title: Activation of the alternative complement pathway in vitreous is controlled by genetics in age-related macular degeneration.
abstract: OBJECTIVE
  To determine if the progression of age-related macular degeneration (AMD) is associated with complement activation in the eye.
  
  
  METHODS
  Immunohistochemistry and ELISAs were used to determine the distribution, concentration, and activation of the alternative pathway complement proteases factor B (FB) and factor D (FD) and the central complement protein C3 in genotyped human postmortem donor eyes graded as having no or minimal drusen (category 1; controls), large drusen (category 3), and large drusen with advanced AMD (category 4).
  
  
  RESULTS
  C3, FB, and FD were present in vitreous and Bruch's membrane choroid (BM/C) interface of the macula of eyes in all tested AMD severity categories (n = 100). C3, FB, and FD were predominantly located to the choroidal vasculature and Bruch's membrane and, together with the serum proteins transferrin and albumin, elevated in BM/C extracts of category 4 eyes (n = 23) compared with category 1 eyes (n = 24). A significant increase in FB activation was found only in vitreous of category 4 eyes (n = 23) compared with category 1 eyes (n = 25). Genetic variants of complement factor H (CFH), C3, C2, and FB associated with increased risk of AMD were correlated with alternative pathway complement activation in vitreous, but not with complement proteins in BM/C protein extracts.
  
  
  CONCLUSIONS
  Increased activation of the alternative complement pathway in vitreous was controlled by disease stage and genetic variation in the complement pathway, supporting a role for complement activation in AMD disease pathogenesis.
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Loyet
authors.forename: Laura E
authors.initials: LE
authors.lastname: Deforge
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Katschke
authors.forename: Lauri
authors.initials: L
authors.lastname: Diehl
authors.forename: Robert R
authors.initials: RR
authors.lastname: Graham
authors.forename: Lily
authors.initials: L
authors.lastname: Pao
authors.forename: Lizette
authors.initials: L
authors.lastname: Sturgeon
authors.forename: Sock-Cheng
authors.initials: SC
authors.lastname: Lewin-Koh
authors.forename: Joe G
authors.initials: JG
authors.lastname: Hollyfield
authors.forename: Menno
authors.initials: M
authors.lastname: van Lookeren Campagne
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016570:Bruch Membrane / Q000378:metabolism; D002829:Choroid / Q000378:metabolism; D003167:Complement Activation; D003176:Complement C3 / Q000235:genetics / Q000378:metabolism*; D011415:Complement Factor B / Q000235:genetics / Q000378:metabolism*; D011416:Complement Factor D / Q000235:genetics / Q000378:metabolism*; D017242:Complement Factor H / Q000235:genetics; D003170:Complement Pathway, Alternative / Q000235:genetics*; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D008268:Macular Degeneration / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D014019:Tissue Donors; D014822:Vitreous Body / Q000378:metabolism*
chemical_list: C493495:CFH protein, human; D003176:Complement C3; D017242:Complement Factor H; D011416:Complement Factor D; D011415:Complement Factor B