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Yi Yu, Robyn Reynolds, Jesen Fagerness, Bernard Rosner, Mark J. Daly, Johanna M. Seddon; Assessment of Genetic Effects on Progression to Intermediate Drusen, Large Drusen and Advanced Stages of Age-related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5220.
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Accumulation of drusen is seen in early and intermediate stages of age-related macular degeneration (AMD) and can progress to advanced AMD. Genetic variants in the complement, HDL and other pathways are associated with advanced AMD (AAMD). Understanding roles of genes related to AMD progression may lead to prevention and treatments of this disease in its early stages.
Progression event and time to each stage of AMD were derived from the longitudinal ocular examinations and fundus photography data of 3066 subjects in the Age-Related Eye Disease Study. SNPs in the CFH, C2, C3, CFB, CFI, ARMS2/HTRA1, and novel LIPC, CETP, ABCA1, TIMP3, COL8A1 genes/regions were genotyped. Genetic effect of each variant was assessed by Markov multi-state models from normal to drusen to AAMD progression. A multivariate multi-state model for progression from normal to intermediate drusen, large drusen, and eventually to choroidal neovascularization (NV) or geographic atrophy (GA) was applied to estimate hazard ratios of each genetic factor on progression to each specific stage. Models are adjusted for baseline age, gender, smoking, body mass index (BMI), education, antioxidant treatment, and the fellow eye status.
Controlling for the demographic and other genetic factors, the T allele of rs10468017 in LIPC decreased the risk of progression to NV (HR=0.57 [0.33-0.98], p=0.04) and may also reduce the risk of intermediate drusen (HR=0.72 [0.5-1.04], p=0.08). The T allele of rs1883025 in ABCA1 was associated with decreased risk of both intermediate drusen (HR= 0.81 [0.69-0.94], p=0.0061) and large drusen (HR=0.78 [0.65-0.94], p=0.0077). COL8A1 may be associated with progression from intermediate drusen to large drusen stage (p=0.02). The effects of previously identified genes CFH, C2, C3, CFB, ARMS2/HTRA1 were associated with progression from intermediate drusen to large drusen, and from large drusen to advanced stages.
Genes in different pathways influence AMD progression in different stages.
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