The CX3CR1 gene is implicated as a candidate gene for age-related macular degeneration (AMD) through several lines of evidence. There is uncertainty, however, as to whether common genetic variants in CX3CR1 alter risk of AMD, since prior studies have been inconsistent and mostly limited to evaluation of two non-synonymous variants, T280M (rs3732378) and V249I (rs3732379).
We aimed to determine if common variants in CX3CR1 predict future risk of AMD.
Prospective nested case-control study within five large study populations with long-term follow-up.
We measured genotypes for T280M, V249I and 13 other common single-nucleotide polymorphisms (SNPs) of the CX3CR1 gene among people who developed AMD (N=1110, including N=369 with neovascular AMD) and 2532 age- and sex-matched controls.
Main outcome measures
We determined the incidence rate ratios (RR) and 95% confidence intervals (CI) for incidence of AMD for each variant, and examined interactions with other AMD-associated variants and modifiable risk factors.
In additive genetic models, we identified non-significant associations with AMD for T280M (RR=0.87, P=0.074) and three other SNPs, rs2853707 (RR=0.88, P=0.069), rs12636547 (RR=0.85, P=0.098), and rs1877563 (RR=0.84, P=0.056), one of which, rs2853707, is positioned in the CX3CR1 promoter region and was associated with neovascular AMD (RR=0.75, P=0.028). We observed that a recessive model was a better fit to the data for some SNPs, with associations between rs11715522 and AMD (RR=1.27, P=0.034), and between rs2669845 (RR=3.10, P=0.035), rs2853707 (RR=0.48, P=0.050) and rs9868689 (RR=0.31, P=0.017) and neovascular AMD. Moreover, in exploratory analyses we identified a number of possible interactions including between V249I and rs2669845 and dietary intake of omega-3 fatty acids (P=0.004, and P=0.009, respectively) for AMD; between rs2669845 and obesity (P=0.031) for neovascular AMD; between T280M and complement component 3 (C3) R102G for AMD (P=0.027); between rs2669845 and Y402H in complement factor H (CFH) for AMD (P=0.037); and between rs2669845, rs2853707, and V249I and C3 R102G for neovascular AMD (P=0.008, 0.039 and 0.002, respectively).
This study failed to identify significant associations between common CX3CR1 variants and AMD after considering the number of SNPs analyzed and multiple comparisons. However, we observed evidence consistent with recessive modes of association, and that an effect of CX3CR1 variants may depend on other factors including dietary intake of omega-3 fatty acids, obesity, and genotypes at CFH Y402H and C3 R102G. If replicated in other populations, these findings would support a role for CX3CR1 in AMD, but also suggest that its role may involve mechanisms that are independent of the T280M/V249I variations.