Unraveling a Multifactorial Late-Onset Disease: From Genetic Susceptibility to Disease Mechanisms for Age-Related Macular Degeneration

Neurobiology-Neurodegeneration & Repair Laboratory (N-NRL), National Eye Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA.
Annual review of genomics and human genetics (Impact Factor: 8.96). 05/2009; 10(1):19-43. DOI: 10.1146/annurev.genom.9.081307.164350
Source: PubMed


Aging-associated neurodegenerative diseases significantly influence the quality of life of affected individuals. Genetic approaches, combined with genomic technology, have provided powerful insights into common late-onset diseases, such as age-related macular degeneration (AMD). Here, we discuss current findings on the genetics of AMD to highlight areas of rapid progress and new challenges. We also attempt to integrate available genetic and biochemical data with cellular pathways involved in aging to formulate an integrated model of AMD pathogenesis.

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Available from: Catherine Bowes Rickman,
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    • "Despite intensive basic and clinical research, the pathogenesis of AMD remains unclear. However, a growing body of evidence indicates that AMD is likely a multifactorial, progressive disease that involves complex interactions between genetic and environmental factors [6]. It is widely accepted that inflammatory and immunologic events might play a role in AMD. "
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    ABSTRACT: Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly, especially in Western countries. Although the prevalence, risk factors, and clinical course of the disease are well described, its pathogenesis is not entirely elucidated. AMD is associated with a variety of biochemical abnormalities, including complement components deposition in the retinal pigment epithelium-Bruch's membrane-choriocapillaris complex. Although the complement system (CS) is increasingly recognized as mediating important roles in retinal biology, its particular role in AMD pathogenesis has not been precisely defined. Unrestricted activation of the CS following injury may directly damage retinal tissue and recruit immune cells to the vicinity of active complement cascades, therefore detrimentally causing bystander damage to surrounding cells and tissues. On the other hand, recent evidence supports the notion that an active complement pathway is a necessity for the normal maintenance of the neurosensory retina. In this scenario, complement activation appears to have beneficial effect as it promotes cell survival and tissue remodeling by facilitating the rapid removal of dying cells and resulting cellular debris, thus demonstrating anti-inflammatory and neuroprotective activities. In this review, we discuss both the beneficial and detrimental roles of CS in degenerative retina, focusing on the diverse aspects of CS functions that may promote or inhibit macular disease.
    Research Journal of Immunology 09/2014; 2014:483960. DOI:10.1155/2014/483960
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    • "AMD is a disease with complex inheritance patterns, and it may be difficult to discover individual susceptibility genes due to multiple genetic and environmental effects and interactions. Identifying several genetic loci revealed that several important biological pathways are involved in AMD pathogenesis, such as the cholesterol, lipid metabolism pathway, complement pathway, extracellular matrix pathway, oxidative stress pathway, and angiogenesis signaling pathway in [20] [21] [22], which provides a foundation for systematically analyzing the biological processes underlying AMD. Gene ontology (GO) is a major bioinformatics tool that standardizes representation and the product attributes of genes across species [23]. "
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    ABSTRACT: Identifying disease genes is one of the most important topics in biomedicine and may facilitate studies on the mechanisms underlying disease. Age-related macular degeneration (AMD) is a serious eye disease; it typically affects older adults and results in a loss of vision due to retina damage. In this study, we attempt to develop an effective method for distinguishing AMD-related genes. Gene ontology and KEGG enrichment analyses of known AMD-related genes were performed, and a classification system was established. In detail, each gene was encoded into a vector by extracting enrichment scores of the gene set, including it and its direct neighbors in STRING, and gene ontology terms or KEGG pathways. Then certain feature-selection methods, including minimum redundancy maximum relevance and incremental feature selection, were adopted to extract key features for the classification system. As a result, 720 GO terms and 11 KEGG pathways were deemed the most important factors for predicting AMD-related genes.
    BioMed Research International 08/2014; 2014:450386. DOI:10.1155/2014/450386 · 1.58 Impact Factor
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    • "Angiogenesis and its downstream effects are important milestones in AMD [4, 5]. Furthermore, increasing evidence supports the fact that OS and apoptosis are closely linked processes and that both are implicated in the pathophysiologic mechanisms of AMD [2, 4, 5]. "
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    ABSTRACT: Purpose. To review the proposed pathogenic mechanisms of age macular degeneration (AMD), as well as the role of antioxidants (AOX) and omega-3 fatty acids ( ω -3) supplements in AMD prevention. Materials and Methods. Current knowledge on the cellular/molecular mechanisms of AMD and the epidemiologic/experimental studies on the effects of AOX and ω -3 were addressed all together with the scientific evidence and the personal opinion of professionals involved in the Retina Group of the OFTARED (Spain). Results. High dietary intakes of ω -3 and macular pigments lutein/zeaxanthin are associated with lower risk of prevalence and incidence in AMD. The Age-Related Eye Disease study (AREDS) showed a beneficial effect of high doses of vitamins C, E, beta-carotene, and zinc/copper in reducing the rate of progression to advanced AMD in patients with intermediate AMD or with one-sided late AMD. The AREDS-2 study has shown that lutein and zeaxanthin may substitute beta-carotene because of its potential relationship with increased lung cancer incidence. Conclusion. Research has proved that elder people with poor diets, especially with low AOX and ω -3 micronutrients intake and subsequently having low plasmatic levels, are more prone to developing AMD. Micronutrient supplementation enhances antioxidant defense and healthy eyes and might prevent/retard/modify AMD.
    Journal of Ophthalmology 01/2014; 2014:901686. DOI:10.1155/2014/901686 · 1.43 Impact Factor
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