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1. A Multi-Omics Approach Identifies Key Regulatory Pathways Induced by Long-Term Zinc Supplementation in Human Primary Retinal Pigment Epithelium

Author

Emri, E, Kortvely, E, Dammeier, S, Klose, F, Simpson, D, Hollander, AI, Ueffing, M, Lengyel, I, Acar, E, Ajana, S, Arango?gonzalez, B, Armento, A, Badura, F, Bartz?schmidt, U, Biarnes, M, Borrell, A, de Breuk, A, De la Cerda, B, Colijn, Annemarie, Cougnard?gregoire, A, Delcourt, C, Diether, S, Endermann, T, Ferraro, LL, Garcia, M, Heesterbeek, TJ, Honisch, S, Kilger, E, Klaver, Caroline, Langen, H, Meester - Smoor, Magda, Merle, BMJ, Mones, J, Nogoceke, E, Peto, T, Pool, FM, Rodriguez, E, Sousa, J, Thee, Eric, Verzijden, T (Timo), Zumbansen, M, and Ophthalmology

Subjects
0301 basic medicine, proteome, retinal pigment epithelium, lcsh:TX341-641, Biology, medicine.disease_cause, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Article, Transforming Growth Factor beta1, Transcriptome, Macular Degeneration, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, TGFB1, Cell Adhesion, Electric Impedance, medicine, Humans, Micronutrients, Cell adhesion, age-related macular degeneration, Cells, Cultured, Nutrition and Dietetics, Retinal pigment epithelium, Microvilli, Pigmentation, zinc, Cell Polarity, gene set enrichment, Extracellular Matrix, Cell biology, Oxidative Stress, Protein Transport, secretome, 030104 developmental biology, medicine.anatomical_structure, Secretory protein, Cell culture, Proteome, 030221 ophthalmology & optometry, sense organs, transcriptome, lcsh:Nutrition. Foods and food supply, Oxidative stress, Signal Transduction, Food Science, Extracellular matrix organization
Abstract

In age-related macular degeneration (AMD), both systemic and local zinc levels decline. Elevation of zinc in clinical studies delayed the progression to end-stage AMD. However, the molecular pathways underpinning this beneficial effect are not yet identified. In this study, we used differentiated primary human fetal retinal pigment epithelium (RPE) cultures and long-term zinc supplementation to carry out a combined transcriptome, proteome and secretome analysis from three genetically different human donors. After combining significant differences, we identified the complex molecular networks using Database for Annotation, Visualization and Integrated Discovery (DAVID) and Ingenuity Pathway Analysis (IPA). The cell cultures from the three donors showed extensive pigmentation, development of microvilli and basal infoldings and responded to zinc supplementation with an increase in transepithelial electrical resistance (TEER) (apical supplementation: 443.2 &plusmn, 79.3%, basal supplementation: 424.9 &plusmn, 116.8%, compared to control: 317.5 &plusmn, 98.2%). Significant changes were observed in the expression of 1044 genes, 151 cellular proteins and 124 secreted proteins. Gene set enrichment analysis revealed changes in specific molecular pathways related to cell adhesion/polarity, extracellular matrix organization, protein processing/transport, and oxidative stress response by zinc and identified a key upstream regulator effect similar to that of TGFB1.

Published
2020
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2. Integrating Metabolomics, Genomics, and Disease Pathways in Age-Related Macular Degeneration: The EYE-RISK Consortium

Author

Acar, ?E, Lores-Motta, L, Colijn, Annemarie, Smoor, Magda, Verzijden, T (Timo), Cougnard-Gregoire, A, Ajana, S, Merle, BMJ, de Breuk, A, Heesterbeek, TJ, Akker, Erik, Daha, MR, Claes, B, Pauleikhoff, D, Hense, H W, Duijn, Cornelia, Fauser, S, Hoyng, CB, Delcourt, C, Klaver, Caroline, Galesloot, TE, Hollander, AI, Arango-Gonzalez, B, Armento, A, Badura, F, Bhatia, V, Bhattacharya, SS, Biarnés, M, Borrell, A, Calado, SM, Dammeier, S, Cerda, BDL, Diaz-Corrales, FJ, Diether, S, Emri, E, Endermann, T, Ferraro, LL, Garcia, M, Honisch, S, Kilger, E, Kortvely, E, Lastrucci, C, Langen, H, Lengyel, I, Luthert, P, Monés, J, Nogoceke, E, Peto, T, Pool, FM, Rodriguez-Bocanegra, E, Serrano, L, Sousa, J, Thee, E, Ueffing, M, Ulrich Bartz-Schmidt, KU, Zumbansen, M, Epidemiology, and Ophthalmology

