title: A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration.
abstract: Age-related macular degeneration (AMD) is the most frequent cause of irreversible blindness in the elderly in developed countries. Our previous studies implicated activation of complement in the formation of drusen, the hallmark lesion of AMD. Here, we show that factor H (HF1), the major inhibitor of the alternative complement pathway, accumulates within drusen and is synthesized by the retinal pigmented epithelium. Because previous linkage analyses identified chromosome 1q25-32, which harbors the factor H gene (HF1/CFH), as an AMD susceptibility locus, we analyzed HF1 for genetic variation in two independent cohorts comprised of approximately 900 AMD cases and 400 matched controls. We found association of eight common HF1 SNPs with AMD; two common missense variants exhibit highly significant associations (I62V, chi2 = 26.1 and P = 3.2 x 10(-7) and Y402H, chi2 = 54.4 and P = 1.6 x 10(-13)). Haplotype analysis reveals that multiple HF1 variants confer elevated or reduced risk of AMD. One common at-risk haplotype is present at a frequency of 50% in AMD cases and 29% in controls [odds ratio (OR) = 2.46, 95% confidence interval (1.95-3.11)]. Homozygotes for this haplotype account for 24% of cases and 8% of controls [OR = 3.51, 95% confidence interval (2.13-5.78)]. Several protective haplotypes are also identified (OR = 0.44-0.55), further implicating HF1 function in the pathogenetic mechanisms underlying AMD. We propose that genetic variation in a regulator of the alternative complement pathway, when combined with a triggering event, such as infection, underlie a major proportion of AMD in the human population.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Cell Biology and Functional Genomics Laboratory, University of Iowa, Iowa City, IA 52240, USA. gregory-hageman@uiowa.edu
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Hageman
authors.forename: Don H
authors.initials: DH
authors.lastname: Anderson
authors.forename: Lincoln V
authors.initials: LV
authors.lastname: Johnson
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Hancox
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Taiber
authors.forename: Lisa I
authors.initials: LI
authors.lastname: Hardisty
authors.forename: Jill L
authors.initials: JL
authors.lastname: Hageman
authors.forename: Heather A
authors.initials: HA
authors.lastname: Stockman
authors.forename: James D
authors.initials: JD
authors.lastname: Borchardt
authors.forename: Karen M
authors.initials: KM
authors.lastname: Gehrs
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
authors.forename: Giuliana
authors.initials: G
authors.lastname: Silvestri
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Russell
authors.forename: Caroline C W
authors.initials: CC
authors.lastname: Klaver
authors.forename: Irene
authors.initials: I
authors.lastname: Barbazetto
authors.forename: Stanley
authors.initials: S
authors.lastname: Chang
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Yannuzzi
authors.forename: Gaetano R
authors.initials: GR
authors.lastname: Barile
authors.forename: John C
authors.initials: JC
authors.lastname: Merriam
authors.forename: R Theodore
authors.initials: RT
authors.lastname: Smith
authors.forename: Adam K
authors.initials: AK
authors.lastname: Olsh
authors.forename: Julie
authors.initials: J
authors.lastname: Bergeron
authors.forename: Jana
authors.initials: J
authors.lastname: Zernant
authors.forename: Joanna E
authors.initials: JE
authors.lastname: Merriam
authors.forename: Bert
authors.initials: B
authors.lastname: Gold
authors.forename: Michael
authors.initials: M
authors.lastname: Dean
authors.forename: Rando
authors.initials: R
authors.lastname: Allikmets
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017242:Complement Factor H / Q000235:genetics*; D004252:DNA Mutational Analysis; D040461:Gene Components; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008268:Macular Degeneration / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics; D016017:Odds Ratio; D010857:Pigment Epithelium of Eye / Q000473:pathology*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D044465:White People
chemical_list: C493495:CFH protein, human; D017242:Complement Factor H