Identification and characterization of a novel promoter variant in placental growth factor for neovascular age-related macular degeneration.

Abstract

PURPOSE\nIntronic variants in the placental growth factor (PGF) gene have been associated with neovascular age-related macular degeneration (AMD). This study is to discover and characterize rare variants in the PGF gene for neovascular AMD.\n\n\nMETHODS\nThe promoter region, coding sequences and splicing regions of the PGF gene were sequenced in a Hong Kong southern Chinese cohort of 235 neovascular AMD patients and 435 controls. A detected 18 base-pair deletion variant in the promoter region of PGF was analyzed in a Shantou southern Chinese cohort of 189 neovascular AMD patients and 846 controls. The transcription activity of this disease-associated promoter variant was determined in human ARPE-19\u202fcells by promoter-luciferase analysis.\n\n\nRESULTS\nA novel 18-base-pair deletion mutation in the promoter region of PGF was identified in 3 (1.28%) patients and 1 (0.23%) control subject (OR\u202f=\u202f5.61; 95% CI 0.58-54.26) in the Hong Kong cohort, and in 2 (1.06%) patients and 2 (0.24%) controls (OR\u202f=\u202f4.51; 95% CI: 0.63-32.25) in the Shantou cohort. In the combined southern Chinese sample, this deletion had a significant association with neovascular AMD (P\u202f=\u202f0.026; OR\u202f=\u202f5.08, 95% CI: 1.21-21.36). The 18-base-pair deletion was predicted to alter the transcription factor binding sites in the PGF promoter, and higher luciferase expression was detected in ARPE-19\u202fcells transfected with the deletion variant plasmid than those transfected with wild type plasmid (P\u202f=\u202f0.0002).\n\n\nCONCLUSIONS\nThis study identified a rare, functional promoter variant in the PGF gene that increases PGF transcription activity and confers a 5-fold risk to neovascular AMD.