Identification of ANGPT2 as a New Gene for Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy in the Chinese and Japanese Populations

Abstract

Citation: Ma L, Brelen ME, Tsujikawa M, et al. Identification of ANGPT2 as a new gene for neovascular age-related macular degeneration and polypoidal choroidal vasculopathy in the Chinese and Japanese populations. Invest Ophthalmol Vis Sci. 2017;58:107658: -108358: . DOI:10.1167 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.Keywords: ANGPT2, gene association, age-related macular degeneration, polypoidal choroidal vasculopathy, gene-gene interaction A ge-related macular degeneration (AMD) is a leading cause of irreversible central vision loss in the elderly, especially in developed countries. Neovascular AMD (nAMD), a major form of advanced AMD characterized by choroidal neovascularization (CNV), accounts for the majority of severe visual loss in AMD patients. Polypoidal choroidal vasculopathy (PCV) is a macular disease characterized by polyp-like lesions in the choroidal vessels, which are best seen in indocyanine green angiography (ICGA).1 Polypoidal choroidal vasculopathy and nAMD have similarities in clinical manifestations. For example, they can cause submacular hemorrhage, exudation, and scarring, leading to central vision loss. Interestingly, CNV and PCV can present concurrently in approximately 3.23% of patients, 2 suggesting that they may have a shared mechanism. However, while the prevalence of nAMD (approximately 0.46%) is similar between Caucasian and Asian populations, 3 the prevalence of PCV is approximately 3-fold higher in Asians than in Caucasians, 4 suggesting an ethnic background is related to the occurrence of PCV. Moreover, nAMD and PCV respond differentl...

Advances in Age-related Macular Degeneration Understanding and Therapy

“…Elevated levels of ANG-2 (43 vs. 9 pg/L) were found in the aqueous humor of patients with neovascular AMD, 145 and a small study from Hong Kong has shown some suggested associations between ANG-2 SNPs and neovascular AMD, particularly polypoidal. 146 Otani et al showed that surgically excised CNV stained positive for ANG-1 and ANG-2 with increased ANG-2 immunoreactivity in the highly vascularized regions of CNV—similar to the staining pattern of VEGF. 147 Heras et al also detected variable amounts of VEGF, ANG-1, and ANG-2 in surgically excised CNV membranes; TIE-2 and VEGF receptor (VEGFR) were not detectable in their study.…”

New Developments in the Classification, Pathogenesis, Risk Factors, Natural History, and Treatment of Branch Retinal Vein Occlusion

“…Recently, a study reported that aqueous angiopoietin-like 4 (ANGPTL4) level in patients with ME due to BRVO is also significantly higher [40]. The ANGPLTL4 mediates the development of vascular permeability and angiogenesis in hypoxic conditions, is overexpressed in general ischemic retinopathy, and promotes the development of CME [41, 42]. If marked hypoxia persists, irreversible structural changes in the macular occur, and the disturbed visual acuity (VA) is almost always lasting.…”

Comparison of cytokine levels in the aqueous humor of polypoidal choroidal vasculopathy and neovascular age-related macular degeneration patients

“…PCV shares many similarities with nAMD, including clinical manifestations, genetic background, and both of them are choroidal vasculopathy associated with subretinal hemorrhage, scars and fibrosis [1], so some views support PCV is a subtype of nAMD. However, they still differ in pathophysiology, histopathological, epidemiology, some clinical characteristics, treatment responses, natural course and special genes [2][3][4][5][6]. There remain controversies as to whether PCV is merely a variant of nAMD or its own distinct entity [7].…”