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Codrut Paun, Dzenita Smailhodzic, Camiel Boon, Lies Hoefsloot, Mohamed Daha, Carel Hoyng, Anneke Den Hollander; Using extremes to identify rare pathogenic variants in age-related-macular degeneration. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3657.
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Age-related macular degeneration (AMD) has a strong genetic component, and it has been estimated that 50% of the heritability of AMD is explained by common variants in the complement system. Despite the progress that has been made in identifying common variants in AMD, few studies have assessed the role of rare variants in the pathogenesis of AMD. The purpose of this study was to identify rare variants in AMD patients with high levels of complement activation.
Complement component C3 and the activation fragment C3d were measured in serum samples of 197 AMD patients and 150 unaffected age-matched controls. The C3d/C3 ratio was calculated as an indicator of C3 activation. DNA samples of patients with high C3d/C3 ratios (>3), were screened for mutations in the CFH gene by Sanger sequencing. DNA samples of 8 patients with the highest C3d/C3 ratios (>4) were analyzed by exome sequencing.
AMD patients displayed an increased median C3d/C3 ratio compared to controls (p<0.001). C3d/C3 ratios >3 were observed in 37 AMD patients, but only in 4 control individuals. Sequence analysis of the CFH gene revealed a heterozygous frameshift mutation (c.1769_1779del; p.Gly590fsX) in a patient with a C3d/C3 ratio of 4.4. Exome sequencing in 8 patients with C3d/C3 ratios >4 revealed rare variants in 5 patients in key components of the complement pathway.
High levels of complement activation in AMD patients can be caused by rare variants in components of the complement pathway, which have previously not been associated with AMD. High complement activation may therefore direct a genetic search toward complement gene abnormalities. This genotype-serotype correlation approach is able to identify new risk factors in AMD.
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