Published
2020

3. Genotype- and Phenotype-Based Subgroups in Geographic Atrophy Secondary to Age-Related Macular Degeneration: The EYE-RISK Consortium

Author

Biarnés, M. (Marc), Colijn, J.M. (Johanna), Sousa, J. (Jose), Ferraro, L.L. (Lucia L.), Garcia, M. (Míriam), Verzijden, T. (Timo), Meester-Smoor, M.A. (Magda), Delcourt, C. (Cécile), Klaver, C.C.W. (Caroline), Hollander, A.I. (Anneke), Lengyel, I. (Imre), Peto, T. (Tünde), Monés, J. (Jordi), Biarnés, M. (Marc), Colijn, J.M. (Johanna), Sousa, J. (Jose), Ferraro, L.L. (Lucia L.), Garcia, M. (Míriam), Verzijden, T. (Timo), Meester-Smoor, M.A. (Magda), Delcourt, C. (Cécile), Klaver, C.C.W. (Caroline), Hollander, A.I. (Anneke), Lengyel, I. (Imre), Peto, T. (Tünde), and Monés, J. (Jordi)

Abstract

Purpose: Geographic atrophy (GA) secondary to age-related macular degeneration is considered a single entity. This study aimed to determine whether GA subgroups exist that can be defined by their genotype and phenotype. Design: Retrospective analysis of cross-sectional data. Participants: Individuals (196 eyes of 196 patients) 50 years of age or older with GA from the EYE-RISK database. Methods: Participants were graded for the presence of each of the following fundus features on color fundus photography: large soft drusen, reticular pseudodrusen (RPD), refractile drusen, hyperpigmentation, location of atrophy (foveal vs. extrafoveal), and multifocal lesions. Genotypes of 33 single nucleotide polymorphisms previously assigned to

Published
2020
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4. A Deep Learning Model for Segmentation of Geographic Atrophy to Study Its Long-Term Natural History

Author

Liefers, B. (Bart), Colijn, J.M. (Johanna), González-Gonzalo, C. (Cristina), Verzijden, T. (Timo), Wang, J.J. (Jie Jin), Joachim, N. (Nichole), Mitchell, P. (Paul), Hoyng, C.B. (Carel), Ginneken, B.T.J. (Berbke) van, Klaver, C.C.W. (Caroline), Sánchez, C.I. (Clara), Liefers, B. (Bart), Colijn, J.M. (Johanna), González-Gonzalo, C. (Cristina), Verzijden, T. (Timo), Wang, J.J. (Jie Jin), Joachim, N. (Nichole), Mitchell, P. (Paul), Hoyng, C.B. (Carel), Ginneken, B.T.J. (Berbke) van, Klaver, C.C.W. (Caroline), and Sánchez, C.I. (Clara)

