Centre for Eye Research Australia (CERA) - Research Publications

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    Disparities in access to anti-vascular endothelial growth factor treatment for neovascular age-related macular degeneration
    Finger, RP ; Xie, J ; Fotis, K ; Parikh, S ; Cummins, R ; Mitchell, P ; Guymer, RH (WILEY, 2017-03-01)
    BACKGROUND: Late neovascular age-related macular degeneration (nvAMD) is very common and causes irreversible severe visual loss unless treated swiftly with vascular endothelial growth factor (VEGF) inhibitors. Although publicly subsidized access to treatment may be inequitable, which is why we assessed treatment provision across Australia. DESIGN: Secondary analysis of Australian data. PARTICIPANTS: All Pharmaceutical Benefits Scheme (including Repatriation PBS) beneficiaries. METHODS: Treatment and incidence data were obtained from Medicare Australia, the Royal Australian and New Zealand College of Ophthalmologists, Optometry Australia, the Blue Mountains Eye Study and the Australian Bureau of Statistics. Data were mapped using geographical information software, and factors associated with treatment provision were assessed using multiple linear regression models. MAIN OUTCOME MEASURE: Unmet need (%) for anti-VEGF treatment for nvAMD. RESULTS: On average, we estimated 7316 incident cases of nvAMD not to be treated per year from 2010 to 2014 (50.1% of total). Number of ophthalmologists and optometrists (per 1000, β = -0.024; 95% confidence interval [CI] -0.041, -0.007) and being located in remote regions (β = 0.186; 95% CI 0.110, 0.262) were associated with percentage of untreated cases. A higher proportion of the population speaking a language other than English at home was associated in univariate analyses only (β = 0.0015; 95% CI -0.0004, 0.0027; P = 0.007). CONCLUSION: A large proportion of incident nvAMD is not treated with anti-VEGF. Not receiving treatment is more likely in regional or remote areas and areas with fewer service providers. Not speaking English at home may further limit access. Service delivery models for more equitable service provision are needed.
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    Ellipsoid zone on optical coherence tomography: a review
    Tao, LW ; Wu, Z ; Guymer, RH ; Luu, CD (WILEY, 2016-07-01)
    Emergence of the high-resolution optical coherence tomography has allowed better delineation of retinal layers, and many of the anatomical correlations of these layers have now been agreed upon. However, some anatomical correlates still remain contentious, such as the second hyper-reflective band, which is now termed ellipsoid zone. Despite the lack of consensus of the actual origin of the ellipsoid zone, there has been much interest in evaluating its integrity and intensity in different disease processes. This review paper aims to provide an overview of the ellipsoid zone and its clinical and research applications.
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    Relationship between reticular pseudodrusen and choroidal thickness in intermediate age-related macular degeneration: response
    Ho, CYD ; Lek, JJ ; Aung, KZ ; McGuinness, MB ; Luu, CD ; Guymer, RH (WILEY, 2018-11-01)
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    Relationship between reticular pseudodrusen and choroidal thickness in intermediate age-related macular degeneration
    Ho, CYD ; Lek, JJ ; Aung, KZ ; McGuinness, MB ; Luu, CD ; Guymer, RH (WILEY, 2018-07-01)
    IMPORTANCE: Reticular pseudodrusen (RPD) is strongly associated with late age-related macular degeneration (AMD) but their aetiology remains unknown. RPD have been associated with reduced choroidal thickness (ChT) but most studies are limited by small sample size and varying severity of AMD. BACKGROUND: To investigate the relationship between choroidal thickness and RPD in eyes with intermediate AMD (iAMD), controlling for variables known to influence ChT. DESIGN: Retrospective cohort study. PARTICIPANTS: Participants were recruited from Centre for Eye Research Australia. METHODS: Colour fundus photographs, fundus auto fluorescence, near-infrared and spectral-domain ocular coherence tomography (OCT) were graded for RPD. ChT was measured from enhanced-depth imaging OCT scans at the centre of fovea, 1500 and 3000 μm nasal, temporal, superior and inferior from centre of fovea. MAIN OUTCOME MEASURES: ChT between RPD and non-RPD group. RESULTS: A total of 297 eyes from 152 subjects were included. A total of 84 (28%) had RPD and were older than non-RPD group (75.1 ± 5.4 years and 68.7 ± 6.9 years, respectively; P < 0.001). In unadjusted analysis, the RPD group was significantly associated with thinner choroids across all measured locations (P ≤ 0.022). After adjustment for variables, the presence of RPD was no longer associated with ChT (P ≥ 0.132 for all locations) but age (P < 0.001) and refractive error (P = 0.002) remained significantly associated with ChT. CONCLUSIONS AND RELEVANCE: Age and refractive error, rather than RPD, was significantly associated with reduced ChT in eyes with iAMD. Choroidal insufficiency may be a less important variable in RPD aetiology than previously considered.
