Copy number variation of age-related macular degeneration relevant genes in the Korean population

Abstract

Purpose: Studies that analyzed single nucleotide polymorphisms (SNP) in various genes have shown that genetic factors are strongly associated with age-related macular degeneration (AMD) susceptibility. Copy number variation (CNV) may be an additional type of genetic variation that contributes to AMD pathogenesis. This study investigated CNV in 4 AMD-relevant genes in Korean AMD patients and control subjects.

Methods: Four CNV candidate regions located in AMD-relevant genes (VEGFA, ARMS2/HTRA1, CFH and VLDLR), were selected based on the outcomes of our previous study which elucidated common CNVs in the Asian populations. Real-time PCR based TaqMan Copy Number Assays were performed on CNV candidates in 273 AMD patients and 257 control subjects.

Results: The predicted copy number (PCN, 0, 1, 2 or 3+) of each region was called using the CopyCaller program. All candidate genes except ARMS2/HTRA1 showed CNV in at least one individual, in which losses of VEGFA and VLDLR represent novel findings in the Asian population. When the frequencies of PCN were compared, only the gain in VLDLR showed significant differences between AMD patients and control subjects (p = 0.025). Comparisons of the raw copy values (RCV) revealed that 3 of 4 candidate genes showed significant differences (2.03 vs. 1.92 for VEGFA, p<0.01; 2.01 vs. 1.97 for CFH, p<0.01; 1.97 vs. 2.01, p<0.01 for ARMS2/HTRA1).

Conclusion: CNVs located in AMD-relevant genes may be associated with AMD susceptibility. Further investigations encompassing larger patient cohorts are needed to elucidate the role of CNV in AMD pathogenesis.

Figure 1. Fundus photographs in patients with copy number (CN) gain or loss.

A 78-year-old man with CN gain at VEGFA showed typical features of neovascular AMD; with choroidal neovascularization in the left eye and confluent drusen in the right eye (A). Fluorescein angiography and spectral domain optical coherence tomography (SD-OCT) show choroidal neovascularization with cystoid macular edema at the center of the choroidal neovascularization in the left eye. The patient with CN loss at CFH gene was a 66-year-old woman with confluent soft drusen in both eyes (B). Flourescein angiography shows multiple hyper-fluorescent lesions at macula of both eyes and SD-OCT shows clumps in the neurosensory retina and focal elevations of retinal pigment epithelial layer.