants in the LIPC and ABCA1 Genes with Intermediate and Large Drusen and Advanced Age-Related Macular Degeneration 
HDL pathway genes LIPC and ABCA1 are associated with intermediate drusen, large drusen, and advanced AMD independent of age, sex, education, smoking, body mass index, antioxidant treatment, and other known genetic variants.
Purpose.
Intermediate and large drusen usually precede advanced age-related macular degeneration (AMD). There is little information about which genes influence drusen accumulation. Discovery of genetic variants associated with drusen may lead to prevention and treatments of AMD in its early stages.
Methods.
A total of 3066 subjects were evaluated on the basis of ocular examinations and fundus photography and categorized as control (n = 221), intermediate drusen (n = 814), large drusen (n = 949), or advanced AMD (n = 1082). SNPs in the previously identified CFH, C2, C3, CFB, CFI, APOE, and ARMS2/HTRA1 genes/regions and the novel genes LIPC, CETP, and ABCA1 in the high-density lipoprotein (HDL) cholesterol pathway were genotyped. Associations between stage of AMD and SNPs were assessed using logistic regression.
Results.
Controlling for age, sex, education, smoking, body mass index, and antioxidant treatment, the number of minor (T) alleles of the genes LIPC and ABCA1 were significantly associated with a reduced risk of intermediate drusen (LIPC [P trend = 0.045], ABCA1 [P = 4.4 × 10−3]), large drusen (LIPC [P = 0.041], ABCA1 [P = 7.7 × 10−4]), and advanced AMD (LIPC [P = 1.8 × 10−3], ABCA1 [P = 3 × 10−4]). After further adjustment for known genetic factors, the protective effect of the TT genotype was significant for intermediate drusen (LIPC [odds ratio (OR), 0.56; 95% confidence interval (CI), 0.33–0.94], ABCA1 [OR, 0.48; 95% CI, 0.27–0.85]), large drusen (LIPC [OR, 0.58; 95% CI, 0.34–0.98)], ABCA1 [OR, 0.41; 95% CI, 0.23–0.74)]), and advanced AMD (LIPC [OR, 0.39; 95% CI, 0.21–0.74)], ABCA1 [OR, 0.35; 95% CI, 0.17–0.71)]). CFH, C3, C2, and ARMS2/HTRA1 were associated with large drusen and advanced AMD.
Conclusions.
LIPC and ABCA1 are related to intermediate and large drusen, as well as advanced AMD. CFH, C3, C2, and ARMS2/HTRA1 are associated with large drusen and advanced AMD. Genes may have varying effects on different stages of AMD.
doi:10.1167/iovs.10-7070
PMCID: PMC3175969  PMID: 21447678
11.  Prospective study of lutein/zeaxanthin intake and risk of age-related macular degeneration2 
Background
The association between lutein/zeaxanthin intake and age-related macular degeneration (AMD) risk may differ by smoking status, vitamin C and E intakes, and body fatness.
Objective
The objective was to evaluate the association between lutein/zeaxanthin intake and AMD risk by smoking status, intake of antioxidant vitamins, and body fatness.
Design
We conducted a prospective follow-up study of 71 494 women and 41 564 men aged ≥50 y and had no diagnosis of AMD or cancer. Diet was assessed with a validated semiquantitative food-frequency questionnaire.
Results
During up to 18 y of follow-up, we documented 673 incident cases of early AMD and 442 incident cases of neovascular AMD with a visual loss of 20/30 or worse due primarily to AMD. Lutein/zeaxanthin intake was not associated with the risk of self-reported early AMD. There was a statistically nonsignificant and nonlinear inverse association between lutein/zeaxanthin intake and neovascular AMD risk; the pooled multivariate relative risks for increasing quintiles of intake were 1.00 (referent), 0.80, 0.84, 0.97, and 0.72 (95% CI: 0.53, 0.99) (P for trend = 0.14). For early AMD, the association with lutein/zeaxanthin intake did not vary by smoking status, intakes of vitamins C and E, or body mass index. For neovascular AMD, a nonlinear inverse association was found among never smokers.
