The Phenotypic Course of Age-Related Macular Degeneration for ARMS2/HTRA1: The EYE-RISK Consortium

Eric F. Thee, Johanna M. Colijn, European Eye Epidemiology Consortium and EYE-RISK Project, Audrey Cougnard-Grégoire, Magda A. Meester-Smoor, Timo Verzijden, Carel B. Hoyng, Sascha Fauser, Hans Werner Hense, Rufino Silva, Catherine Creuzot-Garcher, Marius Ueffing, Cécile Delcourt, Anneke I. den Hollander, Caroline C.W. Klaver*

*Corresponding author for this work

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Abstract

Purpose: Age-related maculopathy susceptibility 2 (ARMS2) is considered the most enigmatic of the genes for age-related macular degeneration (AMD). We investigated the phenotypic course and spectrum of AMD for the risk haplotype at the ARMS2 and high-temperature requirement A serine peptidase 1 (HTRA1) locus in a large European consortium. Design: Pooled analysis of 4 case-control and 6 cohort studies. Participants: Individuals (N = 17 204) aged 55 years or older participating in the European Eye Epidemiology consortium. Methods: Age-related macular degeneration features and macular thickness were determined on multimodal images; data on genetics and phenotype were harmonized. Risks of AMD features for rs3750486 genotypes at the ARMS2/HTRA1 locus were determined by logistic regression and were compared with a genetic risk score (GRS) of 19 variants at the complement pathway. Lifetime risks were estimated with Kaplan–Meier analyses in population-based cohorts. Main Outcome Measures: Age-related macular degeneration features and stage. Results: Of 2068 individuals with late AMD, 64.7% carried the ARMS2/HTRA1 risk allele. For homozygous carriers, the odds ratio (OR) of geographic atrophy was 8.6 (95% confidence interval [CI], 6.5–11.4), of choroidal neovascularization (CNV) was 11.2 (95% CI, 9.4–13.3), and of mixed late AMD was 12.2 (95% CI, 7.3–20.6). Cumulative lifetime risk of late AMD ranged from 4.4% for carriers of the nonrisk genotype to 9.4% and 26.8% for heterozygous and homozygous carriers. The latter received the diagnosis of late AMD 9.6 years (95% CI, 8.0–11.2) earlier than carriers of the nonrisk genotype. The risk haplotype was not associated with hard or soft drusen < 125 μm (OR, 1.2; 95% CI, 0.9–1.7), but risks increased significantly for soft drusen ≥ 125 μm (OR, 2.1; 95% CI, 1.5–3.0), up to an OR of 7.2 (95% CI, 3.8–13.8) for reticular pseudodrusen. Compared with persons with a high GRS for complement, homozygous carriers of ARMS2/HTRA1 showed a higher risk of CNV (OR, 4.1; 95% CI, 3.2–5.4); risks of other characteristics were not different. Conclusions: Carriers of the risk haplotype at ARMS2/HTRA1 have a particularly high risk of late AMD at a relatively early age. Data suggest that risk variants at ARMS2/HTRA1 act as a strong catalyst of progression once early signs are present. The phenotypic spectrum resembles that of complement genes, only with higher risks of CNV.

Original languageEnglish
Pages (from-to)752-764
Number of pages13
JournalOphthalmology
Volume129
Issue number7
Early online date28 Feb 2022
DOIs
Publication statusPublished - 1 Jul 2022

Bibliographical note

Funding Information:
Supported by the European Union ( Horizon 2020 grant no.: 634479 [EYE-RISK Consortium]). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, The Netherlands; the Combined Ophthalmic Research Rotterdam Biobank of both the Department of Ophthalmology and the Rotterdam Eye Hospital is financed through the Combined Ophthalmic Research Rotterdam Foundation; the Netherlands Organization for the Health Research and Development ; the Research Institute for Diseases in the Elderly (RIDE); the Ministry of Education , Culture and Science; the Ministry of Health , Welfare and Sports; the European Commission (Directorate-General for Science, Research and Development [DG XII]); and the Municipality of Rotterdam. The ophthalmic research within the Rotterdam Study was supported by Uitzicht (grant no.: 2015-36 ); Oogfonds; MaculaFonds; Landelijkse Stichting voor Blinden en Slechtzienden , which contributed through Uitzicht (grant no.: 2018-34 ); the Royal Dutch Academy of Sciences (Ammodo Award [C.C.W.K.]); and Novartis Fonds. The sponsors and funding organization had no role in the design or conduct of this research. The ALIENOR 3-City study received financial support from Laboratoires Théa, Clermont-Ferrand, France; the Fondation Voir et Entendre , Paris, France; and Caisse Nationale de Solidarité pour l’Autonomie, Paris, France. Laboratoires Théa participated in the design of the study, but no sponsor participated in the collection, management, statistical analysis, or interpretation of the data, nor in the preparation, review, or approval of the present manuscript. The genome-wide association study genotype data for the ALIENOR 3-City study are managed by the Risk Factors and Molecular Determinants of Aging-Related Diseases group of University of Lille, Institut Pasteur de Lille, and INSERM U1167, Lille, France. MONTRACHET funding was provided by an interregional grant, Programme Hospitalier de Recherche Clinique, and the Regional Council of Burgundy . This study also was funded by National Research Institute for Agriculture, Food and Environment (INRA), Le Centre national de la recherche scientifique (CNRS), Université de Bourgogne, Regional Council of Burgundy France (PARI Agrale 1), Fonds européen de développement régional (FEDER) (European Funding for Regional Economic Development), and a French Government grant managed by the French National Research Agency (gence nationale de la recherche [ANR]) as part of the “Investissements d’Avenir” program (reference no.: ANR-11-LABX-0021-01-LipSTIC Labex). The funding organizations had no role in the design or conduct of this research. The Coimbra Eye Study is an investigator-initiated study sponsored by Association for Innovation and Biomedical Research on Light and Image (AIBILI) that was financially supported by Novartis Pharma AG. The funding organization played no role in the design or conduct of this research.

