title: Prospective study of common variants in CX3CR1 and risk of macular degeneration: pooled analysis from 5 long-term studies.
abstract: OBJECTIVE
  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 2 nonsynonymous variants, T280M (rs3732378) and V249I (rs3732379).
  
  
  OBJECTIVE
  To determine if common variants in CX3CR1 predict future risk of AMD.
  
  
  METHODS
  Prospective nested case-control study within 5 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 369 with neovascular AMD) and 2532 age- and sex-matched controls.
  
  
  METHODS
  We determined the incidence rate ratios (RR) and 95% CIs for incidence of AMD for each variant and examined interactions with other AMD-associated variants and modifiable risk factors.
  
  
  RESULTS
  In additive genetic models, we identified nonsignificant associations with AMD for T280M (RR, 0.87; P = .07) and 3 other SNPs, rs2853707 (RR, 0.88; P = .07), rs12636547 (RR, 0.85; P = .10), and rs1877563 (RR, 0.84; P = .06), 1 of which, rs2853707, is positioned in the CX3CR1 promoter region and was associated with neovascular AMD (RR, 0.75; P = .03). 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 = .03) and between rs2669845 (RR, 3.10; P = .04), rs2853707 (RR, 0.48; P = .050), and rs9868689 (RR, 0.31; P = .02) and neovascular AMD. Moreover, in exploratory analyses, we identified a number of possible interactions including between V249I and rs2669845 and dietary intake of ω-3 fatty acids (P = .004 and P = .009, respectively) for AMD; between rs2669845 and obesity (P = .03) for neovascular AMD; between T280M and complement component 3 (C3) R102G for AMD (P = .03); between rs2669845 and Y402H in complement factor H for AMD (P = .04); and between rs2669845, rs2853707, and V249I and C3 R102G for neovascular AMD (P = .008; .04; and .002, respectively).
  
  
  CONCLUSIONS
  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 ω-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.
authors.affiliation: Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts2The Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts3Department.
authors.forename: Debra A
authors.initials: DA
authors.lastname: Schaumberg
authors.affiliation: Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Lynda
authors.initials: L
authors.lastname: Rose
authors.affiliation: The John A. Moran Eye Center, University of Utah, Salt Lake City.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: DeAngelis
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Semba
authors.affiliation: The John A. Moran Eye Center, University of Utah, Salt Lake City.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Hageman
authors.affiliation: Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Chasman
mesh_terms: D000483:Alleles; D000073883:CX3C Chemokine Receptor 1; D016022:Case-Control Studies; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D003176:Complement C3 / Q000235:genetics; D017242:Complement Factor H / Q000235:genetics; D004042:Dietary Fats, Unsaturated / Q000008:administration & dosage; D004311:Double-Blind Method; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D059647:Gene-Environment Interaction; D005838:Genotype; D006282:Health Personnel; D006801:Humans; D015994:Incidence; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011506:Proteins / Q000235:genetics; D019707:Receptors, Chemokine / Q000235:genetics*; D012307:Risk Factors; D057135:Wet Macular Degeneration / Q000175:diagnosis / Q000235:genetics*
chemical_list: C514392:ARMS2 protein, human; C493495:CFH protein, human; D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D003176:Complement C3; D004042:Dietary Fats, Unsaturated; D015525:Fatty Acids, Omega-3; D011506:Proteins; D019707:Receptors, Chemokine; D017242:Complement Factor H