Conclusions
These data do not support a protective role of lutein/zeaxanthin intake on risk of self-reported early AMD. The suggestion of inverse associations related to the risk of neovascular AMD needs to be examined further.
PMCID: PMC2504741  PMID: 18541575
12.  Genetic Evidence for Role of Carotenoids in Age-Related Macular Degeneration in the Carotenoids in Age-Related Eye Disease Study (CAREDS) 
Purpose.
We tested variants in genes related to lutein and zeaxanthin status for association with age-related macular degeneration (AMD) in the Carotenoids in Age-Related Eye Disease Study (CAREDS).
Methods.
Of 2005 CAREDS participants, 1663 were graded for AMD from fundus photography and genotyped for 424 single nucleotide polymorphisms (SNPs) from 24 candidate genes for carotenoid status. Of 337 AMD cases 91% had early or intermediate AMD. The SNPs were tested individually for association with AMD using logistic regression. A carotenoid-related genetic risk model was built using backward selection and compared to existing AMD risk factors using the area under the receiver operating characteristic curve (AUC).
Results.
A total of 24 variants from five genes (BCMO1, BCO2, NPCL1L1, ABCG8, and FADS2) not previously related to AMD and four genes related to AMD in previous studies (SCARB1, ABCA1, APOE, and ALDH3A2) were associated independently with AMD, after adjusting for age and ancestry. Variants in all genes (not always the identical SNPs) were associated with lutein and zeaxanthin in serum and/or macula, in this or other samples, except for BCO2 and FADS2. A genetic risk score including nine variants significantly (P = 0.002) discriminated between AMD cases and controls beyond age, smoking, CFH Y402H, and ARMS2 A69S. The odds ratio (95% confidence interval) for AMD among women in the highest versus lowest quintile for the risk score was 3.1 (2.0–4.9).
Conclusions.
Variants in genes related to lutein and zeaxanthin status were associated with AMD in CAREDS, adding to the body of evidence supporting a protective role of lutein and zeaxanthin in risk of AMD.
In this study of over 1600 postmenopausal women of the CAREDS, we describe the first evidence that variation in multiple genes related to carotenoid status in the blood and macula are associated with age-related macular degeneration (AMD).
doi:10.1167/iovs.13-13216
PMCID: PMC3908680  PMID: 24346170
macular degeneration; carotenoids; genes
13.  Markers of Inflammation, Oxidative Stress, and Endothelial Dysfunction and the 20-year Cumulative Incidence of Early Age-related Macular Degeneration: The Beaver Dam Eye Study 
JAMA ophthalmology  2014;132(4):446-455.
Importance
Modifying levels of factors associated with age-related macular degeneration (AMD) may decrease risk of visual impairment in older persons.
Objective
To examine the relationships of markers of inflammation, oxidative stress, and endothelial dysfunction to the 20-year cumulative incidence of early AMD.
Design
Longitudinal population-based cohort study.
Setting
Beaver Dam, Wisconsin.
Participants
A random sample of 975 persons in the Beaver Dam Eye Study without signs of AMD who participated in the baseline examination in 1988-1990 and up to four follow-up examinations in 1993-1995, 1998-2000, 2003-2005, and 2008-2010.
Exposures
Serum markers of inflammation (high sensitivity C-reactive protein [hsCRP], tumor necrosis factor-α receptor 2 [TNF-αR2], interleukin-6 [IL-6], and white blood cell count), oxidative stress (8-isoprostane and total carbonyl content), and endothelial dysfunction (soluble vascular cell adhesion molecule-1 [sVCAM-1] and soluble intercellular adhesion molecule-1) were measured. Interactions with Complement Factor H (rs1061170) and Age-Related Maculopathy Susceptibility 2 (rs10490924), C3 (rs2230199) and C2/CFB (rs4151667) were examined using multiplicative models. AMD was assessed from fundus photographs.
