Abstract
Purpose: :
The CX3CR1 fractalkine receptor gene is implicated as a candidate for AMD based on several lines of evidence. Some cross-sectional human studies have linked coding variants (T280M, V249I) with risk of AMD, but a larger case-control study recently called these associations into question. We aimed to determine if common variants in CX3CR1 predict future risk of AMD.
Methods: :
We genotyped 15 common variants in and around CX3CR1 and examined associations with AMD among 1138 cases who developed AMD and 2602 age- and sex-matched controls in a prospective case-control study nested within 5 large cohorts. We also examined interactions with other known AMD-associated variants and modifiable risk factors for all AMD cases and a subset of neovascular AMD cases (N=369).
Results: :
Associations of T280M (OR=0.92, P=0.24) and V249I (OR=1.01, P=0.82) with AMD were not significant, but there were borderline associations of rs2669845 (OR=1.15, P=0.072) and rs1877563 (OR=0.85, P=0.052) with AMD, and rs2853707 (OR=0.82, P=0.072) with neovascular AMD. Moreover, there were significant interactions for neovascular AMD between rs2669845 and the R102G variant of complement component 3 (C3) and obesity (P for interaction=0.0065 and 0.031, respectively), and well as between T280M, V249I, and rs2853707 and C3 R102G (P for interaction =0.046, 0.0017 and 0.038, respectively). There was also a significant interaction between rs2853707 and ARMS2 A69S for all AMD (P=0.036). Interaction effects were such that whereas carriers of the risk allele for either C3 R102G or CX3CR1 T280M, V249I, or rs2669845 alone had an excess risk of neovascular AMD (e.g. OR=5.34 for C3 102G/G among CX3CR1 249V/V participants, and OR=1.84 for CX3CR1 249I/I among C3 102R/R participants), risk was reduced among participants who were doubly homozygous at these loci (OR=0.72). rs2853707 was protective among C3 102R/R participants (OR=0.38), but this protection was completely lost among C3 102G/G participants (OR=3.71).
Conclusions: :
This study revealed significant evidence for interactions of common CX3CR1 variants with C3 R102G, ARMS2 A69S, and obesity to alter risk of AMD. These findings support a role for CX3CR1 in AMD, but also suggest that its role may involve mechanisms that are independent of the T280M/V249I variations.
Keywords: clinical (human) or epidemiologic studies: risk factor assessment • age-related macular degeneration • genetics