A missense variant in FGD6 confers increased risk of polypoidal choroidal vasculopathy
A missense variant in FGD6 confers increased risk of polypoidal choroidal vasculopathy
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FGD6 的错义变异会增加息肉状脉络膜血管病变的风险
DOI：
10.1038/ng.3546
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发表时间：
2016-06-01
期刊：
影响因子：
30.8
通讯作者：
Yang, Zhenglin
中科院分区：
文献类型：
--
作者：
Huang, Lulin;Zhang, Houbin;Yang, Zhenglin
息肉样脉络膜血管病变（PCV）是“湿性”年龄相关性黄斑变性（AMD）的一种亚型，占亚洲患者湿性AMD病例的55%。与脉络膜新生血管（CNV）亚型相比，PCV的遗传危险因素相对未知。一个汉族队列的外显子组测序分析，并在四个独立队列中进行复制，发现FGD6基因中罕见的c.986A>G （P . lys329arg）变异与PCV显著相关(P = 2.19 × 10(-16)，优势比(OR) = 2.12)，但与CNV无关（P = 0.26, OR = 1.13）。FGD6-Arg329的细胞内定位与FGD6-Lys329不同。在体外，FGD6可调节促血管生成活性，氧化磷脂可增加FGD6的表达。FGD6-Arg329比FGD6-Lys329更能促进小鼠视网膜血管的异常发育。总的来说，我们的数据表明氧化磷脂和FGD6-Arg329可能协同作用，增加对PCV的易感性。
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.