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: 11.57). 05/2009; 10:19-43. DOI: 10.1146/annurev.genom.9.081307.164350
Source: PubMed

ABSTRACT 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.

1 Bookmark
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: There have been enormous advances in the past decade for the treatment of age-related macular degeneration (AMD); however, these treatments are expensive and require frequent follow-up and injections which place a tremendous burden on both the healthcare system and patients. Consequently, there remains considerable interest in preventing or slowing the progression of AMD requiring treatment. Epidemiological studies have shown that diet is a modifiable AMD risk factor, and nutrient modification is a particularly appealing treatment for AMD due to the perceived universal benefit and relatively low expense. Recently, the age-related eye disease study part two (AREDS2) was concluded and demonstrated further benefit with the addition of lutein and zeaxanthin as a replacement for the β-carotene of the previous generation formulation. The addition of omega-3 essential fatty acids did not show an added benefit. This review aims to highlight some of the evidenced based body of knowledge that has been accumulated from recent studies regarding the use of nutritional supplements and their effect on AMD, cataracts, and dry eyes.
    Journal of Ophthalmic & Vision Research 10/2014; 9(4):487. DOI:10.4103/2008-322X.150829
  • [Show abstract] [Hide abstract]
    ABSTRACT: Nonsynonymous single nucleotide polymorphisms (SNPs) in complement component 3 (CC3) are associated with the risk of age-related macular degeneration (AMD), however, this association is not consistent among studies. To thoroughly address this issue, we performed an updated meta-analysis to evaluate the association between nine SNPs in the CC3 gene and AMD risk. A search was conducted of the PubMed database through 3rd Aug, 2014. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of associations. Based on the search criteria for manuscripts reporting AMD susceptibility related to CC3 in nine SNPs, 57 case-control studies from 22 different articles were retrieved. Significantly positive associations were found for the rs2230199 C/G SNP and AMD in the Caucasian population, as well as for the rs1047286 C/T SNP. Moreover, a relationship between the rs11569536 G/A SNP and AMD was detected. By contrast, a negative association was observed between rs2250656 A/G SNP and AMD risk. The present meta-analysis suggests that these four SNPs in the CC3 gene are potentially associated with the risk of AMD development. Further studies using larger sample sizes and accounting for gene-environment interactions should be conducted to elucidate the role of CC3 gene polymorphisms in AMD risk. Copyright © 2015. Published by Elsevier B.V.
    Gene 02/2015; DOI:10.1016/j.gene.2015.02.039 · 2.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The eye uses vitamin A as a cofactor to sense light, during this process a fraction of vitamin A dimerizes forming vitamin A dimers. A striking chemical signature of retinas undergoing degeneration in major eye diseases such as age-related macular degeneration (AMD) and Stargardt disease, is the accumulation of these dimers in the retinal pigment epithelium (RPE) and Bruch's membrane (BM). However, it is not known whether dimers of vitamin A are merely secondary symptoms or primary insults that drive degeneration. Here, we present a chromatography free method to prepare gram quantities of the vitamin A dimer, A2E, and show that intravenous administration of A2E to the rabbit results in retinal degeneration. A2E damaged photoreceptors and RPE cells, triggered inflammation, induced remolding of the choroidal vasculature, and triggered a decline in the retina's response to light. Data suggest that vitamin A dimers are not bystanders, but can be primary drivers of retinal degeneration. Thus, preventing dimer formation could be a preemptive strategy to address serious forms of blindness.
    Disease Models and Mechanisms 12/2014; 8(2). DOI:10.1242/dmm.017194 · 5.54 Impact Factor

Full-text (2 Sources)

Available from
Jun 1, 2014