An increased amount of deposit in Bruch's membrane has been associated with the presence and severity of AMD.
28,29 Under normal circumstances, the continuous generation of macular deposition can be eliminated through inflammatory cells attracted to this site through chemokines to achieve a dynamic balance.
30 CX3CL1, the only identified CX3C chemokine, is widely expressed in the eye tissues. As the sole receptor for this protein, CX3CR1 is constitutively expressed in the retina and other ocular tissues, where this receptor protein mediates the migration of macrophages and microglia cells (MCs) to clear accumulated deposits.
31,32 The altered functions of inflammatory cells might be involved in the pathogenesis of AMD. Recently, several studies
14,15 have suggested that T280M and V249I, two common nonsynonymous SNPs located in
CX3CR1, might be associated with the risk for AMD; but these results are inconsistent. The results of the present meta-analysis showed that both of these SNPs were significantly associated with the increased risk of AMD. Several functional studies
12,33 have suggested that these two loci decrease the number of fractalkine receptor binding sites and the binding affinity of the receptor to fractalkine, thus crippling chemokine activity. The inhibition of chemokine activity might in turn lead to the inadequate recruitment of inflammatory cells, such as macrophages and MCs, to ocular tissues where the age-related deposits are progressively accumulated.
31,34 These deposits play a specific role in the development of drusen and CNV, which are the chief characteristics of AMD.
35,36 Moreover, these accumulated deposits might affect the transport of macromolecules, such as oxygen, between the retina and the choroidal vessels, and injure RPE and photoreceptor cells, which enhance the progression and severity of AMD.
37 On the other hand, a lower level of CX3CR1 expression is detected in the macular area than in the peripheral retina of AMD eyes, while control subjects exhibit almost identical CX3CR1 expression in both macular and peripheral retina.
13,16 Thus, relatively lower CX3CR1 expression levels in the cells from AMD patients might reflect the observed AMD susceptibility. However, it is impossible that these two variants directly affect the levels of transcription. DeVries et al.
38 have suggested a moderately strong LD between both these two SNPs in
CX3CR1 and the −15430G → C SNP located in the
CX3CR1 promoter region. This special relationship might affect the transcriptional level of CX3CR1 proteins, thereby contributing to the risk of AMD.