Abstract

__Purpose:__ To develop and validate a deep learning model for the automatic segmentation of geographic atrophy (GA) using color fundus images (CFIs) and its application to study the growth rate of GA. __Design:__ Prospective, multicenter, natural history study with up to 15 years of follow-up. __Participants:__ Four hundred nine CFIs of 238 eyes with GA from the Rotterdam Study (RS) and Blue Mountain Eye Study (BMES) for model development, and 3589 CFIs of 376 eyes from the Age-Related Eye Disease Study (AREDS) for analysis of GA growth rate. __Methods:__ A deep learning model based on an ensemble of encoder–decoder architectures was implemented and optimized for the segmentation of GA in CFIs. Four experienced graders delineated, in consensus, GA in CFIs from the RS and BMES. These manual delineations were used to evaluate the segmentation model using 5-fold cross-validation. The model was applied further to CFIs from the AREDS to study the growth rate of GA. Linear regression analysis was used to study associations between structural biomarkers at baseline and the GA growth rate. A general estimate of the progression of GA area over time was made by combining growth rates of all eyes with GA from the AREDS set. __Main Outcome Measures:__ Automatically segmented GA and GA growth rate. __Results:__ The model obtained an average Dice coefficient of 0.72±0.26 on the BMES and RS set while comparing the automatically segmented GA area with the graders’ manual delineations. An intraclass correlation coefficient of 0.83 was reached between the automatically estimated GA area and the graders’ consensus measures. Nine automatically calculated structural biomarkers (area, filled area, convex area, convex solidity, eccentricity, roundness, foveal involvement, perimeter, and circularity) were significantly associated with growth rate. Combining all growth rates indicated that GA area grows quadratically up to an area of approximately 12 mm2, after which growth rate stabilizes

Published
2020
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6. A multi?omics approach identifies key regulatory pathways induced by long?term zinc supplementation in human primary retinal pigment epithelium

Author

Emri, E, Kortvely, E, Dammeier, S, Klose, F, Simpson, D, Hollander, AI, Ueffing, M, Lengyel, I, Acar, E, Ajana, S, Arango?gonzalez, B, Armento, A, Badura, F, Bartz?schmidt, U, Biarnes, M, Borrell, A, de Breuk, A, De la Cerda, B, Colijn, Annemarie, Cougnard?gregoire, A, Delcourt, C, Diether, S, Endermann, T, Ferraro, LL, Garcia, M, Heesterbeek, TJ, Honisch, S, Kilger, E, Klaver, Caroline, Langen, H, Meester - Smoor, Magda, Merle, BMJ, Mones, J, Nogoceke, E, Peto, T, Pool, FM, Rodriguez, E, Sousa, J, Thee, Eric, Verzijden, T (Timo), Zumbansen, M, Emri, E, Kortvely, E, Dammeier, S, Klose, F, Simpson, D, Hollander, AI, Ueffing, M, Lengyel, I, Acar, E, Ajana, S, Arango?gonzalez, B, Armento, A, Badura, F, Bartz?schmidt, U, Biarnes, M, Borrell, A, de Breuk, A, De la Cerda, B, Colijn, Annemarie, Cougnard?gregoire, A, Delcourt, C, Diether, S, Endermann, T, Ferraro, LL, Garcia, M, Heesterbeek, TJ, Honisch, S, Kilger, E, Klaver, Caroline, Langen, H, Meester - Smoor, Magda, Merle, BMJ, Mones, J, Nogoceke, E, Peto, T, Pool, FM, Rodriguez, E, Sousa, J, Thee, Eric, Verzijden, T (Timo), and Zumbansen, M

Published
2020

7. Genotype- and Phenotype-Based Subgroups in Geographic Atrophy Secondary to Age-Related Macular Degeneration: The EYE-RISK Consortium

Author

Biarnés, M, Colijn, Annemarie, Sousa, J, Ferraro, LL, Garcia, M, Verzijden, T (Timo), Meester - Smoor, Magda, Delcourt, C, Klaver, Caroline, Hollander, AI, Lengyel, I, Peto, T, Monés, J, Biarnés, M, Colijn, Annemarie, Sousa, J, Ferraro, LL, Garcia, M, Verzijden, T (Timo), Meester - Smoor, Magda, Delcourt, C, Klaver, Caroline, Hollander, AI, Lengyel, I, Peto, T, and Monés, J

