Molecular genomics of age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) – to identify new genes and genetic biomarkers for AMD and PCV
Dr CHEN Li Jia, Guy
Publications (*co-first author):
- Chen LJ*, Ma L*, Chu WK, Lai TY, Chen H, Brelén ME, Rong SS, Young AL, Tam PO, Zhang M, Pang CP. Identification of PGF as a new gene for neovascular age-related macular degeneration in a Chinese population. Invest Ophthalmol Vis Sci. 2016 Apr 1;57(4):1714-20.
- Rong SS, Tang FY, Chu WK, Ma L, Yam JC, Tang SM, Li J, Gu H, Young AL, Tham CC, Pang CP, Chen LJ. Genetic Associations of Primary Angle-Closure Disease: A Systematic Review and Meta-analysis. Ophthalmology. 2016 Feb 4. pii: S0161-6420(15)01530-4.
- Ma L, Tang FY, Chu WK, Young AL, Brelen ME, Pang CP, Chen LJ. Association of toll-like receptor 3 polymorphism rs3775291 with age-related macular degeneration: a systematic review and meta-analysis. Sci Rep. 2016 Jan 22;6:19718.
- Ma L, Li Z, Liu K, Rong SS, Brelen ME, Young AL, Kumaramanickavel G, Pang CP, Chen H, Chen LJ. Association of Genetic Variants with Polypoidal Choroidal Vasculopathy: A Systematic Review and Updated Meta-analysis. Ophthalmology. 2015 Sep;122(9):1854-65.
- Ma L, Tang SM, Rong SS, Chen H, Young AL, Kumaramanickavel G, Pang CP, Chen LJ. Association of PEDF polymorphisms with age-related macular degeneration and polypoidal choroidal vasculopathy: a systematic review and meta-analysis. Sci Rep. 2015 Mar 30;5:9497.
- Liu K, Lai TY, Ma L, Lai FH, Young AL, Brelen ME, Tam PO, Pang CP, Chen LJ. Ethnic differences in the association of SERPING1 with age-related macular degeneration and polypoidal choroidal vasculopathy. Sci Rep. 2015 Mar 24;5:9424.
- Lau LC*, Ma L*, Young AL, Rong SS, Jhanji V, Brelen ME, Pang CP, Chen LJ. Association of common variants in TCF4 and PTPRG with Fuchs’ corneal dystrophy: a systematic review and meta-analysis. PLoS One. 2014 Oct 9;9(10):e109142.
Age-related macular degeneration (AMD) is a leading cause of irreversible blindness in the elderly. Neovascular AMD (nAMD), characterized by choroidal neovascularization (CNV), accounts for the majority of severe visual loss in Asian AMD patients. Polypoidal choroidal vasculopathy (PCV) is a macular disease characterized by polyp-like lesions in the choroidal vessels, being different from the CNV in nAMD. The etiologies of AMD and PCV are complex, involving multiple genetic and environmental risk factors. To date, variants in more than 30 genetic loci have been associated with AMD. For PCV, over 10 genes have been found with association [ref #4]. However, these genes altogether account for only a small to moderate proportion of heritability. Therefore, to identify new susceptibility genes will lead to discover more diagnostic or prognostic biomarkers of AMD and PCV, and filling the gap of their missing heritability.
- In 2012, aflibercept, a fusion protein that blocks vascular endothelial growth factor A (VEGFA), VEGFB and placental growth factors (PGF), was approved for treating macular degeneration. The PGF, a target of anti-VEGF therapy, plays an important role in angiogenesis. We determine the associations of the PGF, VEGFA and VEGFB genes with nAMD and PCV, respectively, using haplotype-tagging single-nucleotide polymorphisms (SNPs) and reported functional SNPs. Our results revealed PGF as a new susceptibility gene for nAMD in Chinese.[ref #1]
- In our recent study of genes in the high density lipoprotein (HDL) cholesterol metabolism pathway, a SNP, rs57137919, in the ATP-binding cassette, sub-family G, member 1 (ABCG1) gene showed association with PCV, but not with nAMD. However, rs57137919 was the only SNP that was selected from ABCG1. Therefore, we performed a haplotype-tagging SNP association analysis and found ABCG1 as a susceptibility gene for PCV and nAMD in the Chinese and Japanese populations, with a stronger association in Japanese.[manuscript under review]
- The angiopoietin/angiopoietin receptors cascades are the second most important family by regulating angiogenesis. The ligand, angiopoietin 2 (Ang2), rather than angiopoietin 1 (Ang1), activates integrin β1 (ITGB1), leading to endothelial destabilization in vitro and in vivo. We performed a haplotype-tagging SNP association analysis to determine the association of the ANGPT2 and ITGB1 genes with both nAMD and PCV. We identified ANGPT2 as a new susceptibility gene for nAMD and PCV and gene-gene interaction between CFH and ANGPT2 in the Chinese and Japanese populations.[manuscript in submission]
- We conducted a genome-wide association study (GWAS) on PCV with an aim to identify novel loci for PCV. The CFH SNP rs1329428 showed a genome-wide significant association, with a P value <10-8. A novel SNP rs1906 showed the same trend of effect in the discovery cohort and 6 replication cohorts, although the P value did not reach the GWAS significance level. In contrast, SNP rs1906 was not associated with nAMD. Further replications are in progress to confirm its role in PCV.
These findings have laid important foundation for further genetic, biological and therapeutic studies of nAMD and PCV.