Main Outcome Measure
Early AMD defined by the presence of any size drusen and the presence of pigmentary abnormalities, or by the presence of large-sized drusen (≥125 μm diameter), in the absence of late AMD.
Results
The 20-year cumulative incidence of early AMD was 23.0%. Adjusting for age, sex, and other risk factors, hsCRP (odds ratio [OR] comparing 4th to 1st quartile 2.18, P=0.005), TNF-αR2 (1.78, P=0.04), and IL-6 (1.78, P=0.03) were associated with the incidence of early AMD. Increased incidence of early AMD was associated with sVCAM-1 (OR per standard deviation on the log ng/mL scale 1.21, P=0.04).
Conclusions and Relevance
We found modest evidence of relationships of serum hsCRP, TNF-αR2, and IL-6 and sVCAM-1 to the 20-year cumulative incidence of early AMD independent of age, smoking status, and other factors. It is not known whether these associations represent a cause and effect relationship or if other unknown confounders accounted for the findings. Even if inflammatory processes are a cause of early AMD, it is not known whether interventions that reduce systemic inflammatory processes will reduce the incidence of early AMD.
doi:10.1001/jamaophthalmol.2013.7671
PMCID: PMC4076038  PMID: 24481424
14.  Proof of Concept, Randomized, Placebo-Controlled Study of the Effect of Simvastatin on the Course of Age-Related Macular Degeneration 
PLoS ONE  2013;8(12):e83759.
Background
HMG Co-A reductase inhibitors are ubiquitous in our community yet their potential role in age-related macular degeneration (AMD) remains to be determined.
Methodology/Principal Findings
Objectives: To evaluate the effect of simvastatin on AMD progression and the effect modification by polymorphism in apolipoprotein E (ApoE) and complement factor H (CFH) genes. Design: A proof of concept double-masked randomized controlled study. Participants: 114 participants aged 53 to 91 years, with either bilateral intermediate AMD or unilateral non-advanced AMD (with advanced AMD in fellow eye), BCVA≥20/60 in at least one eye, and a normal lipid profile. Intervention: Simvastatin 40 mg/day or placebo, allocated 1∶1. Main outcome measures: Progression of AMD either to advanced AMD or in severity of non-advanced AMD. Results. The cumulative AMD progression rates were 70% in the placebo and 54% in the simvastatin group. Intent to treat multivariable logistic regression analysis, adjusted for age, sex, smoking and baseline AMD severity, showed a significant 2-fold decrease in the risk of progression in the simvastatin group: OR 0.43 (0.18–0.99), p = 0.047. Post-hoc analysis stratified by baseline AMD severity showed no benefit from treatment in those who had advanced AMD in the fellow eye before enrolment: OR 0.97 (0.27–3.52), p = 0.96, after adjusting for age, sex and smoking. However, there was a significant reduction in the risk of progression in the bilateral intermediate AMD group compared to placebo [adjusted OR 0.23 (0.07–0.75), p = 0.015]. The most prominent effect was observed amongst those who had the CC (Y402H) at risk genotype of the CFH gene [OR 0.08 (0.02–0.45), p = 0.004]. No evidence of harm from simvastatin intervention was detected.
Conclusion/Significance
Simvastatin may slow progression of non-advanced AMD, especially for those with the at risk CFH genotype CC (Y402H). Further exploration of the potential use of statins for AMD, with emphasis on genetic subgroups, is warranted.
Trial Registration
Australian New Zealand Clinical Trial Registry (ANZCTR) ACTRN1260500032065
doi:10.1371/journal.pone.0083759
PMCID: PMC3877099  PMID: 24391822
15.  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
16.  Age related macular degeneration 
BMJ Clinical Evidence  2007;2007:0701.