Published
2020

9. Prevalence of Age-Related Macular Degeneration in Europe: The Past and the Future

Author

Colijn, J.M. (Johanna), Buitendijk, G.H.S. (Gabrielle), Prokofyeva, E. (Elena), Alves, D. (Dalila), Cachulo, M.L. (Maria L.), Khawaja, A.P. (Anthony), Cougnard-Grégoire, A. (Audrey), Merle, B.M.J. (Bénédicte M.J.), Korb, C. (Christina), Erke, M.G. (Maja Gran), Bron, A. (Alain), Anastasopoulos, E. (Eleftherios), Meester-Smoor, M.A. (Magda), Segato, T. (Tatiana), Piermarocchi, S. (Stefano), Jong, P.T.V.M. (Paulus) de, Vingerling, J.R. (Hans), Topouzis, F. (Fotis), Creuzot-Garcher, C. (Catherine), Bertelsen, G. (Geir), Pfeiffer, A.F.H. (Andreas), Fletcher, A.E. (Astrid E.), Foster, P.J. (Paul), Silva, R. (Rufino), Korobelnik, J.-F. (Jean-François), Delcourt, C. (Cécile), Klaver, C.C.W. (Caroline), Ajana, S. (Soufiane), Arango-Gonzalez, B. (Blanca), Arndt, V. (Verena), Bhatia, V. (Vaibhav), Bhattacharya, S.S. (Shomi S.), Biarnés, M. (Marc), Borrell, A. (Anna), Bühren, S. (Sebastian), Calado, S.M. (Sofia M.), Colijn, J.M. (Johanna M.), Dammeier, S. (Sascha), Jong, E.K. (Eiko) de, De la Cerda, B. (Berta), den Hollander, A.I. (Anneke I.), Diaz-Corrales, F.J. (Francisco J.), Diether, S. (Sigrid), Emri, E. (Eszter), Endermann, T. (Tanja), Ferraro, L.L. (Lucia L.), Garcia, M. (Míriam), Heesterbeek, T.J. (Thomas J.), Honisch, S. (Sabina), Hoyng, C.B. (Carel B.), Kersten, E. (Eveline), Kilger, E. (Ellen), Klaver, C.C.W. (Caroline C.W.), Langen, H. (Hanno), Lengyel, I. (Imre), Luthert, P. (Phil), Maugeais, C. (Cyrille), Meester-Smoor, M. (Magda), Monés, J. (Jordi), Nogoceke, E. (Everson), Peto, T. (Tunde), Pool, F.M. (Frances M.), Rodríguez, E. (Eduardo), Ueffing, M. (Marius), Ulrich Bartz-Schmidt, K.U. (Karl U.), van Leeuwen, E.M. (Elisabeth M.), Verzijden, T. (Timo), Zumbansen, M. (Markus), Acar, N. (Niyazi), Anastosopoulos, E. (Eleftherios), Azuara-Blanco, A. (Augusto), Bergen, A.A.B. (Arthur), Binquet, C. (Christine), Bird, A.C. (Alan), Bretillon, L. (Lionel), Buitendijk, G. (Gabrielle), Cachulo, M.L. (Maria Luz), Chakravarthy, U. (Usha), Chan, M. (Michelle), Chang, P. (Petrus), Colijn, J. (Johanna), Cumberland, P. (Phillippa), Cunha-Vaz, J. (José), Daien, V. (Vincent), Deak, G. (Gabor), Delyfer, M.-N. (Marie-Noëlle), Hollander, A.I. (Anneke), Dietzel, M. (Martha), Fauser, S. (Sascha), Finger, R. (Robert), Fletcher, A. (Astrid), Foster, P.J. (Paul J.), Founti, P. (Panayiota), Göbel, A. (Arno), Gorgels, T.G.M.F. (Theo), Grauslund, J. (Jakob), Grus, F. (Franz), Hammond, C.J. (Christopher), Helmer, C. (Catherine), Hense, H.