title: C9-R95X polymorphism in patients with neovascular age-related macular degeneration.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Ophthalmology, Nagoya University School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, Japan. kojinish@med.nagoya-u.ac.jp
authors.forename: Koji M
authors.initials: KM
authors.lastname: Nishiguchi
authors.forename: Tetsuhiro R
authors.initials: TR
authors.lastname: Yasuma
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tomida
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakamura
authors.forename: Kohei
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Masato
authors.initials: M
authors.lastname: Kikuchi
authors.forename: Yuhsuke
authors.initials: Y
authors.lastname: Ohmi
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Niwa
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Hamajima
authors.forename: Koichi
authors.initials: K
authors.lastname: Furukawa
authors.forename: Hiroko
authors.initials: H
authors.lastname: Terasaki
mesh_terms: D000368:Aged; D000818:Animals; D003186:Complement C9 / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D005838:Genotype; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D015861:Retinal Neovascularization / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D003186:Complement C9; D004247:DNA