Introduction
Sight-threatening (late) age-related macular degeneration (AMD) occurs in 2% of people aged over 50 years in industrialised countries, with prevalence increasing with age. Early-stage disease is marked by normal vision, but retinal changes (drusen and pigment changes). Disease progression leads to worsening central vision, but peripheral vision is preserved.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent progression of early- or late-stage age-related macular degeneration; and exudative age-related macular degeneration? We searched: Medline, Embase, The Cochrane Library and other important databases up to March 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 45 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antiangiogenesis (using pegaptanib, ranibizumab, interferon alfa-2a, or anecortave acetate), antioxidant vitamins plus zinc, external beam radiation, laser treatment to drusen, photodynamic therapy with verteporfin, submacular surgery, thermal laser photocoagulation, transpupillary thermotherapy.
Key Points
Sight-threatening (late) age related macular degeneration (AMD) occurs in 2% of people aged over 50 years in industrialised countries, with prevalence increasing with age. Early stage disease is marked by normal vision, but retinal changes (drusen and pigment changes). Disease progression leads to worsening central vision, but peripheral vision is preserved.85% of cases are atrophic (dry) AMD, but exudative (wet) AMD, marked by choroidal neovascularisation, leads to a more rapid loss of sight.The main risk factor is age. Hypertension, smoking, and a family history of AMD are also risk factors.
High dose antioxidant vitamin and zinc supplementation may reduce progression of moderate AMD, but there is no evidence of benefit in people with no, or mild AMD, or those with established late AMD in both eyes.
CAUTION: Beta-carotene, an antioxidant vitamin used in AMD, has been linked to an increased risk of lung cancer in people at high risk of this disease.
Photodynamic treatment with verteporfin reduces the risk of developing moderate or severe loss of visual acuity and legal blindness in people with vision initially better than 20/100 or 20/200, compared with placebo. Photodynamic treatment is associated with an initial loss of vision and photosensitive reactions in a small proportion of people.
Thermal laser photocoagulation can reduce severe visual loss in people with exudative AMD. It is frequently associated with an immediate and permanent reduction in visual acuity if the lesion involves the central macula, but it remains a proven effective treatment for extrafoveal choroidal neovascularisation. About half of people treated with thermal lasers show recurrent choroidal neovascularisation within 3 years.We don't know whether laser treatment of drusen prevents progression of disease, and it may increase short term rates of choroidal neovascularisation.
Antiangiogenesis treatment using vascular endothelial growth factor (VEGF) inhibitors such as ranibizumab or pegaptanib reduces the risk of moderate vision loss, and may improve vision at 12 and 24 months. Antiangiogenesis treatment using anecortave acetate may be as effective as photodynamic therapy in reducing vision loss.
Studies investigating external beam radiotherapy have given contradictory results, and have failed to show an overall benefit in AMD.
Subcutaneous interferon alfa-2a and submacular surgery have not been shown to improve vision, and are associated with potentially severe adverse effects.
We found no RCT evidence on the effects of transpupillary thermotherapy.
PMCID: PMC2943806  PMID: 19454069
17.  Smoking and age related macular degeneration: the number of pack years of cigarette smoking is a major determinant of risk for both geographic atrophy and choroidal neovascularisation 
Background/aims
There is evidence that smoking is a risk factor for age related macular degeneration (AMD). However, not all studies have demonstrated this association and several key questions about the role of smoking in AMD have still to be determined. The aim of this study was to further investigate this relation for both choroidal neovascularisation (CNV) and geographic atrophy (GA).
Methods
To investigate the relation between smoking and the risk of developing age related macular degeneration (AMD) in white people, 435 cases with end stage AMD were compared with 280 controls. All subjects had graded stereoscopic colour fundus photography and AMD was defined as the presence of GA or CNV. Smoking history was assessed using multiple parameters in a detailed questionnaire.
