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1.  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
2.  Visual Impairment as a Function of Visual Acuity in Both Eyes and Its Impact on Patient Reported Preferences 
PLoS ONE  2013;8(12):e81042.
Purpose
To assess the impact of VA loss on patient reported utilities taking both eyes into account compared to taking only the better or the worse eye into account.
Methods
In this cross-sectional study 1085 patients and 254 controls rated preferences with the generic health-related (EQ-5D; n = 868) and vision-specific (Vision and Quality of Life Index (VisQoL); n = 837) multi-attribute utility instruments (MAUIs). Utilities were calculated for three levels of VA in the better and worse eyes, as well as for 6 different vision states based on combinations of the better and worse eye VA.
Results
Using the VisQoL, utility scores decreased significantly with deteriorating vision in both the better and worse eyes when analysed separately. When stratified by the 6 vision states, VisQoL utilities decreased as VA declined in the worse eye despite stable VA in the better eye. Differences in VisQoL scores were statistically significant for cases where the better eye had no vision impairment and the worse seeing fellow eye had mild, moderate or severe vision impairment. In contrast, the EQ-5D failed to capture changes in better or worse eye VA, or any of the six vision states.
Conclusions
Calculating utilities based only on better eye VA or using a generic MAUI is likely to underestimate the impact of vision impairment, particularly when the better eye has no or little VA loss and the worse eye is moderately to severely visually impaired. These findings have considerable implications for the assessment of overall visual impairment as well as economic evaluations within eye health.
doi:10.1371/journal.pone.0081042
PMCID: PMC3855212  PMID: 24339893
3.  Variations in Apolipoprotein E Frequency With Age in a Pooled Analysis of a Large Group of Older People 
American Journal of Epidemiology  2011;173(12):1357-1364.
Variation in the apolipoprotein E gene (APOE) has been reported to be associated with longevity in humans. The authors assessed the allelic distribution of APOE isoforms ε2, ε3, and ε4 among 10,623 participants from 15 case-control and cohort studies of age-related macular degeneration (AMD) in populations of European ancestry (study dates ranged from 1990 to 2009). The authors included only the 10,623 control subjects from these studies who were classified as having no evidence of AMD, since variation within the APOE gene has previously been associated with AMD. In an analysis stratified by study center, gender, and smoking status, there was a decreasing frequency of the APOE ε4 isoform with increasing age (χ2 for trend = 14.9 (1 df); P = 0.0001), with a concomitant increase in the ε3 isoform (χ2 for trend = 11.3 (1 df); P = 0.001). The association with age was strongest in ε4 homozygotes; the frequency of ε4 homozygosity decreased from 2.7% for participants aged 60 years or less to 0.8% for those over age 85 years, while the proportion of participants with the ε3/ε4 genotype decreased from 26.8% to 17.5% across the same age range. Gender had no significant effect on the isoform frequencies. This study provides strong support for an association of the APOE gene with human longevity.
doi:10.1093/aje/kwr015
PMCID: PMC3145394  PMID: 21498624
aged; apolipoprotein E2; apolipoprotein E3; apolipoprotein E4; apolipoproteins E; longevity; meta-analysis; multicenter study
4.  Comprehensive Analysis of Copy Number Variation of Genes at Chromosome 1 and 10 Loci Associated with Late Age Related Macular Degeneration 
PLoS ONE  2012;7(4):e35255.
Copy Number Variants (CNVs) are now recognized as playing a significant role in complex disease etiology. Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in the western world. While a number of genes and environmental factors have been associated with both risk and protection in AMD, the role of CNVs has remained largely unexplored. We analyzed the two major AMD risk-associated regions on chromosome 1q32 and 10q26 for CNVs using Multiplex Ligation-dependant Probe Amplification. The analysis targeted nine genes in these two key regions, including the Complement Factor H (CFH) gene, the 5 CFH-related (CFHR) genes representing a known copy number “hotspot”, the F13B gene as well as the ARMS2 and HTRA1 genes in 387 cases of late AMD and 327 controls. No copy number variation was detected at the ARMS2 and HTRA1 genes in the chromosome 10 region, nor for the CFH and F13B genes at the chromosome 1 region. However, significant association was identified for the CFHR3-1 deletion in AMD cases (p = 2.38×10−12) OR = 0.31, CI-0.95 (0.23–0.44), for both neovascular disease (nAMD) (p = 8.3×10−9) OR = 0.36 CI-0.95 (0.25–0.52) and geographic atrophy (GA) (p = 1.5×10−6) OR = 0.36 CI-0.95 (0.25–0.52) compared to controls. In addition, a significant association with deletion of CFHR1-4 was identified only in patients who presented with bilateral GA (p = 0.02) (OR = 7.6 CI-0.95 1.38–41.8). This is the first report of a phenotype specific association of a CNV for a major subtype of AMD and potentially allows for pre-diagnostic identification of individuals most likely to proceed to this end stage of disease.
