A missense variant in FGD6 confers increased risk of polypoidal choroidal vasculopathy.
Polypoidal choroidal vasculopathy (PCV), a subtype of 'wet' age-related macular degeneration (AMD), constitutes up to 55% of cases of wet AMD in Asian patients. In contrast to the choroidal neovascularization (CNV) subtype, the genetic risk factors for PCV are relatively unknown. Exome sequencing analysis of a Han Chinese cohort followed by replication in four independent cohorts identified a rare c.986A>G (p.Lys329Arg) variant in the FGD6 gene as significantly associated with PCV (P = 2.19 × 10(-16), odds ratio (OR) = 2.12) but not with CNV (P = 0.26, OR = 1.13). The intracellular localization of FGD6-Arg329 is distinct from that of FGD6-Lys329. In vitro, FGD6 could regulate proangiogenic activity, and oxidized phospholipids increased expression of FGD6. FGD6-Arg329 promoted more abnormal vessel development in the mouse retina than FGD6-Lys329. Collectively, our data suggest that oxidized phospholipids and FGD6-Arg329 might act synergistically to increase susceptibility to PCV.
Huang, L; Zhang, H; Cheng, C-Y; Wen, F; Tam, POS; Zhao, P; Chen, H; Li, Z; Chen, L; Tai, Z; Yamashiro, K; Deng, S; Zhu, X; Chen, W; Cai, L; Lu, F; Li, Y; Cheung, C-MG; Shi, Y; Miyake, M; Lin, Y; Gong, B; Liu, X; Sim, K-S; Yang, J; Mori, K; Zhang, X; Cackett, PD; Tsujikawa, M; Nishida, K; Hao, F; Ma, S; Lin, H; Cheng, J; Fei, P; Lai, TYY; Tang, S; Laude, A; Inoue, S; Yeo, IY; Sakurada, Y; Zhou, Y; Iijima, H; Honda, S; Lei, C; Zhang, L; Zheng, H; Jiang, D; Zhu, X; Wong, T-Y; Khor, C-C; Pang, C-P; Yoshimura, N; Yang, Z
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