C9-R95X polymorphism in patients with neovascular age-related macular degeneration.
ABSTRACT A non-sense mutation at codon 95 in the gene encoding complement factor C9 (C9-R95X) is found most frequently among Japanese. The authors investigated the association between C9-R95X and Japanese patients with neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV).
The presence of the C9-R95X polymorphism was assessed by direct sequencing in Japanese patients with either PCV (n = 105) or neovascular AMD (n = 198) and 396 control subjects. Multivariate regression analyses were conducted. Photocoagulation was applied in the eyes of mice with a heterozygous defect in the C3 gene and control wild-type mice. Photocoagulation was also applied to wild-type mice before either anti-C9 antibody or isotype IgG was injected into the eyes. The eyes were collected later for measurement of vascular endothelial growth factor (VEGF) and histological evaluation of choroidal neovascularization (CNV).
The frequency of those with one or two C9-R95X variants was lower in neovascular AMD (2.02%) than in PCV (5.71%) and controls (6.05%). The presence of C9-R95X conferred a 4.7-fold reduction (95% confidence interval, 1.2-18.1; P = 0.021) in the risk for neovascular AMD after adjusting for the major AMD risk factors. A heterozygous defect in the C3 gene was associated with the reduced growth of laser-induced CNV, as was intraocular injection of anti-C9 antibody. This reduced CNV growth was accompanied by a decreased level of secreted VEGF in the intraocular fluid.
These findings support the notion that the haploinsufficiency of C9, a terminal complement complex component, engenders reduced intraocular secretion of VEGF and decreased risk for CNV development.
- SourceAvailable from: sciencedirect.com[show abstract] [hide abstract]
ABSTRACT: Complement is a key component of immune defence against infection; it potently drives inflammation at sites of pathology and is essential for killing of pathogens. Genetic linkage of common complement polymorphisms to disease has advanced the concept that subtle changes in complement activity significantly affect disease risk. Functional analyses of disease-linked polymorphic variants demonstrate that, although individual polymorphisms cause only small changes in activity, when combined, the aggregate effects are large. The inherited set of common variants, the complotype, thus has a major impact on susceptibility to inflammatory and infectious diseases. Assessing the complotype of an individual will aid prediction of disease risk and inform intervention to reduce or eliminate risk.Trends in Immunology 06/2012; 33(10):513-21. · 9.49 Impact Factor