doi:10.1371/journal.pone.0035255
PMCID: PMC3338825  PMID: 22558131
5.  Perifoveal Müller Cell Depletion in a Case of Macular Telangiectasia Type 2 
Ophthalmology  2010;117(12):2407-2416.
PURPOSE
To assess the histopathological changes in a postmortem sample derived from an eye donor with Macular Telangiectasia Type 2 (MacTel type 2) to gain further insight into the cause of the disease.
DESIGN
Clinicopathological case report
PARTICIPANTS
Postmortem tissue was collected from 5 different donors: one MacTel type 2 patient, one healthy control, two type 2 diabetic patients; one with retinopathy and one without retinopathy, and one patient with unilateral Coat’s disease.
METHODS
Macular pigment distribution in the posterior part of freshly dissected eyes was documented by macro photography. Paraffin sections from both the macular and peripheral regions were assessed using antigen retrieval and immunohistochemistry to study the distribution of cell-specific markers. Blood vessels were visualized with antibodies directed against collagen IV and claudin5, glial cells with antibodies against glial fibrillary acidic protein (GFAP), vimentin, glutamine synthetase (GS) and retinaldehyde binding protein (RLBP1, also known as CRALBP), microglia with an antibody against allograft inflammatory factor 1 (AIF1, also known as Iba1) and photoreceptors with antibodies against rhodopsin and opsin. Using anatomical landmarks the sections were then matched with the macular pigment distribution and a fluorescein angiogram of the patient that was taken before the patient’s death.
MAIN OUTCOME MEASURES
Presence and distribution of macular pigment and cell-specific markers.
RESULTS
Macular pigment was absent in the macula. Furthermore, abnormally dilated capillaries were identified in a macular region that correlated spatially with regions of fluorescein leakage in an angiogram that was taken 12 years prior to death. These telangiectatic vessels displayed a marked reduction of the basement membrane component collagen IV, indicating vascular pathology. GFAP was limited to retinal astrocytes and no reactive Müller cells were identified. Importantly, reduced immunoreactivity with Müller cell markers (vimentin, GS and RLBP1) in the macula was observed. The area that lacked Müller cells corresponded with the region of depleted macular pigment.
CONCLUSIONS
These findings suggest that macular Müller cell loss or dysfunction is a critical component of MacTel type 2, which may have implications for future treatment strategies.
doi:10.1016/j.ophtha.2010.04.001
PMCID: PMC2974049  PMID: 20678804
6.  Clinical validation of a genetic model to estimate the risk of developing choroidal neovascular age-related macular degeneration 
Human Genomics  2011;5(5):420-440.
Predictive tests for estimating the risk of developing late-stage neovascular age-related macular degeneration (AMD) are subject to unique challenges. AMD prevalence increases with age, clinical phenotypes are heterogeneous and control collections are prone to high false-negative rates, as many control subjects are likely to develop disease with advancing age. Risk prediction tests have been presented previously, using up to ten genetic markers and a range of self-reported non-genetic variables such as body mass index (BMI) and smoking history. In order to maximise the accuracy of prediction for mainstream genetic testing, we sought to derive a test comparable in performance to earlier testing models but based purely on genetic markers, which are static through life and not subject to misreporting. We report a multicentre assessment of a larger panel of single nucleotide polymorphisms (SNPs) than previously analysed, to improve further the classification performance of a predictive test to estimate the risk of developing choroidal neovascular (CNV) disease. We developed a predictive model based solely on genetic markers and avoided inclusion of self-reported variables (eg smoking history) or non-static factors (BMI, education status) that might otherwise introduce inaccuracies in calculating individual risk estimates. We describe the performance of a test panel comprising 13 SNPs genotyped across a consolidated collection of four patient cohorts obtained from academic centres deemed appropriate for pooling. We report on predictive effect sizes and their classification performance. By incorporating multiple cohorts of homogeneous ethnic origin, we obtained >80 per cent power to detect differences in genetic variants observed between cases and controls. We focused our study on CNV, a subtype of advanced AMD associated with a severe and potentially treatable form of the disease. Lastly, we followed a two-stage strategy involving both test model development and test model validation to present estimates of classification performance anticipated in the larger clinical setting. The model contained nine SNPs tagging variants in the regulators of complement activation (RCA) locus spanning the complement factor H (CFH), complement factor H-related 4 (CFHR4), complement factor H-related 5 (CFHR5) and coagulation factor XIII B subunit (F13B) genes; the four remaining SNPs targeted polymorphisms in the complement component 2 (C2), complement factor B (CFB), complement component 3 (C3) and age-related maculopathy susceptibility protein 2 (ARMS2) genes. The pooled sample size (1,132 CNV cases, 822 controls) allowed for both model development and model validation to confirm the accuracy of risk prediction. At the validation stage, our test model yielded 82 per cent sensitivity and 63 per cent specificity, comparable with metrics reported with earlier testing models that included environmental risk factors. Our test had an area under the curve of 0.80, reflecting a modest improvement compared with tests reported with fewer SNPs.
