Centre for Eye Research Australia (CERA) - Research Publications
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ItemNo Preview AvailableCan HMG Co-A reductase inhibitors ("statins") slow the progression of age-related macular degeneration? The Age-Related Maculopathy Statin Study (ARMSS)(DOVE MEDICAL PRESS LTD, 2008)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.
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ItemCommon variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration(OXFORD UNIV PRESS, 2011-09-15)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.
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ItemProof of Concept, Randomized, Placebo-Controlled Study of the Effect of Simvastatin on the Course of Age-Related Macular Degeneration(PUBLIC LIBRARY SCIENCE, 2013-12-31)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. 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.
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ItemNovel measures of cardiovascular health and its association with prevalence and progression of age-related macular degeneration: the CHARM study(BMC, 2008)BACKGROUND: To determine if novel measures of cardiovascular health are associated with prevalence or progression of age-related macular degeneration (AMD). METHODS: Measures of the cardiovascular system: included intima media thickness (IMT), pulse wave velocity (PWV), systemic arterial compliance (SAC), carotid augmentation index (AI). For the prevalence study, hospital-based AMD cases and population-based age- and gender-matched controls with no signs of AMD in either eye were enrolled. For the progression component, participants with early AMD were recruited from two previous studies; cases were defined as progression in one or both eyes and controls were defined as no progression in either eye. RESULTS: 160 cases and 160 controls were included in the prevalence component. The upper two quartiles of SAC, implying good cardiovascular health, were significantly associated with increased risk of AMD (OR = 2.54, 95% CL = 1.29, 4.99). High PWV was associated with increased prevalent AMD. Progression was observed in 82 (32.3%) of the 254 subjects recruited for the progression component. Higher AI (worse cardiovascular function) was protective for AMD progression (OR = 0.30, 95%CL = 0.13, 0.69). Higher aortic PWV was associated with increased risk of AMD progression; the highest risk was seen with the second lowest velocity (OR = 6.22, 95% CL = 2.35, 16.46). CONCLUSION: The results were unexpected in that better cardiovascular health was associated with increased risk of prevalent AMD and progression. Inconsistent findings between the prevalence and progression components could be due to truly different disease etiologies or to spurious findings, as can occur with inherent biases in case control studies of prevalence. Further investigation of these non-invasive methods of characterizing the cardiovascular system should be undertaken as they may help to further elucidate the role of the cardiovascular system in the etiology of prevalent AMD and progression.