Article

Multilocus analysis of age-related macular degeneration

SAIC-Frederick, Basic Science Program, Human Genetics Section, Frederick, MD 21702-1201, USA.
European journal of human genetics: EJHG (Impact Factor: 4.23). 04/2009; 17(9):1190-9. DOI: 10.1038/ejhg.2009.23
Source: PubMed

ABSTRACT Age-related macular degeneration (AMD) is a late onset vision disorder. Recent studies demonstrate that alterations in complement cascade genes are associated with AMD. Of the three identified complement loci, variants in complement factor H (CFH) have the highest impact as does an independent locus at 10q26. Our matched case-control study using the Age-Related Eye Disease Study (AREDS) cohort confirms and extends the associations in these loci. Subjects were genotyped for single nucleotide polymorphisms (SNPs) from CFH, complement component 2 (C2), complement component 3 (C3), complement factor B (CFB), age-related maculopathy susceptibility (ARMS2), HtrA serine peptidase 1 (HTRA1), and apolipoprotein E (APOE). Individual SNPs, and haplotypes showed risk trends consistent with those seen in other population studies for CFH, C3, C2, and CFB. SNP rs10490924 on chromosome 10 in exon 1 of the ARMS2 gene showed a highly significant association with an odds ratio (OR) of 3.2 (95% CI 2.4-4.2) for the risk allele and rs11200638 located in the proximal promoter region of HTRA1 showed a higher significant association with an OR of 3.4 (95% CI 2.5-4.6) with our AMD cases. We found that APOE haplotypes were not significantly associated with disease status. Adjustments for other risk factors did not significantly alter the observed associations. This study validates the complement pathway's involvement in AMD and suggests that allelic variants in complement genes have a direct role in disease. These results also support previous findings that variants in the region of 10q26 exert an independent risk for AMD.

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    • "Although AMD is not considered a typical inflammatory disease, the pathogenic role of immunologic processes in the occurrence and progression of AMD is well documented. The correlation between immunological/inflammatory gene polymorphisms and AMD indicates the involvement of inflammation and immunemediated processes—complement activation, in the pathogenesis of this disease (Bergeron-Sawitzke et al. 2009; Ryu et al. 2010). Furthermore, immunocompetent cells, such as macrophages and lymphocytes, were present in the chorioretinal tissues affected by AMD (Penfold et al. 1985; Lopez et al. 1991). "
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    ABSTRACT: Cells in aerobic condition are constantly exposed to reactive oxygen species (ROS), which may induce damage to biomolecules, including proteins, nucleic acids and lipids. In normal circumstances, the amount of ROS is counterbalanced by cellular antioxidant defence, with its main components-antioxidant enzymes, DNA repair and small molecular weight antioxidants. An imbalance between the production and neutralization of ROS by antioxidant defence is associated with oxidative stress, which plays an important role in the pathogenesis of many age-related and degenerative diseases, including age-related macular degeneration (AMD), affecting the macula-the central part of the retina. The retina is especially prone to oxidative stress due to high oxygen pressure and exposure to UV and blue light promoting ROS generation. Because oxidative stress has an established role in AMD pathogenesis, proper functioning of antioxidant defence may be crucial for the occurrence and progression of this disease. Antioxidant enzymes play a major role in ROS scavenging and changes of their expression or/and activity are reported to be associated with AMD. Therefore, the enzymes in the retina along with their genes may constitute a perspective target in AMD prevention and therapy.
    Biogerontology 09/2013; 14(5). DOI:10.1007/s10522-013-9463-2 · 3.01 Impact Factor
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    • "Major risk factors for the disease include increasing age, smoking and a family history of AMD [2], [3], [4]. In the recent years evidence has accumulated indicating that genetic factors are associated with AMD [5], [6], [7], [8]. A polymorphism of factor H (HGNC:4883), a complement control protein, was the first gene shown to be involved in the development and progression of AMD [9], [10], [11], [12]. "
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    ABSTRACT: A common polymorphism in the complement factor H gene (rs1061170, Y402H) is associated with a high risk of age-related macular degeneration (AMD). In the present study we hypothesized that healthy young subjects homozygous for the high-risk haplotype (CC) show abnormal choroidal blood flow (ChBF) regulation decades before potentially developing the disease. A total of 100 healthy young subjects were included in the present study, of which 4 subjects were excluded due to problems with genotyping or blood flow measurements. ChBF was measured continuously using laser Doppler flowmetry while the subjects performed isometric exercise (squatting) for 6 minutes. The increase in ChBF was less pronounced than the response in ocular perfusion pressure (OPP), indicating for some degree of choroidal blood flow regulation. Eighteen subjects were homozygous for C, 47 subjects were homozygous for T and 31 subjects were heterozygous (CT). The increase in OPP during isometric exercise was not different between groups. By contrast the increase in ChBF was more pronounced in subjects homozygous for the high risk C allele (p = 0.041). This was also evident from the pressure/flow relationship, where the increase in ChBF in homozygous C carriers started at lower OPPs as compared to the other groups. Our data indicate that the regulation of ChBF is abnormal in rs1061170 CC carriers. So far this polymorphism has been linked to age related macular degeneration (AMD) mainly via inflammatory pathways associated with the complement system dysfunction. Our results indicate that it could also be related to vascular factors that have been implicated in AMD pathogenesis.
    PLoS ONE 04/2013; 8(4):e60424. DOI:10.1371/journal.pone.0060424 · 3.23 Impact Factor
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    • "In Caucasian English and Scottish populations, sequencing studies showed that within exon 3 of C3, the common functional R102G polymorphism (rs2230199; 120700.0001) was strongly associated with AMD [48]–[50]. Studies show that AMD individuals have significantly elevated levels of C3a des Arg in their plasma compared with the age-matched control group, irrespective of the CFH polymorphism status [51]. In AMD eyes, drusen have an accumulation of complement-associated proteins including C3 [52], [53]. "
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