A missense variant in FGD6 confers increased risk of polypoidal choroidal vasculopathy

Lulin Huang; Houbin Zhang; Ching-Yu Cheng; Feng Wen; Pancy O S Tam; Peiquan Zhao; Haoyu Chen; Zheng Li; Lijia Chen; Zhengfu Tai; Kenji Yamashiro; Shaoping Deng; Xianjun Zhu; Weiqi Chen; Li Cai; Fang Lu; Yuanfeng Li; Chui-Ming G Cheung; Yi Shi; Masahiro Miyake; Yin Lin; Bo Gong; Xiaoqi Liu; Kar-Seng Sim; Jiyun Yang; Keisuke Mori; Xiongzhe Zhang; Peter D Cackett; Motokazu Tsujikawa; Kohji Nishida; Fang Hao; Shi Ma; He Lin; Jing Cheng; Ping Fei; Timothy Y Y Lai; Sibo Tang; Augustinus Laude; Satoshi Inoue; Ian Y Yeo; Yoichi Sakurada; Yu Zhou; Hiroyuki Iijima; Shigeru Honda; Chuntao Lei; Lin Zhang; Hong Zheng; Dan Jiang; Xiong Zhu; Tien-Ying Wong; Chiea-Chuen Khor; Chi-Pui Pang; Nagahisa Yoshimura; Zhenglin Yang

doi:10.1038/ng.3546

A missense variant in FGD6 confers increased risk of polypoidal choroidal vasculopathy

Nat Genet. 2016 Jun;48(6):640-7. doi: 10.1038/ng.3546. Epub 2016 Apr 18.

Authors

Lulin Huang^{1

2

3

4}, Houbin Zhang^{1

4}, Ching-Yu Cheng^{5

6

7}, Feng Wen⁸, Pancy O S Tam⁸, Peiquan Zhao⁹, Haoyu Chen¹⁰, Zheng Li^{5

6

11}, Lijia Chen¹², Zhengfu Tai^{1

2

3

4}, Kenji Yamashiro¹³, Shaoping Deng^{1

4}, Xianjun Zhu^{1

4}, Weiqi Chen¹⁰, Li Cai¹, Fang Lu¹, Yuanfeng Li¹, Chui-Ming G Cheung^{5

6}, Yi Shi^{1

4}, Masahiro Miyake¹³, Yin Lin^{1

4}, Bo Gong¹, Xiaoqi Liu¹, Kar-Seng Sim^{5

8

11}, Jiyun Yang¹, Keisuke Mori¹⁴, Xiongzhe Zhang⁸, Peter D Cackett^{5

15}, Motokazu Tsujikawa¹⁶, Kohji Nishida¹⁶, Fang Hao¹, Shi Ma¹, He Lin¹, Jing Cheng¹, Ping Fei⁹, Timothy Y Y Lai¹², Sibo Tang⁸, Augustinus Laude¹⁷, Satoshi Inoue¹⁸, Ian Y Yeo^{5

7}, Yoichi Sakurada¹⁹, Yu Zhou¹, Hiroyuki Iijima²⁰, Shigeru Honda¹⁹, Chuntao Lei²¹, Lin Zhang^{1

4}, Hong Zheng¹, Dan Jiang¹, Xiong Zhu¹, Tien-Ying Wong^{5

6

7}, Chiea-Chuen Khor^{5

6

11}, Chi-Pui Pang¹², Nagahisa Yoshimura¹³, Zhenglin Yang^{1

2

3

4}

Affiliations

¹ Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
² Institute of Chengdu Biology, Chinese Academy of Sciences, Chengdu, China.
³ Sichuan Translational Medicine Hospital, Chinese Academy of Sciences, Chengdu, China.
⁴ Center of Information in Biomedicine, University of Electronic Science and Technology of China, Chengdu, China.
⁵ Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
⁶ Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
⁷ Duke-National University of Singapore Graduate Medical School, Singapore.
⁸ State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
⁹ Department of Ophthalmology, Xinhua Hospital, Shanghai Jiaotong University, Shanghai, China.
¹⁰ Joint Shantou International Eye Center, Shantou University and Chinese University of Hong Kong, Shantou, China.
¹¹ Department of Human Genetics, Genome Institute of Singapore, Singapore.
¹² Department of Ophthalmology and Visual Sciences, Chinese University of Hong Kong, Hong Kong, China.
¹³ Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
¹⁴ Department of Ophthalmology, Saitama Medical University, Iruma, Japan.
¹⁵ Princess Alexandra Eye Pavilion, Edinburgh, UK.
¹⁶ Department of Ophthalmology, Osaka University Medical School, Osaka, Japan.
¹⁷ National Health care Group Eye Institute, Tan Tock Seng Hospital, Singapore.
¹⁸ Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
¹⁹ Department of Surgery, Division of Ophthalmology, Kobe University Graduate School of Medicine, Kobe, Japan.
²⁰ Department of Ophthalmology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
²¹ Department of Ophthalmology, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China.

PMID: 27089177
DOI: 10.1038/ng.3546

Abstract

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.

MeSH terms

Cells, Cultured
China
Cohort Studies
Endothelium, Vascular / cytology
Endothelium, Vascular / metabolism
Ethnicity
Gene Expression Profiling
Guanine Nucleotide Exchange Factors / genetics*
Guanine Nucleotide Exchange Factors / metabolism
Humans
Mutation, Missense*
Polymorphism, Single Nucleotide
Subcellular Fractions / metabolism
Wet Macular Degeneration / genetics*

Substances

FGD6 protein, human
Guanine Nucleotide Exchange Factors