湿性老年黄斑变性（wAMD）是全世界致盲的主要原因之一，息肉状脉络膜血管病变(PCV)是wAMD的特殊类型。在包括中国人在内的亚洲人群中，PCV发病率仅次于脉络膜新生血管(CNV)，占接近50%。已发现的AMD易感基因均为PCV和CNV共有，尚未鉴定公认的PCV特有的易感基因/位点，不利于PCV的早期诊断和有效治疗。本实验室经过多年努力，通过全外显子组测序关联分析及验证，在共3318例PCV， 2457例CNV及9087例对照的研究中发现，FGD6基因的一个稀有变异rs77466370与中国汉族人PCV有极显著相关而与CNV无关。本课题组将在前期研究工作的基础上，展开进一步研究，包括FGD6基因上另三个稀有突变验证，FGD6体外功能，FGD6与HTRA1和CFH的调控关系，以及构建hFGD6转基因以及hFGD6点突变p.329Arg基因敲入小鼠动物模型，研究FGD6的PCV的致病机制。

Wet age-related macular degeneration (wet AMD) is one of the leading causes of blindness in the world. Polypoidal choroidal vasculopathy (PCV) is a special type of wet AMD. In Asia, the incidence of PCV is only next to choroidal neovascularization (CNV). However, the molecular mechanisms underlying in PCV is not well defined. In previous work, we discovered a rare variant (rs61751584) in the FGD6 gene through whole exome sequencing followed by large samples’ replication (totally including 3318 PCV cases, 2457 CNV cases and 9087 controls); which showed that FGD6 was strongly associated with PCV but not CNV. In order to understand the role of FGD6 in pathogenesis of PCV, firstly, we plan to determine the association of other three rare mutations in the FGD6 gene and PCV to further genetically confirming the risk of FGD6 for PCV. Secondly, we propose to investigate the function of FGD6 by in-vitro cell biology methods and explore the regulation role of FGD6 with HTRA1 and CFH. Finally, we are prepared to breed choroid layer expression hFGD6 transgenic mice and FGD6 p.329Arg knockin mice to investigate the in-vivo function of FGD6 and to elucidate the interplay of FGD6 and PCV. This proposed research will provide valuable information for PCV and be helpful to study of disease mechanisms and therapy development in PCV.