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    Multi-focal electro-retinogram response following sub-threshold nano-second laser intervention in age-related macular degeneration
    Luu, CD ; Makeyeva, G ; Caruso, E ; Baglin, E ; Sivarajah, P ; Wu, Z ; Guymer, RH (WILEY, 2020-08-04)
    IMPORTANCE: The effect of sub-threshold nano-second laser (SNL) treatment on retinal function remains unknown. BACKGROUND: SNL treatment has been studied as a potential intervention in intermediate age-related macular degeneration (iAMD). This study investigated the longitudinal effect of SNL treatment on retinal function. DESIGN: This was a sub-study of the LEAD trial; a 36-month, multi-centre, randomized and sham-controlled trial. PARTICIPANTS: Subjects with iAMD. METHODS: Eligible participants were assigned randomly to receive SNL or sham treatment to the study eye at 6-monthly visits. Multi-focal electro-retinography (mfERG) was performed at each study visit from a study site. The mfERG responses were grouped into three regions (central, middle and outer rings) and compared between the SNL and sham group. MAIN OUTCOME MEASURES: mfERG P1 response amplitude and implicit time. RESULTS: Data were collected from 50 subjects (26 in the SNL group, 24 in the sham group). At baseline, the P1 amplitudes of both the study eyes and the fellow eyes were similar between the groups at all rings. In the sham group, the P1 amplitude gradually decreased over time (P < .05). In the SNL group, there was an improvement in P1 amplitude which became statistically significant at the 36-month visit, detected in both the treated and fellow eyes at the central (P = .005) and middle ring (P = .007) but not at the outer ring (P = .070). No difference in P1 implicit time detected between the groups (P > .05). CONCLUSIONS AND RELEVANCE: SNL treatment improved electro-physiological function. mfERG could be useful for monitoring AMD progression and evaluating the efficacy of SNL treatment.
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    A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants
    Fritsche, LG ; Igl, W ; Bailey, JNC ; Grassmann, F ; Sengupta, S ; Bragg-Gresham, JL ; Burdon, KP ; Hebbring, SJ ; Wen, C ; Gorski, M ; Kim, IK ; Cho, D ; Zack, D ; Souied, E ; Scholl, HPN ; Bala, E ; Lee, KE ; Hunter, DJ ; Sardell, RJ ; Mitchell, P ; Merriam, JE ; Cipriani, V ; Hoffman, JD ; Schick, T ; Lechanteur, YTE ; Guymer, RH ; Johnson, MP ; Jiang, Y ; Stanton, CM ; Buitendijk, GHS ; Zhan, X ; Kwong, AM ; Boleda, A ; Brooks, M ; Gieser, L ; Ratnapriya, R ; Branham, KE ; Foerster, JR ; Heckenlively, JR ; Othman, MI ; Vote, BJ ; Liang, HH ; Souzeau, E ; McAllister, IL ; Isaacs, T ; Hall, J ; Lake, S ; Mackey, DA ; Constable, IJ ; Craig, JE ; Kitchner, TE ; Yang, Z ; Su, Z ; Luo, H ; Chen, D ; Hong, O ; Flagg, K ; Lin, D ; Mao, G ; Ferreyra, H ; Starke, K ; von Strachwitz, CN ; Wolf, A ; Brandl, C ; Rudolph, G ; Olden, M ; Morrison, MA ; Morgan, DJ ; Schu, M ; Ahn, J ; Silvestri, G ; Tsironi, EE ; Park, KH ; Farrer, LA ; Orlin, A ; Brucker, A ; Li, M ; Curcio, CA ; Mohand-Said, S ; Sahel, J-M ; Audo, I ; Benchaboune, M ; Cree, AJ ; Rennie, CA ; Goverdhan, SV ; Grunin, M ; Hagbi-Levi, S ; Campochiaro, P ; Katsanis, N ; Holz, FG ; Blond, F ; Blanche, H ; Deleuze, J-F ; Igo, RP ; Truitt, B ; Peachey, NS ; Meuer, SM ; Myers, CE ; Moore, EL ; Klein, R ; Hauser, MA ; Postel, EA ; Courtenay, MD ; Schwartz, SG ; Kovach, JL ; Scott, WK ; Liew, G ; Tan, AG ; Gopinath, B ; Merriam, JC ; Smith, RT ; Khan, JC ; Shahid, H ; Moore, AT ; McGrath, JA ; Laux, R ; Brantley, MA ; Agarwal, A ; Ersoy, L ; Caramoy, A ; Langmann, T ; Saksens, NTM ; de Jong, EK ; Hoyng, CB ; Cain, MS ; Richardson, AJ ; Martin, TM ; Blangero, J ; Weeks, DE ; Dhillon, B ; van Duijn, CM ; Doheny, KF ; Romm, J ; Klaver, CCW ; Hayward, C ; Gorin, MB ; Klein, ML ; Baird, PN ; den Hollander, AI ; Fauser, S ; Yates, JRW ; Allikmets, R ; Wang, JJ ; Schaumberg, DA ; Klein, BEK ; Hagstrom, SA ; Chowers, I ; Lotery, AJ ; Leveillard, T ; Zhang, K ; Brilliant, MH ; Hewitt, AW ; Swaroop, A ; Chew, EY ; Pericak-Vance, MA ; DeAngelis, M ; Stambolian, D ; Haines, JL ; Iyengar, SK ; Weber, BHF ; Abecasis, GR ; Heid, IM (NATURE PUBLISHING GROUP, 2016-02-01)
    Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.
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    Seven new loci associated with age-related macular degeneration
    Fritsche, LG ; Chen, W ; Schu, M ; Yaspan, BL ; Yu, Y ; Thorleifsson, G ; Zack, DJ ; Arakawa, S ; Cipriani, V ; Ripke, S ; Igo, RP ; Buitendijk, GHS ; Sim, X ; Weeks, DE ; Guymer, RH ; Merriam, JE ; Francis, PJ ; Hannum, G ; Agarwal, A ; Armbrecht, AM ; Audo, I ; Aung, T ; Barile, GR ; Benchaboune, M ; Bird, AC ; Bishop, PN ; Branham, KE ; Brooks, M ; Brucker, AJ ; Cade, WH ; Cain, MS ; Campochiaroll, PA ; Chan, C-C ; Cheng, C-Y ; Chew, EY ; Chin, KA ; Chowers, I ; Clayton, DG ; Cojocaru, R ; Conley, YP ; Cornes, BK ; Daly, MJ ; Dhillon, B ; Edwards, A ; Evangelou, E ; Fagemess, J ; Ferreyra, HA ; Friedman, JS ; Geirsdottir, A ; George, RJ ; Gieger, C ; Gupta, N ; Hagstrom, SA ; Harding, SP ; Haritoglou, C ; Heckenlively, JR ; Hoz, FG ; Hughes, G ; Ioannidis, JPA ; Ishibashi, T ; Joseph, P ; Jun, G ; Kamatani, Y ; Katsanis, N ; Keilhauer, CN ; Khan, JC ; Kim, IK ; Kiyohara, Y ; Klein, BEK ; Klein, R ; Kovach, JL ; Kozak, I ; Lee, CJ ; Lee, KE ; Lichtner, P ; Lotery, AJ ; Meitinger, T ; Mitchell, P ; Mohand-Saied, S ; Moore, AT ; Morgan, DJ ; Morrison, MA ; Myers, CE ; Naj, AC ; Nakamura, Y ; Okada, Y ; Orlin, A ; Ortube, MC ; Othman, MI ; Pappas, C ; Park, KH ; Pauer, GJT ; Peachey, NS ; Poch, O ; Priya, RR ; Reynolds, R ; Richardson, AJ ; Ripp, R ; Rudolph, G ; Ryu, E ; Sahel, J-A ; Schaumberg, DA ; Scholl, HPN ; Schwartz, SG ; Scott, WK ; Shahid, H ; Sigurdsson, H ; Silvestri, G ; Sivakumaran, TA ; Smith, RT ; Sobrin, L ; Souied, EH ; Stambolian, DE ; Stefansson, H ; Sturgill-Short, GM ; Takahashi, A ; Tosakulwong, N ; Truitt, BJ ; Tsironi, EE ; Uitterlinden, AG ; van Duijn, CM ; Vijaya, L ; Vingerling, JR ; Vithana, EN ; Webster, AR ; Wichmann, H-E ; Winkler, TW ; Wong, TY ; Wright, AF ; Zelenika, D ; Zhang, M ; Zhao, L ; Zhang, K ; Klein, ML ; Hageman, GS ; Lathrop, GM ; Stefansson, K ; Allikmets, R ; Baird, PN ; Gorin, MB ; Wang, JJ ; Klaver, CCW ; Seddon, JM ; Pericak-Vance, MA ; Iyengar, SK ; Yates, JRW ; Swaroop, A ; Weber, BHF ; Kubo, M ; DeAngelis, MM ; Leveillard, T ; Thorsteinsdottir, U ; Haines, JL ; Farrer, LA ; Heid, IM ; Abecasis, GR (NATURE PUBLISHING GROUP, 2013-04-01)
    Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 × 10(-8). These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P < 5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.
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    Can HMG Co-A reductase inhibitors ("statins") slow the progression of age-related macular degeneration? The Age-Related Maculopathy Statin Study (ARMSS)
    Guymer, RH ; Dimitrov, PN ; Varsamidis, M ; Lim, LL ; Baird, PN ; Vingrys, AJ ; Robman, L (DOVE MEDICAL PRESS LTD, 2008-01-01)
    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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    Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration
    Yu, Y ; Bhangale, TR ; Fagerness, J ; Ripke, S ; Thorleifsson, G ; Tan, PL ; Souied, EH ; Richardson, AJ ; Merriam, JE ; Buitendijk, GHS ; Reynolds, R ; Raychaudhuri, S ; Chin, KA ; Sobrin, L ; Evangelou, E ; Lee, PH ; Lee, AY ; Leveziel, N ; Zack, DJ ; Campochiaro, B ; Campochiaro, P ; Smith, RT ; Barile, GR ; Guymer, RH ; Hogg, R ; Chakravarthy, U ; Robman, LD ; Gustafsson, O ; Sigurdsson, H ; Ortmann, W ; Behrens, TW ; Stefansson, K ; Uitterlinden, AG ; van Duijn, CM ; Vingerling, JR ; Klaver, CCW ; Allikmets, R ; Brantley, MA ; Baird, PN ; Katsanis, N ; Thorsteinsdottir, U ; Ioannidis, JPA ; Daly, MJ ; Graham, RR ; Seddon, JM (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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    Proof of Concept, Randomized, Placebo-Controlled Study of the Effect of Simvastatin on the Course of Age-Related Macular Degeneration
    Guymer, RH ; Baird, PN ; Varsamidis, M ; Busija, L ; Dimitrov, PN ; Aung, KZ ; Makeyeva, GA ; Richardson, AJ ; Lim, L ; Robman, LD ; Wedrich, A (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. 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.