-W. (Hans-Werner), Hermann, M. (Manuel), Hoehn, R. (René), Hogg, R. (Ruth), Holz, F.G. (Frank), Hoyng, C.B. (Carel), Jansonius, N.M. (Nomdo), Janssen, S.F. (Sarah), Khawaja, A. (Anthony), Lamparter, J. (Julia), Le Goff, M. (Mélanie), Leal, S. (Sergio), Lechanteur, Y.T.E. (Yara T. E.), Lehtimäki, T. (Terho), Lotery, A.J. (Andrew), Leung, I. (Irene), Mauschitz, M. (Matthias), Merle, B. (Bénédicte), Meyer zu Westrup, V. (Verena), Midena, E. (Edoardo), Miotto, S. (Stefania), Mirshahi, A. (Alireza), Mohan-Saïd, S. (Sadek), Mueller, M. (Michael), Muldrew, A. (Alyson), Nunes, S. (Sandrina), Oexle, K. (Konrad), Peto, T. (Tünde), Rahi, J. (Jugnoo), Raitakari, O. (Olli), Ribeiro, L. (Luisa), Rougier, M.-B. (Marie-Bénédicte), Sahel, J.-A. (José-Alain), Salonikiou, A. (Aggeliki), Sanchez, C. (Clarisa), Schmitz-Valckenberg, S. (Steffen), Schweitzer, C.M.C. (C. M C), Shehata, J. (Jasmin), Silvestri, G. (Giuliana), Simader, C. (Christian), Souied, E.H. (Eric), Springelkamp, H. (Henriët), Tapp, R. (Robyn), Verhoeven, V. (Virginie), Von Hanno, T. (Therese), Vujosevic, S. (Stela), Williams, K. (Katie), Wolfram, C. (Christian), Yip, J. (Jennifer), Zerbib, J. (Jennyfer), Zwiener, I. (Isabella), Colijn, J.M. (Johanna), Buitendijk, G.H.S. (Gabrielle), Prokofyeva, E. (Elena), Alves, D. (Dalila), Cachulo, M.L. (Maria L.), Khawaja, A.P. (Anthony), Cougnard-Grégoire, A. (Audrey), Merle, B.M.J. (Bénédicte M.J.), Korb, C. (Christina), Erke, M.G. (Maja Gran), Bron, A. (Alain), Anastasopoulos, E. (Eleftherios), Meester-Smoor, M.A. (Magda), Segato, T. (Tatiana), Piermarocchi, S. (Stefano), Jong, P.T.V.M. (Paulus) de, Vingerling, J.R. (Hans), Topouzis, F. (Fotis), Creuzot-Garcher, C. (Catherine), Bertelsen, G. (Geir), Pfeiffer, A.F.H. (Andreas), Fletcher, A.E. (Astrid E.), Foster, P.J. (Paul), Silva, R. (Rufino), Korobelnik, J.-F. (Jean-François), Delcourt, C. (Cécile), Klaver, C.C.W. (Caroline), Ajana, S. (Soufiane), Arango-Gonzalez, B. (Blanca), Arndt, V. (Verena), Bhatia, V. (Vaibhav), Bhattacharya, S.S. (Shomi S.), Biarnés, M. (Marc), Borrell, A. (Anna), Bühren, S. (Sebastian), Calado, S.M. (Sofia M.), Colijn, J.M. (Johanna M.), Dammeier, S. (Sascha), Jong, E.K. (Eiko) de, De la Cerda, B. (Berta), den Hollander, A.I. (Anneke I.), Diaz-Corrales, F.J. (Francisco J.), Diether, S. (Sigrid), Emri, E. (Eszter), Endermann, T. (Tanja), Ferraro, L.L. (Lucia L.), Garcia, M. (Míriam), Heesterbeek, T.J. (Thomas J.), Honisch, S. (Sabina), Hoyng, C.B. (Carel B.), Kersten, E. (Eveline), Kilger, E. (Ellen), Klaver, C.C.W. (Caroline C.W.), Langen, H. (Hanno), Lengyel, I. (Imre), Luthert, P. (Phil), Maugeais, C. (Cyrille), Meester-Smoor, M. (Magda), Monés, J. (Jordi), Nogoceke, E. (Everson), Peto, T. (Tunde), Pool, F.M. (Frances M.), Rodríguez, E. (Eduardo), Ueffing, M. (Marius), Ulrich Bartz-Schmidt, K.U. (Karl U.), van Leeuwen, E.M. (Elisabeth M.), Verzijden, T. (Timo), Zumbansen, M. (Markus), Acar, N. (Niyazi), Anastosopoulos, E. (Eleftherios), Azuara-Blanco, A. (Augusto), Bergen, A.A.B. (Arthur), Binquet, C. (Christine), Bird, A.C. (Alan), Bretillon, L. (Lionel), Buitendijk, G. (Gabrielle), Cachulo, M.L. (Maria Luz), Chakravarthy, U. (Usha), Chan, M. (Michelle), Chang, P. (Petrus), Colijn, J. (Johanna), Cumberland, P. (Phillippa), Cunha-Vaz, J. (José), Daien, V. (Vincent), Deak, G. (Gabor), Delyfer, M.