Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration: characterization, ethnic distribution and evolutionary implications.
BACKGROUND
Variants in the complement factor H gene (CFH) are associated with age-related macular degeneration (AMD). CFH and five CFH-related genes (CFHR1-5) lie within the regulators of complement activation (RCA) locus on chromosome 1q32. Aims and Methods. In this study, the structural and evolutionary relationships between these genes and AMD was refined using a combined genetic, molecular and immunohistochemical approach.


RESULTS
We identify and characterize a large, common deletion that encompasses both the CFHR1 and CFHR3 genes. CFHR1, an abundant serum protein, is absent in subjects homozygous for the deletion. Genotyping analyses of AMD cases and controls from two cohorts demonstrates that deletion homozygotes comprise 1.1% of cases and 5.7% of the controls (chi-square=32.8; P= 1.6 E-09). CFHR1 and CFHR3 transcripts are abundant in liver, but undetectable in the ocular retinal pigmented epithelium/choroid complex. AMD-associated CFH/CFHR1/CFHR3 haplotypes are widespread in human populations.


CONCLUSIONS
The absence of CFHR1 and/or CFHR3 may account for the protective effects conferred by some CFH haplotypes. Moreover, the high frequencies of the 402H allele and the delCFHR1/CFHR3 alleles in African populations suggest an ancient origin for these alleles. The considerable diversity accumulated at this locus may be due to selection, which is consistent with an important role for the CFHR genes in innate immunity.
Hageman
Gregory S
GS
Department of Ophthalmology and Visual Sciences, Cell Biology and Functional Genomics Laboratory, The University of Iowa, 11190E PFP, 200 Hawkins Drive, Iowa City, Iowa 52240, USA. gregory-hageman@uiowa.edu
Hancox
Lisa S
LS
Taiber
Andrew J
AJ
Gehrs
Karen M
KM
Anderson
Don H
DH
Johnson
Lincoln V
LV
Radeke
Monte J
MJ
Kavanagh
David
D
Richards
Anna
A
Atkinson
John
J
Meri
Seppo
S
Bergeron
Julie
J
Zernant
Jana
J
Merriam
Joanna
J
Gold
Bert
B
Allikmets
Rando
R
Dean
Michael
M
D015153:Blotting, Western; D016022:Case-Control Studies; D015331:Cohort Studies; D017242:Complement Factor H / Q000032:analysis / Q000235:genetics*; D017353:Gene Deletion; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics*; D018807:Polymorphism, Single-Stranded Conformational; D044469:Racial Groups / Q000235:genetics
D017242:Complement Factor H