Results
Comparison of current and former smokers with non‐smokers was consistent with smoking being a risk factor for AMD but did not reach statistical significance. There was a strong association between AMD and pack years of cigarette smoking (p = 0.002), the odds ratio increasing with the amount smoked; for subjects with more than 40 pack years of smoking the odds ratio was 2.75 (95% CI 1.22 to 6.20) compared with non‐smokers. Both types of AMD showed a similar relation; smoking more than 40 pack years of cigarettes was associated with an odds ratio of 3.43 (95% CI 1.28 to 9.20) for GA and 2.49 (95% CI 1.06 to 5.82) for CNV. Stopping smoking was associated with reduced odds of AMD and the risk in those who had not smoked for over 20 years was comparable to non‐smokers. The risk profile was similar for males and females. Passive smoking exposure was associated with an increased risk of AMD (OR 1.87; 95% CI 1.03 to 3.40) in non‐smokers.
Conclusions
The authors have demonstrated a strong association between the risk of both GA and CNV and pack years of cigarette smoking. This provides support for a causal relation between smoking and AMD. They also show an increased risk for AMD in non‐smokers exposed to passive smoking. Stopping smoking appears to reduce the risk of developing AMD.
doi:10.1136/bjo.2005.073643
PMCID: PMC1856879  PMID: 16361672
age related macular degeneration; smoking; case control
18.  MITOCHONDRIAL VARIATION AND THE RISK OF AGE-RELATED MACULAR DEGENERATION ACROSS DIVERSE POPULATIONS 
Substantial progress has been made in identifying susceptibility variants for age-related macular degeneration (AMD). The majority of research to identify genetic variants associated with AMD has focused on nuclear genetic variation. While there is some evidence that mitochondrial genetic variation contributes to AMD susceptibility, to date, these studies have been limited to populations of European descent resulting in a lack of data in diverse populations. A major goal of the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) study is to describe the underlying genetic architecture of common, complex diseases across diverse populations. This present study sought to determine if mitochondrial genetic variation influences risk of AMD across diverse populations. We performed a genetic association study to investigate the contribution of mitochondrial DNA variation to AMD risk. We accessed samples from the National Health and Nutrition Examination Surveys, a U.S population-based, cross-sectional survey collected without regard to health status. AMD cases and controls were selected from the Third NHANES and NHANES 2007-2008 datasets which include non-Hispanic whites, non-Hispanic blacks, and Mexican Americans. AMD cases were defined as those > 60 years of age with early/late AMD, as determined by fundus photography. Targeted genotyping was performed for 63 mitochondrial SNPs and participants were then classified into mitochondrial haplogroups. We used logistic regression assuming a dominant genetic model adjusting for age, sex, body mass index, and smoking status (ever vs. never). Regressions and meta-analyses were performed for individual SNPs and mitochondrial haplogroups J, T, and U. We identified five SNPs associated with AMD in Mexican Americans at p < 0.05, including three located in the control region (mt16111, mt16362, and mt16319), one in MT-RNR2 (mt1736), and one in MT-ND4 (mt12007). No mitochondrial variant or haplogroup was significantly associated in non-Hispanic blacks or non-Hispanic whites in the final meta-analysis. This study provides further evidence that mitochondrial variation plays a role in susceptibility to AMD and contributes to the knowledge of the genetic architecture of AMD in Mexican Americans.
PMCID: PMC4299880  PMID: 25592585
19.  Evaluation of variants in the selectin genes in age-related macular degeneration 
BMC Medical Genetics  2011;12:58.
Background
Age-related macular degeneration (AMD) is a common disease of the elderly that leads to loss of the central visual field due to atrophic or neovascular events. Evidence from human eyes and animal models suggests an important role for macrophages and endothelial cell activation in the pathogenesis of AMD. We sought to determine whether common ancestral variants in genes encoding the selectin family of proteins are associated with AMD.
