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H. P. Scholl, M. Fleckenstein, L. G. Fritsche, S. Schmitz-Valckenberg, C. N. Keilhauer, C. Adrion, U. Mansmann, F. G. Holz, T. Becker, B. H. Weber; CFH, ARMS2 and C3 Confer Risk for Susceptibility but Not for Disease Progression of Geographic Atrophy Due to Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2009;50(13):1598.
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Age-related macular degeneration (AMD) is the most prevalent cause of blindness in industrialized societies. Variants in the complement factor H (CFH), the complement component 3 (C3) and the age-related maculopathy susceptibility 2 (ARMS2) genes have been established to confer significant risks for disease susceptibility. Their role for disease progression and thus their significance for developing therapeutic intervention was investigated.
We tested for an association between genetic variants in CFH, C3 and ARMS2 and disease progression of late atrophic AMD (geographic atrophy). Patients were selected from the multicenter FAM study cohort (n=619) and compared with 612 controls. Patients were investigated by fundus autofluorescence imaging. A quantitative phenotype of disease progression was computed based on longitudinal observations.
In a subset of 99 cases with pure bilateral geographic atrophy, variants in CFH (Y402H), ARMS2 (A69S) and C3 (R102G) were strongly associated with disease (P=1.6x10-9, P=2.6x10-12, and 3.2x10-3, respectively). Median progression rate of geographic atrophy over a mean follow-up of 3.0 years was 1.61 mm2/year with high concordance between the two eyes. Despite sufficient power, no association between the progression rate and the genetic risk variants at the three loci was observed (P>0.13).
Variants at CFH, C3, and ARMS2 confer high risks for geographic atrophy, but not for disease progression. As a consequence, therapeutic options specifically addressing the three susceptibility factors may not be helpful to alleviate disease progression once late atrophic AMD has developed. Other so far unknown susceptibility factors may be involved.
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