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

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.

Polypoidal Choroidal Vasculopathy: Clinical Features and Genetic Predisposition

“…The 2 major AMD susceptibility loci (CFH and ARMS2/HTRA1) have been shown to influence the risk of PCV [18,19,20,94,95,96,97,98,99,100]. In particular, SNPs in the ARMS2 / HTRA1 locus, rs10490924 (A69S) and rs11200638, are significantly associated with PCV [18,20,22,23,24].…”

Association of Genetic Variants with Polypoidal Choroidal Vasculopathy

“…Eleven studies tested the most investigated SNP, ARMS2 rs10490924, involving 2250 patients with PCV and 1984 patients with nAMD (Table 7). 13,16,61,67,71,80,85,94,96,97,104 The frequency of the T allele was significantly lower in PCV than in nAMD (summary OR, 0.67; 95% CI, 0.61e0.74; P ¼ 6.83Â10 À17 ) ( Table 7 and Fig 3A, available at www.aaojournal.org). Five studies tested the HTRA1 SNP rs11200638.…”

“…Five studies tested the HTRA1 SNP rs11200638. 15,61,71,74,91 The A allele frequency was lower in PCV, with a summary OR of 0.69 (95% CI, 0.59e0.81; P ¼ 3.32Â10 À6 ) ( Table 7 and Fig 3B, available at www.aaojournal.org). The other 10 SNPs, namely, rs3750848, rs36212731, rs36212732, rs36212733, rs3750847, rs3750846, rs10664316, c.372_815del443ins54, rs2014307, and rs2672587, were evaluated in 2 to 3 cohorts and showed significant differences between PCV and nAMD (P values between 7.19Â10 À9 and 0.05) ( Table 7).…”

Gene–gene interaction of CFH, ARMS2, and ARMS2/HTRA1 on the risk of neovascular age-related macular degeneration and polypoidal choroidal vasculopathy in Chinese population

“…7 Evidence suggests that nAMD and PCV, despite their different phenotypic manifestations, may share common genetic risk factors. [8][9][10][11][12] Susceptibility to nAMD is complex, involving genetic, lifestyle, and environmental factors, although the specifics of the etiology remain unresolved.…”