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.
Duke Scholars
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Related Subject Headings
- Wet Macular Degeneration
- Subcellular Fractions
- Polymorphism, Single Nucleotide
- Mutation, Missense
- Humans
- Guanine Nucleotide Exchange Factors
- Gene Expression Profiling
- Ethnicity
- Endothelium, Vascular
- Developmental Biology
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Wet Macular Degeneration
- Subcellular Fractions
- Polymorphism, Single Nucleotide
- Mutation, Missense
- Humans
- Guanine Nucleotide Exchange Factors
- Gene Expression Profiling
- Ethnicity
- Endothelium, Vascular
- Developmental Biology