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H.P. Scholl, A. Bindewald–Wittich, S. Schmitz–Valckenberg, M. Fleckenstein, A. Rivera, B.H. F. Weber, F.G. Holz, FAM Study Group; Correlation of CFH Y402h Allele Distribution and Risk of Progression of Geographic Atrophy in Patients With Age–Related Macular Degeneration (AMD) . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4338.
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© ARVO (1962-2015); The Authors (2016-present)
To determine if the common missense variant, Y402H, in the Complement Factor H (CFH) gene confers risk of progression of geographic atrophy (GA) due to age–related macular degeneration (AMD) by correlating CFH genotypes and longitudinal phenotypic data.
In the prospective, multicenter natural history FAM (Fundus Autofluorescence in AMD) Study repeated standardized fundus autofluorescence (FAF) images were obtained from 225 eyes of 147 patients over a median of 21 months. On the basis of a recently developed FAF classification system (BJO 2005; 89:874–8), patients were grouped into two different classes based on longitudinal FAM study data. The high–risk patient group (mean progression rate 2.05 ± 1.93 mm2/year) involved either a diffusely or patchy increased FAF in a larger area outside the GA, whereas the low–risk patient group (mean progression rate 1.29 ± 1.02 mm2/year) involved other phenotypic types of only minor FAF changes outside the GA (in both eyes, resp.). Patients with any sign of choroidal neovascularization in either eye were excluded. Blood samples were genotyped for the CFH Y402H allele.
Blood samples were available in 65 GA patients. Based the FAF findings in both eyes, 41 patients could be classified unambiguously as being either low–risk or high–risk. Eleven patients of the high–risk group (n=30) and three patients of the low–risk group (n=11) were homozygous for the risk allele; 13 in the high–risk group and 8 in the low–risk group were heterozygous, respectively. However, the CFH Y402H allele distribution did not differ significantly between the two groups (p>=0.14, Fisher's exact test).
Extensive phenotyping to dissect specific phenotypic variants necessarily reduces sample sizes and may affect power to detect genetic effects. However, it has been shown that small sample sizes can be sufficient when many genotypic makers are tested. Similarly, extremely well–phenotyped patient cohorts are needed when the role of CFH in AMD pathogenesis shall be elucidated. Based on previous phenotype–genotype correlations of AMD patient cohorts involving both neovascular and dry forms, it has been hypothesized that the CFH Y402H allele confers risk for early AMD pathogenesis and that additional genetic and/or environmental factors may be required for progression to advanced forms of AMD. Our data are in agreement with this notion.
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