The involvement of sequence variation and expression of CX3CR1 in the pathogenesis of age-related macular degeneration - PubMed (original) (raw)

Jingsheng Tuo et al. FASEB J. 2004 Aug.

Abstract

This study examined the association between the sequence variation/expression of CX3CR1, a chemokine receptor, and age-related macular degeneration (AMD). Peripheral blood from 85 AMD patients and 105 subjects without AMD (controls), as well as ocular tissue from 40 pathological sections with AMD and two normal eye sections, were screened for V249I and T280M, two single nucleotide polymorphisms (SNPs) in CX3CR1. An increased prevalence, with the highest odds ratio of 3.57, of the I249 and M280 carriers was found among the AMD cases as compared with the controls. When comparing CX3CR1 expression in the archived eye sections, CX3CR1 transcripts were not detectable in the maculae of AMD eyes bearing T/M280; however, transcripts were detected in the maculae of normal eyes bearing T/T280 or T/M280 as well as in the AMD maculae bearing T/T280. Furthermore, lower CX3CR1 protein expression was observed in the maculae of AMD eyes bearing T/M280 compared with the controls bearing T/T280. The I249 and M280 alleles result in a lowered number of receptor binding sites and a decreased ligand affinity. Our data suggest that a decrease, caused by sequence variation and/or lower CX3CR1 expression, in CX3CR1-induced cellular activities could contribute to AMD development.

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Figures

Figure 1

Figure 1

RT-PCR of CX3CR1 in maculae obtained from AMD and normal paraffin-embedded slides of eyes with different SNP types. Small amplicons of 100 bp spanning exon 1 and exon 2 of CX3CR1 and 103 bp spanning from exon 5 to exon 6 of β-actin were amplified using 32P-labeled primers.

Figure 2

Figure 2

a) Flowchart of proposed model that may account for the association of AMD with the CX3CR1 I249/M280 sequence variants. CX3CR1 sequence variation results in a decreased number of binding sites and diminished ligand binding affinity, thus crippling chemokine activity. A decrease in proper chemokine function may lead to the inadequate recruitment and subsequent decrease in activity of macro-phages in macular regions where the age-related deposit is progressively accumulated, b) Schematic diagram showing that in the wild-type a dynamic balance is struck between the generation of macular deposition and elimination of these deposits by inflammatory cells, c) Aberrant macrophage activity in individuals with the T/M280 and V/I249. The macro-phages are not successfully recruited to sites of macular deposit, allowing a buildup of age-accumulated deposition. This buildup contributes to the formation of drusen and destruction of the RPE cells resulting in the development of AMD.

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