doi:10.1186/1479-7364-5-5-420
PMCID: PMC3525964  PMID: 21807600
age-related macular degeneration (AMD); choroidal neovascularisation (CNV); complement factor H (CFH); genetic testing
7.  Cost-effectiveness of smoking cessation to prevent age-related macular degeneration 
Background
Tobacco smoking is a risk factor for age-related macular degeneration, but studies of ex-smokers suggest quitting can reduce the risk.
Methods
We fitted a function predicting the decline in risk of macular degeneration after quitting to data from 7 studies involving 1,488 patients. We assessed the cost-effectiveness of smoking cessation in terms of its impact on macular degeneration-related outcomes for 1,000 randomly selected U.S. smokers. We used a computer simulation model to predict the incidence of macular degeneration and blindness, the number of quality-adjusted life-years (QALYs), and direct costs (in 2004 U.S. dollars) until age 85 years. Cost-effectiveness ratios were based on the cost of the Massachusetts Tobacco Control Program. Costs and QALYs were discounted at 3% per year.
Results
If 1,000 smokers quit, our model predicted 48 fewer cases of macular degeneration, 12 fewer cases of blindness, and a gain of 1,600 QALYs. Macular degeneration-related costs would decrease by $2.5 million if the costs of caregivers for people with vision loss were included, or by $1.1 million if caregiver costs were excluded. At a cost of $1,400 per quitter, smoking cessation was cost-saving when caregiver costs were included, and cost about $200 per QALY gained when caregiver costs were excluded. Sensitivity analyses had a negligible impact. The cost per quitter would have to exceed $77,000 for the cost per QALY for smoking cessation to reach $50,000, a threshold above which interventions are sometimes viewed as not cost-effective.
Conclusion
Smoking cessation is unequivocally cost-effective in terms of its impact on age-related macular degeneration outcomes alone.
doi:10.1186/1478-7547-6-18
PMCID: PMC2562365  PMID: 18783631
8.  Can HMG Co-A reductase inhibitors (“statins”) slow the progression of age-related macular degeneration? The Age-Related Maculopathy Statin Study (ARMSS) 
Clinical Interventions in Aging  2008;3(3):581-593.
Age-related macular degeneration (AMD) is responsible for the majority of visual impairment in the Western world. The role of cholesterol-lowering medications, HMG Co-A reductase inhibitors or statins, in reducing the risk of AMD or of delaying its progression has not been fully investigated. A 3-year prospective randomized controlled trial of 40 mg simvastatin per day compared to placebo in subjects at high risk of AMD progression is described. This paper outlines the primary aims of the Age-Related Maculopathy Statin Study (ARMSS), and the methodology involved. Standardized clinical grading of macular photographs and comparison of serial macular digital photographs, using the International grading scheme, form the basis for assessment of primary study outcomes. In addition, macular function is assessed at each visit with detailed psychophysical measurements of rod and cone function. Information collected in this study will assist in the assessment of the potential value of HMG Co-A reductase inhibitors (statins) in reducing the risk of AMD progression.
PMCID: PMC2682391  PMID: 18982929
age-related macular degeneration; progression; randomized controlled trial; HMG Co-A reductase inhibitor; statin; visual function
9.  Cost-effectiveness of ranibizumab for neovascular age-related macular degeneration 
Background
Intravitreal ranibizumab prevents vision loss and improves visual acuity in patients with neovascular age-related macular degeneration, but it is expensive, and efficacy beyond 2 years is uncertain.
