Identification ofPGFas a New Gene for Neovascular Age-Related Macular Degeneration in a Chinese Population

Abstract

PURPOSE.To determine the associations of the VEGFA, VEGFB, and placental growth factor (PGF) genes with neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV).METHODS. Seven single-nucleotide polymorphisms (SNPs) in VEGFA, three SNPs in VEGFB, and five SNPs in PGF were genotyped in 1722 unrelated Chinese participants, including a Hong Kong cohort of 214 nAMD patients, 236 PCV patients, and 365 controls, and an independent Shantou cohort of 189 nAMD patients, 187 PCV patients, and 531 controls, using TaqMan genotyping assays.RESULTS. Placental growth factor SNPs rs2268615 (G allele, P ¼ 0.0047; odds ratio [OR] ¼ 1.54, 95% confidence interval [CI], 1.14-2.08) and rs2268614 (G allele, P ¼ 0.015; OR ¼ 1.46, 95% CI, 1.07-1.97) were associated with nAMD. A significant omnibus haplotype association with nAMD was detected for a two-SNP window containing rs2268615 and rs2268614, with a haplotype G-G conferring a 1.54-fold increased risk (P ¼ 0.0042) in the Hong Kong cohort and a 1.42-fold risk (P ¼ 0.012) in the Shantou cohort. Pooling of the Hong Kong and Shantou data enhanced the association of nAMD with rs2268615 (P ¼ 0.0022; OR ¼ 1.38, 95% CI, 1.12-1.69; I 2 ¼ 0%), rs2268614 (P ¼ 0.0067; OR ¼ 1.33, 95% CI, 1.08-1.63; I 2 ¼ 0%), and the G-G haplotype (P ¼ 0.0013; OR ¼ 1.46, 95% CI, 1.16-1.84; I 2 ¼ 0%). In contrast, the PGF SNPs and haplotype were not associated with PCV. Our results also revealed no association of SNPs in VEGFA and VEGFB with nAMD or PCV.CONCLUSION. Placental growth factor is a susceptibility gene for nAMD in a Chinese population, providing new evidence to support a biological role of PGF in choroidal neovascularization.Keywords: PGF, AMD, genetic association A ge-related macular degeneration (AMD) is a leading cause of irreversible central visual impairment among elderly individuals in developed countries. Age-related macular degeneration is characterized by degenerative features at the macula affecting the photoreceptors and retinal pigment epithelium (RPE), often presenting with macular drusen in the early stage. Advanced AMD can be classified into geographic atrophy (dry AMD) and neovascular AMD (nAMD; or wet AMD). Prevalence of advanced AMD has been estimated to be 0.59% in Caucasian populations and 0.56% in Asian populations aged 40 to 79 years.1 Neovascular AMD accounts for the majority of severe visual loss in Asian AMD patients. Retinal pigment epithelium detachment, subretinal fluid, hemorrhage, and fibrotic scar are common features in nAMD. Polypoidal choroidal vasculopathy (PCV) is another serious macular disease usually presented with subretinal polyp-like lesions, RPE detachment, retinal edema, and subretinal hemorrhage. In PCV, the inner choroidal vascular networks terminated in polypoidal lesions, which are different from the generalized choroidal neovascularization (CNV) in nAMD and best detected by indocyanine green angiography (ICGA). 3Polypoidal choroidal vasculopathy is reportedly more prevalent among Asians and African-Americans compared ...

Endocan Blockade Suppresses Experimental Ocular Neovascularization in Mice

“…1 Clinical investigations have shown that the expressions of PIGF, VEGF, and endocan are upregulated in vitreous fluid from patients with proliferative diabetic retinopathy. 25,26 Based on our results, inhibition of endocan caused a decrease in VEGF, PIGF and their receptors in the OIR and CNV models, suggesting that the blockade of endocan can modulate angiogenic activities in pathologic NV progression by interacting with VEGF family members. Our results were consistent with previous reports showing that VEGF signaling was reduced in the absence of endocan in the early postnatal mouse retina.…”

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

“…24 A P value less than 0.0012 (0.05/42, where 42 is the pairs of interaction) defined a significantly statistical interaction. After identifying a significant interaction between ANGPT2 rs13269021 and CFH rs800292, the study subjects were stratified by using dominant and recessive models of the risk G allele of ANGPT2 rs13269021.…”

Genetic interaction between placental growth factor and vascular endothelial growth factor A in psoriasis

“…We were most interested in the two most commonly occurring SNPs within the PGF gene, rs2268614 and the rs2268615, owing to their previously described association with plasma levels of PGF 9 and the association with genetic susceptibility to angiogenesis-driven disease. 8 Genotyping was successfully performed for Genotyping of the vascular endothelial growth factor A single nucleotide polymorphisms À460 (rs833061) and +405 (rs2010963)…”

“…7 A significant association between the haploblock-tagging SNPs rs2286614 and rs2268615 and neovascular age-related macular degeneration has been reported in two Chinese cohorts, suggesting a role for PGF as a susceptibility gene in a disease with a putative angiogenic basis. 8 Furthermore, the rs2268614 SNP has been associated with plasma levels of PGF in two independent European populations. 9 Little is known about what regulates PGF gene expression, although several studies have implicated VEGFA as a key regulatory factor.…”