title: Impact of the common genetic associations of age-related macular degeneration upon systemic complement component C3d levels.
abstract: Age-related macular degeneration (AMD) is a common condition that leads to severe vision loss and dysregulation of the complement system is thought to be associated with the disease. To investigate associations of polymorphisms in AMD susceptibility genes with systemic complement activation, 2655 individuals were genotyped for 32 single nucleotide polymorphisms (SNPs) in or near 23 AMD associated risk genes. Component 3 (C3) and its catabolic fragment C3d were measured in serum and AMD staging was performed using multimodal imaging. The C3d/C3 ratio was calculated and associations with environmental factors, SNPs and various haplotypes of complement factor H (CFH) genes and complement factor B (CFB) genes were analyzed. Linear models were built to measure the influence of genetic variants on the C3d/C3 ratio. The study cohort included 1387 patients with AMD and 1268 controls. Higher C3d/C3 ratios were found for current smoker (p = 0.002), higher age (p = 1.56 × 10(-7)), AMD phenotype (p = 1.15 × 10(-11)) and the two SNPs in the C3 gene rs6795735 (p = 0.04) and rs2230199 (p = 0.04). Lower C3d/C3 ratios were found for diabetes (p = 2.87 × 10(-6)), higher body mass index (p = 1.00 × 10(-13)), the SNPs rs1410996 (p = 0.0001), rs800292 (p = 0.003), rs12144939 (p = 4.60 × 10(-6)) in CFH, rs4151667 (p = 1.01 × 10(-5)) in CFB and individual haplotypes in CFH and CFB. The linear model revealed a corrected R-square of 0.063 including age, smoking status, gender, and genetic polymorphisms explaining 6.3% of the C3d/C3 ratio. After adding the AMD status the corrected R-square was 0.067. In conclusion, none of the evaluated genetic polymorphisms showed an association with increased systemic complement activation apart from two SNPs in the C3 gene. Major genetic and non-genetic factors for AMD were not associated with systemic complement activation.
authors.affiliation: Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Ristau
authors.affiliation: Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Constantin
authors.initials: C
authors.lastname: Paun
authors.affiliation: Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Lebriz
authors.initials: L
authors.lastname: Ersoy
authors.affiliation: Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Hahn
authors.affiliation: Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Yara
authors.initials: Y
authors.lastname: Lechanteur
authors.affiliation: Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Carel
authors.initials: C
authors.lastname: Hoyng
authors.affiliation: Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Eiko K
authors.initials: EK
authors.lastname: de Jong
authors.affiliation: Department of Nephrology, Leiden University Nijmegen Medical Center, Leiden, the Netherlands.
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Daha
authors.affiliation: Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Kirchhof
authors.affiliation: Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Anneke I
authors.initials: AI
authors.lastname: den Hollander
authors.affiliation: Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Fauser
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D003167:Complement Activation; D015933:Complement C3d / Q000235:genetics* / Q000276:immunology; D011415:Complement Factor B / Q000235:genetics* / Q000276:immunology; D017242:Complement Factor H / Q000235:genetics* / Q000276:immunology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012907:Smoking / Q000503:physiopathology
chemical_list: D015933:Complement C3d; D017242:Complement Factor H; D011415:Complement Factor B