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

Yong Cheng,Lvzhen Huang,Wotan Zeng,Chunfang Zhang,Peng Zhou,Xiaoxin Li,Hoong-Chien Lee

doi:10.1371/journal.pone.0053665

Abstract

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.

Highlights

Age-related macular degeneration (AMD) causes irreversible central vision loss and is the leading cause of blindness in the elderly population, characterized as chronic and progressive degeneration of photoreceptors, the underlying retinal pigment epithelium (RPE), Bruch’s membrane, and possibly, the choriocapillaris in the macula. [1,2,3,4,5] AMD is divided clinically into dry and wet AMD
Four polymorphisms in which there was statistically significant among AMD patients, Polypoidal choroidal vasculopathy (PCV) patients and control subjects were identified
The distributions of the polymorphisms and genotypes of the ARMS2 gene for the 284 participants were presented in Table 2 and 3

Summary

Introduction

Age-related macular degeneration (AMD) causes irreversible central vision loss and is the leading cause of blindness in the elderly population, characterized as chronic and progressive degeneration of photoreceptors, the underlying retinal pigment epithelium (RPE), Bruch’s membrane, and possibly, the choriocapillaris in the macula. [1,2,3,4,5] AMD is divided clinically into dry and wet AMD. Polypoidal choroidal vasculopathy (PCV) is a macular disease found in the elderly that is as prevalent as exudative AMD in the Asian population, accounting for approximately 30% to 50% of the total number of eyes with senile macular diseases in elderly Asians [7,8]. It is characterized by an abnormal choroidal vascular network with characteristic aneurismal dilations at the border of the vascular network [9,10]. PCV has been described as a separate clinical entity differing from AMD and other disease associated with subretinal neovascularization and it remains controversial as to whether or not PCV represents a subtype of nAMD [10]

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