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      Genetic Factors Associated with Age-Related Macular Degeneration

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          Abstract

          Age-related macular degeneration (AMD) is a complex, multifactorial disease associated with environmental and genetic factors. This review emphasizes the clinical impact of the major genetic factors mainly located in the complement factor H gene and on the 10q26 locus, and their current and future implications for the management of AMD.

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          Newly identified loci that influence lipid concentrations and risk of coronary artery disease.

          Cristen J Willer, Serena Sanna, Anne U. Jackson … (2008)
          To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.
          Article 0 comments Cited 480 times – based on 0 reviews     Review now
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            A role for local inflammation in the formation of drusen in the aging eye.

            Don H Anderson, Robert F. Mullins, Gregory Hageman … (2002)
            The accumulation of numerous or confluent drusen, especially in the macula, is a significant risk factor for the development of age-related macular degeneration (AMD). Identifying the origin and molecular composition of these deposits, therefore, has been an important, yet elusive, objective for many decades. Recently, a more complete profile of the molecular composition of drusen has emerged. In this focused review, we discuss these new findings and their implications for the pathogenic events that give rise to drusen and AMD. Tissue specimens from one or both eyes of more than 400 human donors were examined by light, confocal or electron microscopy, in conjunction with antibodies to specific drusen-associated proteins, to help characterize the transitional events in drusen biogenesis. Quantification of messenger RNA from the retinal pigment epithelium (RPE)/choroid of donor eyes was used to determine if local ocular sources for drusen-associated molecules exist. The results indicate that cellular remnants and debris derived from degenerate RPE cells become sequestered between the RPE basal lamina and Bruch's membrane. We propose that this cellular debris constitutes a chronic inflammatory stimulus, and a potential "nucleation" site for drusen formation. The entrapped cellular debris then becomes the target of encapsulation by a variety of inflammatory mediators, some of which are contributed by the RPE and, perhaps, other local cell types; and some of which are extravasated from the choroidal circulation. The results support a role for local inflammation in drusen biogenesis, and suggest that it is analogous to the process that occurs in other age-related diseases, such as Alzheimer's disease and atherosclerosis, where accumulation of extracellular plaques and deposits elicits a local chronic inflammatory response that exacerbates the effects of primary pathogenic stimuli.
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              The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited.

              Don H Anderson, Monte Radeke, Natasha Gallo … (2010)
              During the past ten years, dramatic advances have been made in unraveling the biological bases of age-related macular degeneration (AMD), the most common cause of irreversible blindness in western populations. In that timeframe, two distinct lines of evidence emerged which implicated chronic local inflammation and activation of the complement cascade in AMD pathogenesis. First, a number of complement system proteins, complement activators, and complement regulatory proteins were identified as molecular constituents of drusen, the hallmark extracellular deposits associated with early AMD. Subsequently, genetic studies revealed highly significant statistical associations between AMD and variants of several complement pathway-associated genes including: Complement factor H (CFH), complement factor H-related 1 and 3 (CFHR1 and CFHR3), complement factor B (CFB), complement component 2 (C2), and complement component 3 (C3). In this article, we revisit our original hypothesis that chronic local inflammatory and immune-mediated events at the level of Bruch's membrane play critical roles in drusen biogenesis and, by extension, in the pathobiology of AMD. Secondly, we report the results of a new screening for additional AMD-associated polymorphisms in a battery of 63 complement-related genes. Third, we identify and characterize the local complement system in the RPE-choroid complex - thus adding a new dimension of biological complexity to the role of the complement system in ocular aging and AMD. Finally, we evaluate the most salient, recent evidence that bears directly on the role of complement in AMD pathogenesis and progression. Collectively, these recent findings strongly re-affirm the importance of the complement system in AMD. They lay the groundwork for further studies that may lead to the identification of a transcriptional disease signature of AMD, and hasten the development of new therapeutic approaches that will restore the complement-modulating activity that appears to be compromised in genetically susceptible individuals. Copyright 2009 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Journal ID (publisher-id): OPH
                Journal ID (nlm-ta): Ophthalmologica
                Journal ID (doi): 10.1159/issn.0030-3755
                Title: Ophthalmologica
                Publisher: S. Karger AG
                ISSN (Print): 0030-3755
                ISSN (Electronic): 1423-0267
                Publication date Subscription-year: 2011
                Publication date (Print): September 2011
                Publication date (Electronic): 14 July 2011
                Volume: 226
                Issue: 3
                Pages: 87-102
                Affiliations
                Departments of Ophthalmology, aHôpital Intercommunal de Créteil, University of Paris XII, and bFaculté de Médecine Henri-Mondor, UPEC, Créteil, France
                Author notes
                *Dr. Nicolas Leveziel, Service d’Ophtalmologie, Hôpital Henri-Mondor, 51, avenue du Maréchal-de-Lattre-de-Tassigny, FR–94010 Créteil Cedex (France), Tel. +33 1 45 17 52 22, E-Mail nicolas.leveziel@chicreteil.fr
                Article
                Publisher ID: 328981 Other ID: Ophthalmologica 2011;226:87–102
                DOI: 10.1159/000328981
                PubMed ID: 21757876
                SO-VID: 9af84fa0-4b04-4e37-b19f-db928ed960e0
                Copyright © © 2011 S. Karger AG, Basel
                License:

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                Date received : 27 April 2011
                Date accepted : 27 April 2011
                Page count
                Pages: 16
                Categories
                Subject: EURETINA – Review

                ScienceOpen disciplines: Vision sciences,Ophthalmology & Optometry,Pathology
                Keywords: HtrA serine peptidase 1 gene (HTRA1),Atrophic age-related macular degeneration,Age-related maculopathy,Missing heritability,Age-related maculopathy susceptibility 2 gene (ARMS2),Asian,Exudative age-related macular degeneration,Complement component 2, 3, 9 (C2, C3, C9),Genome-wide association studies,LOC387715,Complement factor H gene (CFH),Age-related macular degeneration,Genetic factors,Personalized medicine,Genetic profiling
                Data availability:
                ScienceOpen disciplines: Vision sciences, Ophthalmology & Optometry, Pathology
                Keywords: HtrA serine peptidase 1 gene (HTRA1), Atrophic age-related macular degeneration, Age-related maculopathy, Missing heritability, Age-related maculopathy susceptibility 2 gene (ARMS2), Asian, Exudative age-related macular degeneration, Complement component 2, 3, 9 (C2, C3, C9), Genome-wide association studies, LOC387715, Complement factor H gene (CFH), Age-related macular degeneration, Genetic factors, Personalized medicine, Genetic profiling

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