title: Risk alleles in CFH and ARMS2 are independently associated with systemic complement activation in age-related macular degeneration.
abstract: OBJECTIVE
  Systemic complement activation is associated with age-related macular degeneration (AMD) and has mainly been attributed to a risk allele in the complement factor H (CFH) gene. Whether other important AMD genes also influence complement activation is unclear. In the present case-control study, complement activity and concentrations of complement components and their activation products are measured in AMD patients and in unaffected controls and correlated with genetic variants in the CFH, ARMS2, C3, CFI, and CFB genes.
  
  
  METHODS
  Case-control study.
  
  
  METHODS
  A cohort of 197 confirmed AMD patients and 150 unaffected age-matched controls were recruited prospectively for the study.
  
  
  METHODS
  Hemolytic complement assays (AP50, CP50, and LP50), complement components (C3, CFB, CFI, and CFH), and the activation products (C3d, C5a, and SC5b-9) were analyzed in serum or plasma. The DNA samples were genotyped for 5 single nucleotide polymorphisms (SNPs) previously associated with AMD in the CFH, ARMS2, C3, CFB, and CFI genes.
  
  
  METHODS
  Complement concentrations and their associations with SNPs in the CFH, ARMS2, C3, CFB, and CFI genes.
  
  
  RESULTS
  The AMD patients had increased activation of the alternative complement pathway (P = 0.003) and elevated levels of complement activation components C3d (P<0.0001) and C5a (P<0.0001), CFB (P<0.0001), and an increased C3d/C3 ratio (P<0.0001) calculated as a measure of C3 activation. While the CFH risk genotype was significantly associated with the elevated C3d/C3 ratios obtained, in the absence of CFH risk alleles the ARMS2 risk genotype also showed significantly increased levels of complement activation (P = 0.013). Furthermore, the carriers of the CFB protective allele had lower CFB concentrations.
  
  
  CONCLUSIONS
  The current study found evidence showing that in AMD risk alleles in CFH and ARMS2 are independently associated with complement activation. Especially the C3d/C3 ratio seems to be a strong marker for AMD. The findings suggest that CFH and ARMS2 share a common pathway in the pathogenesis of AMD.
authors: Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors: Dzenita
authors: D
authors: Smailhodzic
authors: Caroline C W
authors: CC
authors: Klaver
authors: B Jeroen
authors: BJ
authors: Klevering
authors: Camiel J F
authors: CJ
authors: Boon
authors: Joannes M M
authors: JM
authors: Groenewoud
authors: Bernd
authors: B
authors: Kirchhof
authors: Mohamed R
authors: MR
authors: Daha
authors: Anneke I
authors: AI
authors: den Hollander
authors: Carel B
authors: CB
authors: Hoyng
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016022:Case-Control Studies; D003167:Complement Activation; D003176:Complement C3 / Q000235:genetics; D015933:Complement C3d / Q000378:metabolism; D015936:Complement C5a / Q000378:metabolism; D011415:Complement Factor B / Q000235:genetics; D017242:Complement Factor H / Q000235:genetics; D017244:Complement Factor I / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008268:Macular Degeneration / Q000097:blood / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011506:Proteins / Q000235:genetics*; D012307:Risk Factors
chemical_list: C514392:ARMS2 protein, human; C493495:CFH protein, human; D003176:Complement C3; D011506:Proteins; D015933:Complement C3d; D015936:Complement C5a; D017242:Complement Factor H; C493611:CFI protein, human; D017244:Complement Factor I; D011415:Complement Factor B