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Kirstan Anne Vessey, Ben J Gu, James S Wiley, Paul N Baird, Robyn H Guymer, Erica L Fletcher; Loss of P2X7 receptor function increases the risk of age related macular degeneration: Investigation of human genetics and mouse models. Invest. Ophthalmol. Vis. Sci. 2016;57(12):6561.
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© ARVO (1962-2015); The Authors (2016-present)
Age related macular degeneration (AMD) is a leading cause of blindness in Western countries. Recently a novel pathway, involving the scavenger receptor function of the P2X7 receptors (P2RX7) expressed on microglia/macrophages was identified as a risk factor for advanced AMD. Our aim was to determine whether single nucleotide polymorphisms (SNPs) in P2RX7 may be correlated with early AMD. In addition, the ocular phenotype of P2RX7null mice was characterised to determine whether they displayed phenotypic characteristics of early AMD with age.
Patients with early and intermediate drusen (n=738, early AMD) and age-matched controls (n=349) were genotyped for 12 functional SNPs in the P2RX7 gene and analysed by PLINK. P2RX7null mice and C57blk6J-mice (n>6 at each age/outcome) were investigated at 4, 12 and 18 months of age. Retinal appearance of the mice was assessed in vivo using a Micron fundus camera and ex vivo using histology at the confocal and transmission electron microscope. The function of the rod and cone pathways was assessed using the electroretinogram (ERG).
Inheritance of the P2RX7 SNPs, R270H/R307Q haplotype together with E496A was found to be a risk factor for patients in the early AMD cohort when compared with age-matched control patients (OR=1.21, p<0.041). These SNPs are known to impart loss of function to the P2X7 receptor. Homozygous loss of P2RX7 function in mice induced abnormal fundus lesions, accompanied by loss of rod photoreceptor function (~35%) at 18 months when compared with age-matched C57blk6J-mice (p<0.01). Histological evaluation indicated no loss of photoreceptor nuclei but a significant increase in Bruch’s membrane thickness (~90%) and RPE cell loss in P2RX7null versus C57blk6J-mice at 18 months (p<0.05 for BM and RPE changes). In addition, P2RX7null mice had a significant increase in microglia/macrophage numbers in the subretinal space at 18 months (p<0.05) and subtle changes in intraretinal microglial morphology and function from 4 months of age.
In humans, inheritance of loss of function P2RX7 SNPs is a risk factor for the early stages of AMD and in aged mice, loss of this receptor induces ocular changes characteristic of early AMD providing a valuable model in which to investigate the role of scavenger receptor function and the innate immune system in the development of this disease.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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