PURPOSE: 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.
PURPOSE: 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: S Scott Whitmore; Elliott H Sohn; Kathleen R Chirco; Arlene V Drack; Edwin M Stone; Budd A Tucker; Robert F Mullins Journal: Prog Retin Eye Res Date: 2014-12-05 Impact factor: 21.198
Authors: O McMahon; T M Hallam; S Patel; C L Harris; A Menny; W M Zelek; R Widjajahakim; A Java; T E Cox; N Tzoumas; D H W Steel; V G Shuttleworth; K Smith-Jackson; V Brocklebank; H Griffiths; A J Cree; J P Atkinson; A J Lotery; D Bubeck; B P Morgan; K J Marchbank; J M Seddon; D Kavanagh Journal: Hum Mol Genet Date: 2021-06-17 Impact factor: 5.121
Authors: Elizabeth C Schramm; Simon J Clark; Michael P Triebwasser; Soumya Raychaudhuri; Johanna Seddon; John P Atkinson Journal: Mol Immunol Date: 2014-07-15 Impact factor: 4.407
Authors: Scott M Whitcup; Akrit Sodhi; John P Atkinson; V Michael Holers; Debasish Sinha; Bärbel Rohrer; Andrew D Dick Journal: Int J Inflam Date: 2013-05-23
Authors: Johanna M Seddon; Yi Yu; Elizabeth C Miller; Robyn Reynolds; Perciliz L Tan; Sivakumar Gowrisankar; Jacqueline I Goldstein; Michael Triebwasser; Holly E Anderson; Jennyfer Zerbib; David Kavanagh; Eric Souied; Nicholas Katsanis; Mark J Daly; John P Atkinson; Soumya Raychaudhuri Journal: Nat Genet Date: 2013-09-15 Impact factor: 38.330