A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration.
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.
Hageman
Gregory S
GS
Department of Ophthalmology and Visual Sciences, Cell Biology and Functional Genomics Laboratory, University of Iowa, Iowa City, IA 52240, USA. gregory-hageman@uiowa.edu
Anderson
Don H
DH
Johnson
Lincoln V
LV
Hancox
Lisa S
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Taiber
Andrew J
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Hardisty
Lisa I
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Hageman
Jill L
JL
Stockman
Heather A
HA
Borchardt
James D
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Gehrs
Karen M
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Smith
Richard J H
RJ
Silvestri
Giuliana
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Russell
Stephen R
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Klaver
Caroline C W
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Barbazetto
Irene
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Chang
Stanley
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Yannuzzi
Lawrence A
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Barile
Gaetano R
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Merriam
John C
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Smith
R Theodore
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Olsh
Adam K
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Bergeron
Julie
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Zernant
Jana
J
Merriam
Joanna E
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Gold
Bert
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Dean
Michael
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Allikmets
Rando
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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
C493495:CFH protein, human; D017242:Complement Factor H