Copy Number Variations in Candidate Genes in Neovascular Age-Related Macular Degeneration

Abstract

PURPOSE.The pathogenesis of age-related macular degeneration (AMD) is strongly influenced by genetic factors, and single nucleotide polymorphisms have been consistently linked to AMD. Copy number variation (CNV), or variation in the number of copies of a particular segment of DNA, may also contribute to AMD pathogenesis. This study evaluated CNVs in candidate genes that have been reported to be linked to AMD. METHODS. Study participants were 131 patients with neovascular AMD and 103 elderly persons without AMD who were evaluated by retinal specialists at the National Eye Institute. DNA was collected from peripheral whole blood, and duplex RT-PCR based copy number (CN) assays were performed for the genes CCR3, CFH, CX3CR1, ERCC6, HTRA1, and VEGF. Quantitative CNs (CN ϭ 0, 1, 2, or 3ϩ) were determined. RESULTS. Novel CNVs were discovered in CCR3, CX3CR1, and ERCC6. The unadjusted data suggested that CN ϭ 3ϩ for CX3CR1 might be mildly protective against AMD, but this trend did not persist after adjustment for age. AMD patients appeared to have an elevated mean CFH CN relative to controls 1 AMD is characterized by the formation of drusen in Bruch's membrane, the degeneration of photoreceptors and the underlying retinal pigment epithelium in the macula, geographic atrophy, and choroidal neovascularization. It is widely accepted that there is a complex involvement of both genetic and environmental factors in the pathogenesis of AMD. Studies have identified myriad AMD-associated genes in mechanistic pathways related to complement system activation, inflammation, microglial recruitment, DNA repair, extracellular matrix function, and neovascularization.2

Risk factors and biomarkers of age-related macular degeneration

“…Skiv2L is expressed at higher levels in T and B lymphocytes and dendritic cells (Fernando et al, 2007; Liu et al, 2013; Liu et al, 2011), hypothesizing that it may be protective in development of AMD through immune response modulation (Kondo et al, 2009a; Liu et al, 2013). Interestingly, while the minority A allele is thought to be protective in an American study (Kopplin et al, 2010), more recent studies in Han Chinese have implicated it as being pathogenic in AMD (Liu et al, 2011; Lu et al, 2013). As differences in genetic background can account for wider phenotypic variation with regard to the effect of the same mutation in different mouse strains, it is possible that the same applies to humans.…”

“…Consistent with an immunological role, the Skiv2L gene maps to the MHCIII region and is in linkage disequilibrium with other loci implicated in AMD (C2, CFB), but is also postulated to exert an independent effect (Kondo et al, 2009b). Skiv2L is expressed in the retina and RPE in both humans and mice (Liu et al, 2011), however, given that the polymorphism associated with AMD is intronic, it is difficult to speculate with regard to its impact on protein structure and function. A different Skiv2L polymorphism, rs2075702, conferred a reduced risk of PCV in a Japanese cohort (Kondo et al, 2009b).…”

“…Copy number variations involving this gene may also influence AMD susceptibility (Liu et al, 2011). Excision repair cross-complementation group 6 (ERCC6) is involved in transcription coupled excision repair of new DNA mutations, interacting with a complex of functionally similar proteins at DNA repair sites (Gene ID: 2074).…”

Prospective Study of Common Variants inCX3CR1and Risk of Macular Degeneration

“…43 Finally, a small study of copy number variation in CX3CR1 in relation to AMD demonstrated a mildly protective effect that was diminished after adjustment for age. 44 …”

Copy Number Variations of DNA Repair Genes and the Age-Related Cataract: Jiangsu Eye Study

“…10 DNA repair gene polymorphisms have previously been associated with age-related macular degeneration and ARC. [14][15][16] Previous studies have demonstrated several genes to be associated with ARC, such as heat shock factor protein 4 (HSF4), eph-receptor tyrosinekinase-type A2 (EPHA2), and glutathione S-transferase (GST). HSF4 regulates the expression of several heat shock protein (HSP) genes.…”