-N. (Marie-Noëlle), Hollander, A.I. (Anneke), Dietzel, M. (Martha), Fauser, S. (Sascha), Finger, R. (Robert), Fletcher, A. (Astrid), Foster, P.J. (Paul J.), Founti, P. (Panayiota), Göbel, A. (Arno), Gorgels, T.G.M.F. (Theo), Grauslund, J. (Jakob), Grus, F. (Franz), Hammond, C.J. (Christopher), Helmer, C. (Catherine), Hense, H.-W. (Hans-Werner), Hermann, M. (Manuel), Hoehn, R. (René), Hogg, R. (Ruth), Holz, F.G. (Frank), Hoyng, C.B. (Carel), Jansonius, N.M. (Nomdo), Janssen, S.F. (Sarah), Khawaja, A. (Anthony), Lamparter, J. (Julia), Le Goff, M. (Mélanie), Leal, S. (Sergio), Lechanteur, Y.T.E. (Yara T. E.), Lehtimäki, T. (Terho), Lotery, A.J. (Andrew), Leung, I. (Irene), Mauschitz, M. (Matthias), Merle, B. (Bénédicte), Meyer zu Westrup, V. (Verena), Midena, E. (Edoardo), Miotto, S. (Stefania), Mirshahi, A. (Alireza), Mohan-Saïd, S. (Sadek), Mueller, M. (Michael), Muldrew, A. (Alyson), Nunes, S. (Sandrina), Oexle, K. (Konrad), Peto, T. (Tünde), Rahi, J. (Jugnoo), Raitakari, O. (Olli), Ribeiro, L. (Luisa), Rougier, M.-B. (Marie-Bénédicte), Sahel, J.-A. (José-Alain), Salonikiou, A. (Aggeliki), Sanchez, C. (Clarisa), Schmitz-Valckenberg, S. (Steffen), Schweitzer, C.M.C. (C. M C), Shehata, J. (Jasmin), Silvestri, G. (Giuliana), Simader, C. (Christian), Souied, E.H. (Eric), Springelkamp, H. (Henriët), Tapp, R. (Robyn), Verhoeven, V. (Virginie), Von Hanno, T. (Therese), Vujosevic, S. (Stela), Williams, K. (Katie), Wolfram, C. (Christian), Yip, J. (Jennifer), Zerbib, J. (Jennyfer), and Zwiener, I. (Isabella)

Abstract

Purpose Age-related macular degeneration (AMD) is a frequent, complex disorder in elderly of European ancestry. Risk profiles and treatment options have changed considerably over the years, which may have affected disease prevalence and outcome. We determined the prevalence of early and late AMD in Europe from 1990 to 2013 using the European Eye Epidemiology (E3) consortium, and made projections for the future. Design Meta-analysis of prevalence data. Participants A total of 42 080 individuals 40 years of age and older participating in 14 population-based cohorts from 10 countries in Europe. Methods AMD was diagnosed based on fundus photographs using the Rotterdam Classification. Prevalence of early and late AMD was calculated using random-effects meta-analysis stratified for age, birth cohort, gender, geographic region, and time period of the study. Best-corrected visual acuity (BCVA) was compared between late AMD subtypes; geographic atrophy (GA) and choroidal neovascularization (CNV). Main Outcome Measures Prevalence of early and late AMD, BCVA, and number of AMD cases. Results Prevalence of early AMD increased from 3.5% (95% confidence interval [CI] 2.1%–5.0%) in those aged 55–59 years to 17.6% (95% C

Published
2017
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