Genes in the High-Density Lipoprotein Metabolic Pathway in Age-related Macular Degeneration and Polypoidal Choroidal Vasculopathy

Liu, Ke; Chen, Li Jia; Lai, Timothy Y. Y.; Tam, Peter; Ho, Mary; Chiang, Sylvia W. Y.; Liu, David T.L.; Young, Alvin L.; Yang, Zhenglin; Pang, Chi Pui

doi:10.1016/j.ophtha.2013.10.042

Cited by 58 publications

(60 citation statements)

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“…Polypoidal choroidal vasculopathy was diagnosed based on the presence of nodular polypoidal lesions as shown by ICGA. [16][17][18] Diagnosis of nAMD and PCV was distinguished by FA and ICGA. Patients with other causes of CNV, such as myopic CNV, or with CNV and PCV in the same or fellow eye, were excluded.…”

Section: Study Participantsmentioning

confidence: 99%

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

Brelén

Tsujikawa

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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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...

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Section: Study Participantsmentioning

confidence: 99%

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

Brelén

Tsujikawa

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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“…10,15,33 The genetic effects of two significant PGF SNPs, rs2268615 and rs2268614, were estimated in the context of both CFH rs800292 and HTRA1 rs11200638 in an additive model by using logistic regression analysis in PLINK. The CFH SNP rs1061170 was not involved in the logistic regression analysis since it is rare and not associated with nAMD in Chinese.…”

Section: Discussionmentioning

confidence: 99%

“…Polypoidal choroidal vasculopathy was diagnosed upon a choroidal origin of polypoidal lesions as shown by ICGA. 10,[15][16][17] Diagnosis of nAMD and PCV were distinguished by FFA and ICGA. Subjects with any eye having nAMD and PCV lesions concurrently or other causes of CNV were excluded.…”

Section: Study Participants In the Hong Kong Cohortmentioning

confidence: 99%

“…8 No GWAS of large scale has been conducted in PCV, but there are reported associations of PCV with AMD-associated genes such as CFH, ARMS2-HTRA1, complement component 2 iovs.arvojournals.org j ISSN: 1552-5783 (C2), and cholesteryl ester transfer protein (CETP). 9,10 In a recent systematic review and meta-analysis, the majority of genes that were associated with PCV were also associated with AMD. One clear exception was the ARMS2-HTRA1 polymorphisms, which were significantly different between nAMD and PCV, 7 suggesting that the genetic components of AMD and PCV are partially different.…”

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

Chen

Chu

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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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 ...

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“…Between 50 and 60% of the disease etiology can be attributed to genetic variations that encode the complement factor H (CFH), ARMS2, and interleukin-8 (IL-8) (Cascella et al, 2014). Genes in the complement pathway, such as CFH (Edwards et al, 2005;Klein et al, 2005;Raychaudhuri et al, 2011), angiogenesis pathway, such as vascular endothelial growth factor (VEGF) (Yu et al, 2011), high-density lipoprotein metabolic pathway, such as cholesteryl ester transfer protein (CETP) (Liu et al, 2014), as well as the HtrA serine peptidase 1 (HTRA1) gene (Dewan et al, 2006) have been associated with AMD. In addition, complement components 3 and 9 have recently been found to be associated with AMD (Yanagisawa et al, 2011;Seddon et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Effect of ARMS2 gene polymorphism on intravitreal ranibizumab treatment for neovascular age-related macular degeneration

Bardak

Erçalik

et al. 2016

Genet. Mol. Res.

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ABSTRACT. Age-related macular degeneration (AMD) is a leading cause of blindness in developed countries. The ARMS2 gene has been found to be associated with AMD. Currently, intravitreal ranibizumab (IVR) treatment is one of the widely used treatments for neovascular AMD. The aim of this study was to investigate the association between the genotype of ARMS2 rs10490924 polymorphism and IVR treatment responsiveness in patients with neovascular AMD. The study included 39 patients with advanced neovascular AMD (patient group) and 250 healthy individuals with exome sequencing data (control group). The patient group was divided into three subgroups: GG (N = 10), TG (N = 14), and TT (N = 15). Before IVR treatment, all patients had intraretinal or subretinal fluid or both. They received three monthly IVR-injection treatments. One month after the third injection, the patients were evaluated as either "responders" or "non-responders" based on the presence or absence of intraretinal or subretinal fluid or both. The patient subgroups TG and TT had an 8.56-and 39-fold higher risk of AMD, respectively, than patient subgroup GG had. The allele frequency was 0.537 and 0.10 in the patient and control groups, respectively. Within the patient subgroup TT, there was a significant difference between the "responders" and "non-responders" (P = 0.025). In conclusion, in neovascular AMD patients undergoing IVR treatment, TT genotype tended to be a better predictor of good short-term treatment response, compared to the GG and TG genotypes. Further studies using confirmed genetic biomarkers for individualized optimal treatments are required.

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Genes in the High-Density Lipoprotein Metabolic Pathway in Age-related Macular Degeneration and Polypoidal Choroidal Vasculopathy

Cited by 58 publications

References 35 publications

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

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

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

Effect of ARMS2 gene polymorphism on intravitreal ranibizumab treatment for neovascular age-related macular degeneration

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