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Desi Schoo, Aditi Khanna, Kai Wang, Megan Streb, Edwin Stone, Robert Mullins; Choroidal Vascular Pathology in Human Eyes with the Y402H Allele of Complement Factor H. Invest. Ophthalmol. Vis. Sci. 2013;54(15):339.
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Age-related macular degeneration (AMD) is the leading cause of permanent blindness in the developed world. A common polymorphism (Y402H) in the alternative complement pathway inhibitor, complement factor H (CFH), is strongly associated with the incidence of AMD. Despite its importance, relatively little is known about the mechanism by which this polymorphism leads to AMD. In the current study, we sought to assess the role of the Y402H allele in the health of the choroidal vasculature and the retinal pigment epithelium (RPE).
Human donor eyes were genotyped for the CFH Y402H polymorphism (15 YY, 12 HY, 6HH) and maculas were utilized for morphological measurements. With genotypes masked, sections were collected and stained with UEA-I lectin. The percent vascular density (PVD) was determined, along with the number of ghost vessels per μm of Bruch’s membrane (identified as endothelial cell-free zones between two intercapillary pillars). The thickness of the RPE and choroid were also assessed based on multiple, evenly spaced random measurements along the length of each sample. Following morphometric assessment, donor CFH status was unmasked and statistical analysis was performed. In addition, C-reactive protein levels were assessed in human donor RPE/choroid tissue homozygous for either the H or Y allele. Western blot and ELISA assays were performed to analyze the relative abundance of the CFH variants within the samples based on the genotype.
The presence of 1 or more copies of theY402H allele was associated with an increase in choriocapillaris ghost vessel density (>2x increase, p <0.05 after correction for age and early AMD status). RPE thickness and total choroidal thickness were not significantly different in eyes with 1 or more Y402H allele. Choroidal CRP levels were slightly higher on average in eyes homozygous for the Y402H variant, but this difference did not reach statistical significance.
Previous studies have shown that microvascular changes are related to the pathogenesis of AMD. The choriocapillaris—the major site of membrane attack complex deposition in the human macula—shows degenerative changes in eyes with the Y402H polymorphism. These data suggest that the Y402H allele in CFH may affect risk of AMD by failing to protect the choriocapillaris from complement induced injury, and that changes in the RPE in AMD may be secondary to choriocapillaris pathology.
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