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: 4.35). 04/2009; 17(9):1190-9. DOI: 10.1038/ejhg.2009.23
Source: PubMed


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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    • "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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    • "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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