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Age-related maculopathy susceptibility 2( ARMS2 ) was suggested to be associated with neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) in multiple genetic studies in Caucasians and Japanese. To date, no biological properties have been attributed to the putative protein in nAMD and PCV. The complete genes of  ARMS2  and  HTRA1  including all exons and the promoter region were assessed using direct sequencing technology in 284 unrelated mainland northern Chinese individuals: 96 nAMD patients, 92 PCV patients and 96 controls. Significant associations with both nAMD and PCV were observed in 2 polymorphisms of  ARMS2  and  HTRA1  rs11200638, with different genotypic distributions between nAMD and PCV ( p <0.001). After adjusting for rs11200638,  ARMS2  rs10490924 remained significantly associated with nAMD and PCV ( p <0.001). Then we overexpressed wild-type ARMS2 and ARMS2 A69S mutation (rs10490924) in RF/6A cells and RPE cells as in vitro study model. Cell proliferation, attachment, migration and tube formation were analyzed for the first time. Compare with wild-type ARMS2, A69S mutation resulted in a significant increase in proliferation and attachment but inhibited cell migration. Moreover, neither wild-type ARMS2 nor A69S mutation affected tube formation of RF/6A cells. There is a strong and consistent association of the  ARMS2/HTRA1  locus with both nAMD and PCV, suggesting the two disorders share, at least partially, similar molecular mechanisms. Neither wild-type ARMS2 nor A69S mutation had direct association with neovascularisation in the pathogenesis of AMD.

Genetic and Functional Dissection of ARMS2 in Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy