Age-Related Macular Degeneration: Genetic Variations and Animal Model

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Age-related macular degeneration (AMD) causes irreversible central visual loss in the aged population worldwide. Various studies suggest that AMD has a significant genetic component. Current evidence supports the hypothesis that gene variation creates a predisposition to the disease. In 2003, we initiated this project by recruiting advanced AMD patients and age-matched control individuals with normal retinas. Up to date, 476 individuals have been enrolled and 107 histopathological cases with AMD have been collected. We continue to analyze parts of 835 DNA samples from the Blue Mountain Eye Study in Australia and 534 DNA samples from the AREDS project in USA because some DNA samples had been ran out. We have compared the allelic frequencies of single nucleotide polymorphisms (SNPs) within candidate genes between AMD and control subjects, followed by functional studies of these SNPs by in vitro and/or in vivo experiments. Through this approach, we have identified genetic risk factors of AMD and the possible roles of these gene variations in the pathogenesis of the disease. Based on the information obtained from the above approaches, a genetically engineered animal (Ccl2/Cx3cr1 double deficiencies on rd8 background mice, DKO rd8) was generated to act as an AMD model in 2007. While caution must always be taken in translating findings in mouse models to findings in humans, the AMD-like phenotype of DKO rd8 makes the model an useful tool for evaluating potential therapies for AMD. In FY2014, (1) we continue working with collaborators to use our DKO rd8 model to study disease pathogenesis and therapeutic options of AMD, by evaluating the roles of PEDF (collaboration with Dr. S. Patricia Becerra), anti-LRP6 antibody in wnt singaling pathway(collaboration with Drs. Jinxing Ma and Heping Xu); (2) we provided DKO rd8 retina for studying the microRNAs role in AMD (collaboration with Drs. Shusheng Wang and Mengqing Xiang); (3) we published the association study between RBD51B and AMD in our cohorts; (4) a large scale SNP association study on the role of FBN2 in AMD was published. A similar study on the role of SNPs in 3-UTR regions of various genes in AMD is ongoing; (4) Some subjects recruited in this protocol were screened for their AMD related genotypes and will be used in the iPS project in collaboration with Drs. Sheldon Miller and Kapil Bharti; (5) we performed in vitro studies with ARPE-19 cells, human fetal RPE cells (collaboration with Dr. Sheldon Miller), and mouse retinal stem cells (collaboration with Ting Xie); (6) In this period, we published a total of 14 original or review papers including the novel findings of FBN2 gene in AMD.