Funding Information:
Supported by the European Union (Horizon 2020 grant no.: 634479 [EYE-RISK Consortium]). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, The Netherlands; the Combined Ophthalmic Research Rotterdam Biobank of both the Department of Ophthalmology and the Rotterdam Eye Hospital is financed through the Combined Ophthalmic Research Rotterdam Foundation; the Netherlands Organization for the Health Research and Development; the Research Institute for Diseases in the Elderly (RIDE); the Ministry of Education, Culture and Science; the Ministry of Health, Welfare and Sports; the European Commission (Directorate-General for Science, Research and Development [DG XII]); and the Municipality of Rotterdam. The ophthalmic research within the Rotterdam Study was supported by Uitzicht (grant no.: 2015-36); Oogfonds; MaculaFonds; Landelijkse Stichting voor Blinden en Slechtzienden, which contributed through Uitzicht (grant no.: 2018-34); the Royal Dutch Academy of Sciences (Ammodo Award [C.C.W.K.]); and Novartis Fonds. The sponsors and funding organization had no role in the design or conduct of this research. The ALIENOR 3-City study received financial support from Laboratoires Théa, Clermont-Ferrand, France; the Fondation Voir et Entendre, Paris, France; and Caisse Nationale de Solidarité pour l'Autonomie, Paris, France. Laboratoires Théa participated in the design of the study, but no sponsor participated in the collection, management, statistical analysis, or interpretation of the data, nor in the preparation, review, or approval of the present manuscript. The genome-wide association study genotype data for the ALIENOR 3-City study are managed by the Risk Factors and Molecular Determinants of Aging-Related Diseases group of University of Lille, Institut Pasteur de Lille, and INSERM U1167, Lille, France. MONTRACHET funding was provided by an interregional grant, Programme Hospitalier de Recherche Clinique, and the Regional Council of Burgundy. This study also was funded by National Research Institute for Agriculture, Food and Environment (INRA), Le Centre national de la recherche scientifique (CNRS), Université de Bourgogne, Regional Council of Burgundy France (PARI Agrale 1), Fonds européen de développement régional (FEDER) (European Funding for Regional Economic Development), and a French Government grant managed by the French National Research Agency (gence nationale de la recherche [ANR]) as part of the “Investissements d'Avenir” program (reference no.: ANR-11-LABX-0021-01-LipSTIC Labex). The funding organizations had no role in the design or conduct of this research. The Coimbra Eye Study is an investigator-initiated study sponsored by Association for Innovation and Biomedical Research on Light and Image (AIBILI) that was financially supported by Novartis Pharma AG. The funding organization played no role in the design or conduct of this research.The MARS study was supported in part by grants from Deutsche Forschungsgemeinschaft (grant no.: HE 2293/5-1, 5-2, 5-3); the Intramural IMF fund of the University of Muenster; the Pro Retina Foundation; and the Jackstaedt Foundation. The EUGENDA was funded by grants from the Oogfonds, MaculaFonds, Landelijke Stiching voor Blinden en Slechtzienden, Stichting Blindenhulp, Stichting A.F. Deutman Oogheelkunde Researchfonds, the Netherlands Organization for Scientific Research (Vidi Innovational Research Award no.: 016.096.309), and the European Research Council (ERC) under the European Union's Seventh Framework Programme (grant no.: FP/2007-2013; ERC grant agreement no. 310644 MACULA). This research was supported by the Dutch Organization for Scientific Research (grant no.: 016.Vici.170.024 [A.I.d.H.]).The generation and management of GWAS genotype data for the Rotterdam Study (I, II, and III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. The GWAS datasets are supported by the Netherlands Organization of Scientific Research (Nederlandse organisatie voor wetenschappelijk onderzoek [NWO]) Investments (nos.: 175.010.2005.011 and 911-03-012); the Genetic Laboratory of the Department of Internal Medicine, Erasmus Medical Center; the Research Institute for Diseases in the Elderly (grant no.: 014-93-015 [RIDE2]); and the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research and Netherlands Consortium for Healthy Aging (grant no.: 050-060-810). C.C-G.: Financial support – Allergan, Bayer, Bausch & Lomb, Novartis, Horus Pharma, Roche, Théa Obtained funding: Ueffing, Klaver, Delcourt, den Hollander, Hoyng

Publisher Copyright:
© 2022 American Academy of Ophthalmology

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