Methods
Expression of E-selectin, L-selectin and P-selectin was examined in choroid and retina by quantitative PCR and immunofluorescence. Samples from patients with AMD (n = 341) and controls (n = 400) were genotyped at a total of 34 SNPs in the SELE, SELL and SELP genes. Allele and genotype frequencies at these SNPs were compared between AMD patients and controls as well as between subtypes of AMD (dry, geographic atrophy, and wet) and controls.
Results
High expression of all three selectin genes was observed in the choroid as compared to the retina. Some selectin labeling of retinal microglia, drusen cores and the choroidal vasculature was observed. In the genetic screen of AMD versus controls, no positive associations were observed for SELE or SELL. One SNP in SELP (rs3917751) produced p-values < 0.05 (uncorrected for multiple measures). In the subtype analyses, 6 SNPs (one in SELE, two in SELL, and three in SELP) produced p-values < 0.05. However, when adjusted for multiple measures with a Bonferroni correction, only one SNP in SELP (rs3917751) produced a statistically significant p-value (p = 0.0029).
Conclusions
This genetic screen did not detect any SNPs that were highly associated with AMD affection status overall. However, subtype analysis showed that a single SNP located within an intron of SELP (rs3917751) is statistically associated with dry AMD in our cohort. Future studies with additional cohorts and functional assays will clarify the biological significance of this discovery. Based on our findings, it is unlikely that common ancestral variants in the other selectin genes (SELE and SELL) are risk factors for AMD. Finally, it remains possible that sporadic or rare mutations in SELE, SELL, or SELP have a role in the pathogenesis of AMD.
doi:10.1186/1471-2350-12-58
PMCID: PMC3096910  PMID: 21521525
20.  Diabetes Mellitus and Risk of Age-Related Macular Degeneration: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(9):e108196.
Age-related macular degeneration (AMD) is a major cause of severe vision loss in elderly people. Diabetes mellitus is a common endocrine disorder with serious consequences, and diabetic retinopathy (DR) is the main ophthalmic complication. DR and AMD are different diseases and we seek to explore the relationship between diabetes and AMD. MEDLINE, EMBASE, and the Cochrane Library were searched for potentially eligible studies. Studies based on longitudinal cohort, cross-sectional, and case-control associations, reporting evaluation data of diabetes as an independent factor for AMD were included. Reports of relative risks (RRs), hazard ratios (HRs), odds ratio (ORs), or evaluation data of diabetes as an independent factor for AMD were included. Review Manager and STATA were used for the meta-analysis. Twenty four articles involving 27 study populations were included for meta-analysis. In 7 cohort studies, diabetes was shown to be a risk factor for AMD (OR, 1.05; 95% CI, 1.00–1.14). Results of 9 cross-sectional studies revealed consistent association of diabetes with AMD (OR, 1.21; 95% CI, 1.00–1.45), especially for late AMD (OR, 1.48; 95% CI, 1.44–1.51). Similar association was also detected for AMD (OR, 1.29; 95% CI, 1.13–1.49) and late AMD (OR, 1.16; 95% CI, 1.11–1.21) in 11 case-control studies. The pooled ORs for risk of neovascular AMD (nAMD) were 1.10 (95% CI, 0.96–1.26), 1.48 (95% CI, 1.44–1.51), and 1.15 (95% CI, 1.11–1.21) from cohort, cross-sectional and case-control studies, respectively. No obvious divergence existed among different ethnic groups. Therefore, we find diabetes a risk factor for AMD, stronger for late AMD than earlier stages. However, most of the included studies only adjusted for age and sex; we thus cannot rule out confounding as a potential explanation for the association. More well-designed prospective cohort studies are still warranted to further examine the association.
doi:10.1371/journal.pone.0108196
PMCID: PMC4169602  PMID: 25238063
21.  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
22.  Genome-wide association analyses of genetic, phenotypic, and environmental risks in the age-related eye disease study 
Molecular Vision  2010;16:2811-2821.
