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L. Sobrin, R. C. Reynolds, J. A. Fagerness, B. M. Neale, N. Leveziel, P. S. Bernstein, E. H. Souied, M. J. Daly, J. M. Seddon; Differential Genetic Susceptibility to Geographic Atrophy and Choroidal Neovascularization in Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1624.
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To determine if genetic variants that have been reliably associated with advanced age-related macular degeneration (AMD) have a differential effect on the risk of geographic atrophy (GA) and choroidal neovascularization (NV) in a large sample size of both phenotypes.
Participants were derived from ongoing AMD study protocols with similar procedures including the Progression of AMD Study, AMD Registry Study, Family Study of AMD, the US Twin Study of AMD, the Age-Related Eye Disease Study, University of Utah, and Hopital Intercommunal de Creteil. AMD grade was assigned based on fundus photography and ocular examination using the clinical age-related maculopathy grading system (CARMS) in which grade 4 is GA anywhere within the macula (central or non-central) and grade 5 is NV. Participants were assigned a grade based on the highest grade in either eye. All samples were genotyped on the Sequenom Iplex platform for previously associated single nucleotide polymorphism (SNPs), including CFH rs1061170, CFH rs1410996, CFI rs10033900, CFB/C2 rs641153, and C3 rs2230199 in the complement pathway; ARMS2/HTRA1 rs10490924; and new loci TIMP3 rs9621532; and LIPC rs493258. We performed association testing comparing allele frequencies between participants with GA and participants with NV using PLINK. We performed stratified analyses by recruitment site.
748 participants with GA and 2775 participants with NV were included in the analysis. The frequency of the T allele of ARMS2/HTRA1 rs10490924 was significantly more common in participants with NV than those with GA (odds ratio, 1.41; 95% confidence interval, 1.24 -1.60; p value = 2.5 X 10-7). This result remained statistically significant when the association testing was performed excluding individuals who had GA in one eye and NV in the contralateral eye. None of the other SNPs examined showed a differential effect for NV vs. GA.
Genetic variation at the ARMS2/HTRA1 locus confers a differential risk for NV vs. GA in a well-powered sample. Future identification of other loci with similar differential effects could lead to biological insights into the mechanisms associated with development of NV vs. GA in patients with AMD.
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