Debra A Schaumberg1, Lynda Rose2, Margaret M DeAngelis3, Richard D Semba4, Gregory S Hageman3, Daniel I Chasman2. 1. 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. 2. Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. 3. The John A. Moran Eye Center, University of Utah, Salt Lake City. 4. Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Abstract
IMPORTANCE: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. MAIN OUTCOMES AND MEASURES: 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 AND RELEVANCE: 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.
RCT Entities:
IMPORTANCE: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. MAIN OUTCOMES AND MEASURES: 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 C3R102G for neovascular AMD (P = .008; .04; and .002, respectively). CONCLUSIONS AND RELEVANCE: 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 CFHY402H and C3R102G. 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: E Cho; S Hung; W C Willett; D Spiegelman; E B Rimm; J M Seddon; G A Colditz; S E Hankinson Journal: Am J Clin Nutr Date: 2001-02 Impact factor: 7.045
Authors: Nathan Congdon; Benita O'Colmain; Caroline C W Klaver; Ronald Klein; Beatriz Muñoz; David S Friedman; John Kempen; Hugh R Taylor; Paul Mitchell Journal: Arch Ophthalmol Date: 2004-04
Authors: Shari S Bassuk; Christine M Albert; Nancy R Cook; Elaine Zaharris; Jean G MacFadyen; Eleanor Danielson; Martin Van Denburgh; Julie E Buring; Joann E Manson Journal: J Womens Health (Larchmt) Date: 2004 Jan-Feb Impact factor: 2.681
Authors: Jingsheng Tuo; Brena C Smith; Christine M Bojanowski; Annal D Meleth; Igal Gery; Karl G Csaky; Emily Y Chew; Chi-Chao Chan Journal: FASEB J Date: 2004-06-18 Impact factor: 5.191
Authors: Anu Kauppinen; Jussi J Paterno; Janusz Blasiak; Antero Salminen; Kai Kaarniranta Journal: Cell Mol Life Sci Date: 2016-02-06 Impact factor: 9.261
Authors: Sandra M Cardona; Andrew S Mendiola; Ya-Chin Yang; Sarina L Adkins; Vanessa Torres; Astrid E Cardona Journal: ASN Neuro Date: 2015-10-29 Impact factor: 4.146
Authors: Alessandro Iannaccone; Francesco Giorgianni; David D New; T J Hollingsworth; Allison Umfress; Albert H Alhatem; Indira Neeli; Nataliya I Lenchik; Barbara J Jennings; Jorge I Calzada; Suzanne Satterfield; Dennis Mathews; Rocio I Diaz; Tamara Harris; Karen C Johnson; Steve Charles; Stephen B Kritchevsky; Ivan C Gerling; Sarka Beranova-Giorgianni; Marko Z Radic Journal: PLoS One Date: 2015-12-30 Impact factor: 3.240