Methods
We assessed the cost-effectiveness of ranibizumab compared with no ranibizumab over 10 years, using randomized trial efficacy data for the first 2 years, post-trial efficacy assumptions, and ranibizumab acquisition costs ranging from the wholesale price ($1,950 per dose) to the price of bevazicumab ($50), a similar molecule which may be equally efficacious. We used a computer simulation model to estimate the probability of blindness, the number of quality-adjusted life-years (QALYs), direct costs (in 2004 U.S. dollars), and cost-effectiveness ratios for a 67-year old woman. Costs and QALYs were discounted at 3% per year.
Results
The probability of blindness over 10 years was reduced from 56% to 34% if ranibizumab was efficacious for only 2 years, 27% if efficacy was maintained for a further 2 years only (base-case scenario), and 17% if visual acuity at 4 years was then sustained. It was cost-saving under all price assumptions, when caregiver costs were included. When caregiver costs were excluded, the cost per QALY for the base-case ranged from $5,600, assuming the bevazicumab price, to $91,900 assuming the wholesale ranibizumab price. The cost per QALY was < $50,000 when the cost of ranibizumab was less than $1000.
Conclusion
From a societal perspective, ranibizumab was cost-saving. From a health care funder's perspective, ranibizumab was an efficient treatment when it cost less than $1000 per dose.
doi:10.1186/1478-7547-6-12
PMCID: PMC2443361  PMID: 18573218
10.  Dietary antioxidants and primary prevention of age related macular degeneration: systematic review and meta-analysis 
BMJ : British Medical Journal  2007;335(7623):755.
Objective To evaluate the effectiveness of dietary antioxidants in the primary prevention of age related macular degeneration (AMD).
Design Systematic review and meta-analysis.
Data sources Search of seven databases without limits on year or language of publication, and retrieval of references in pertinent reviews and articles.
Methods Two reviewers independently searched the databases and selected the studies, using standardised criteria. Randomised clinical trials and prospective cohort studies were included. Of the 4192 abstracts initially identified, 12 studies (nine prospective cohort studies and three randomised clinical trials) met the selection criteria and were included. Data extraction and study quality evaluation were independently reviewed, using standardised criteria. Results were pooled quantitatively using meta-analytic methods.
Results The nine prospective cohort studies included 149 203 people, with 1878 incident cases of early AMD. The antioxidants investigated differed across studies, and not all studies contributed to the meta-analysis of each antioxidant. Pooled results from prospective cohort studies indicated that vitamin A, vitamin C, vitamin E, zinc, lutein, zeaxanthin, α carotene, β carotene, β cryptoxanthin, and lycopene have little or no effect in the primary prevention of early AMD. The three randomised clinical trials did not show that antioxidant supplements prevented early AMD.
Conclusions There is insufficient evidence to support the role of dietary antioxidants, including the use of dietary antioxidant supplements, for the primary prevention of early AMD.
doi:10.1136/bmj.39350.500428.47
PMCID: PMC2018774  PMID: 17923720
11.  Hypomethylation of IL17RC Promoter Associates with Age-related Macular Degeneration 
Cell reports  2012;2(5):1151-1158.
SUMMARY
Age related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly population worldwide. While recent studies have demonstrated strong genetic associations of single nucleotide polymorphisms within a number of genes and AMD, other modes of regulation are also likely to play a role in its etiology. We identified a significantly decreased level of methylation on the IL17RC promoter in AMD patients. Further, we showed that hypomethylation of the IL17RC promoter in AMD patients led to an elevated expression of its protein and mRNA in peripheral blood as well as in the affected retina and choroid, suggesting that the DNA methylation pattern and expression of IL17RC may potentially serve as a biomarker for the diagnosis of AMD and likely plays a role in disease pathogenesis.
doi:10.1016/j.celrep.2012.10.013
PMCID: PMC3513594  PMID: 23177625
12.  Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration 
Human Molecular Genetics  2011;20(18):3699-3709.
Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P = 1.1 × 10−8] and rs4711751 on 6p12 near VEGFA (OR 1.15; P = 8.7 × 10−9). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genome-wide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD.
doi:10.1093/hmg/ddr270
PMCID: PMC3159552  PMID: 21665990

Results 1-12 (12)