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Johanna Seddon, Robyn Reynolds, Yi Yu, Soumya Raychaudhuri, Bernard Rosner; Three New Genetic Loci (R1210C mutation in CFH , SNPs in COL8A1 and RAD51B) are Related to Progression to Advanced Stages of Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2013;54(15):6178.
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There is a strong genetic component and an important environmental influence on the development of age-related macular degeneration (AMD). We discovered a novel rare variant (R1210C) in CFH and new common variants were found based on analyses of several genome-wide case-control association studies. We determined the relative impact of these new variants on progression to advanced stages, controlling for previously known genes, as well as demographic and behavioral factors.
In this longitudinal study of 2743 individuals in AREDS, 775 subjects progressed to advanced AMD with geographic atrophy or neovascular AMD during 12 years of follow-up. Cox proportional hazards regression analyses were performed to calculate hazard ratios (HR) for progression. Covariates included demographic and environmental factors, 9 variants in 8 genes, baseline macular drusen size, and presence and type of advanced AMD in one eye at baseline.
In multivariate models, age, smoking, body mass index, and common SNP’s in the known genes CFH, ARMS2/HTRA1, C3, C2, CFB were independently associated with AMD progression. R1210C in CFH was related to progression from early or intermediate to advanced stages of AMD: HR 2.5, 95% confidence interval (CI) 1.2-5.2, P= 0.013. Common variants in the genes COL8A1 (HR 2.0, 95% CI 1.1-3.4, P=0.016) and RAD51B (HR 0.8, 95% CI 0.60-0.99, P= 0.038) were also independently associated with progression.
We identified 3 new genes that add predictive power to risk models for progression to advanced AMD, in addition to drusen size, baseline AMD status, demographic and environmental factors. These models will be useful for AMD surveillance and for designing clinical trials.
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