Purpose
To present genome-wide association analyses of genotypic and environmental risks on age-related macular degeneration (AMD) using 593 subjects from the age-related eye disease study (AREDS), after adjusting for population stratification and including questionable controls.
Methods
Single nucleotide polymorphism (SNP) associations with AMD for the non-Hispanic white population were investigated using a log-additive model after adjusting for population stratification. Replication of possible SNP-disease association was performed by genotyping an independent group of 444 AMD case and 300 control subjects. Logistic regression models were used to assess interaction effects between smoking and SNPs associated with AMD. Independent genetic risk effects among the disease-associated SNPs were also investigated using multiple logistic regression models.
Results
Population stratification was observed among the individuals having a self-reported race of non-Hispanic white. Risk allele frequencies at established AMD loci demonstrated that questionable control subjects were similar to control subjects in the AREDS, suggesting that they could be used as true controls in the analyses. Genetic loci (complement factor H [CFH], complement factor B [CFB], the age-related maculopathy susceptibility 2 locus containing the hypothetical gene [LOC387715]/the high-temperature requirement A-1 [HTRA1], and complement component 3 [C3]) that were already known to be associated with AMD were identified. An additional 26 novel SNPs potentially associated with AMD were identified, but none were definitely replicated in a second independent group of subjects. Smoking did not interact with known AMD loci, but was associated with late AMD. Statistically independent genetic signals were observed within the Pleckstrin homology domain-containing family A member 1 (PLEKHA1) region near LOC387715/HTRA1 and within a haplotype spanning exon 19 of the C3 gene.
Conclusions
Population stratification among Caucasian subjects from the multicentered AREDS was observed, suggesting that it should be adjusted for in future studies. The AREDS questionable control subjects can be used as control subjects in the AREDS genome-wide association study (GWAS). Smoking was an independent risk factor for advanced AMD in the AREDS subjects. There continues to be evidence that the 10q26 (age-related maculopathy susceptibility 2 gene [ARMS2]) locus spanning PLEKHA1-LOC387715-HTRA1 and the C3 gene may contain multiple independent genetic risks contributing to AMD.
PMCID: PMC3008720  PMID: 21197116
23.  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
24.  Cigarette Smoking and the Natural History of Age-related Macular Degeneration: the Beaver Dam Eye Study 
Ophthalmology  2014;121(10):1949-1955.
Objective
To examine the association of current cigarette smoking and pack-years smoked to the incidence and progression of age-related macular degeneration (AMD) and to examine the interactions of current smoking and pack-years smoked with Complement Factor H (CFH, rs1061170) and Age-Related Maculopathy Susceptibility 2 (ARMS2, rs10490924) genotype.
Design
A longitudinal population-based study of AMD in a representative American community. Examinations were performed every 5 years over a 20-year period.
Participants
4439 participants in the population-based Beaver Dam Eye Study.
Methods
AMD status was determined from grading retinal photographs. Multi-state models were used to model the relationship of current smoking and pack-years smoked and interactions with CFH and ARMS2 to the incidence and progression of AMD over the entire age range.
Main Outcome Measures
Incidence and progression of AMD over a 20-year period and interactions between current smoking and pack-years smoked with CFH and ARMS2 genotype.
Results
The incidence of early AMD over the 20-year period was 24.4% and the incidence of late AMD was 4.5%. Current smoking was associated with an increased risk of transitioning from minimal to moderate early AMD. A greater number of pack-years smoked was associated with an increased risk of transitioning from no AMD to minimal early AMD and from severe early AMD to late AMD. Current smoking and a greater number of pack-years smoked were associated with an increased risk of death. There were no statistically significant multiplicative interactions between current smoking or pack-years smoked and CFH or ARMS2 genotype.
Conclusions
Current smoking and a greater number of pack-years smoked increase the risk of the progression of AMD. This has important health care implications because smoking is a modifiable behavior.
doi:10.1016/j.ophtha.2014.04.040
PMCID: PMC4177947  PMID: 24953792
25.  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

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