Nature Genetics: 中國團隊 解密溼性黃斑部病變Polypoidal choroidal vasculopathy (PCV) 單基因變異FGD6-Arg329

溼性老年黃斑部病變 陸科學家發現易感基因 2016-05-23 18:36 中央社 台北23日電 新華社報導，大陸中國科學院成都生物研究所科學家發現溼性老年黃斑部病變的易感基因。這項研究相關成果發表於知名國際遺傳學期刊「自然遺傳學」（Nature Genetics）。報導指出，溼性老年黃斑部病變是全球老年人視力喪失的主因之一，主要分為脈絡膜新生血管（CNV）和息肉狀脈絡膜血管病變（PCV）這兩種類型。先前發現的溼性老年黃斑部病變易感基因都是兩種類型共有，未發現個別類型獨有的易感基因，不利疾病早期診斷和有效治療。報導表示，中科院成都生物所客座研究員楊正林研究團隊透過全外顯子組測序，發現位於FGD6基因上的稀有變異，在氨基酸的第329位，由離胺酸變為精氨酸，這個位點與東亞人群的息肉狀脈絡膜血管病變有顯著相關，與脈絡膜新生血管無關。楊正林說，這項發現為進一步闡明致病機制提供線索，同時，為臨床分子診斷、預防和基因治療提供重要資訊。

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.