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Purpose We determine the angiopoietin 2 (ANGPT2) gene as a new susceptibility gene for neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV). Methods A total of 34 haplotype-tagging single-nucleotide polymorphisms (SNPs) were first genotyped in an exploratory Hong Kong Chinese cohort. Suggestive SNPs were replicated in a Shantou Chinese cohort and an Osaka Japanese cohort, with a total of 2343 subjects. The SNP rs800292 in the complement factor H (CFH) gene was genotyped in all the subjects. Genetic association and gene-gene interaction were analyzed. Results In the Hong Kong cohort, four SNPs in ANGPT2 (rs13255574, rs4455855, rs13269021, and rs11775442) were nominally associated with nAMD and PCV. The four ANGPT2 SNPs showed the same trends of association in the Shantou and Osaka cohorts. Combining the data from the 3 study cohorts revealed that SNPs rs4455855 and rs13269021 achieved study-wise significance (P < 0.0016), conferring an approximately 1.3-fold of increased risk for nAMD and PCV. Interaction analysis revealed the CFH SNP rs800292 has a highly significant interaction with the ANGPT2 SNP rs13269021 in nAMD and PCV in the combined analysis. Subsequent stratification analysis confirmed the interaction. Conclusions This study reveals ANGPT2 as a new susceptibility gene for nAMD and PCV, and it may affect disease susceptibility in association with CFH. Thus, this report provides new insights into the genetic architecture of nAMD and PCV.

Purpose We investigated the association of the ATP-binding cassette, subfamily G, member 1 (ABCG1) gene with polypoidal choroidal vasculopathy (PCV) and neovascular age-related macular degeneration (nAMD) in independent Chinese and Japanese cohorts. Methods A total of 12 haplotype-tagging single-nucleotide polymorphisms (SNPs) and the SNP rs57137919 in the ABCG1 gene were first analyzed in a Hong Kong Chinese cohort of 235 nAMD, 236 PCV, and 365 controls, using TaqMan genotyping assays. Two SNPs (rs57137919 and rs225396) that showed a disease-association were genotyped in a Shantou Chinese cohort of 189 nAMD, 187 PCV, and 670 controls, and an Osaka Japanese cohort of 192 nAMD, 204 PCV, and 157 controls, totaling 2435 subjects. Association analysis was performed in individual cohorts, followed by a pooled analysis of the data from all three cohorts. Results In the Hong Kong cohort, SNP rs57137919 was associated with PCV (odds ratio [OR] = 1.35). A tagging SNP rs225396 was associated with nAMD (OR = 1.28) and PCV (OR = 1.32). In the Osaka cohort, SNP rs225396 was associated with nAMD (OR = 1.42) and PCV (OR = 1.74). In the pooled analysis involving the 3 study cohorts, rs225396 showed an enhanced association with nAMD (P = 0.01, OR = 1.21, I2 = 14%) and PCV (P = 0.0001, OR = 1.35, I2 = 46%). Conclusions In this study, we have newly identified a haplotype-tagging SNP, rs225396, in ABCG1 to be associated with PCV and nAMD in Chinese and Japanese cohorts. This provides new evidence to support ABCG1 as a susceptibility gene for PCV and nAMD. Further replication in other populations should be warranted.