• Gregory S Hageman, Lisa S Hancox, Andrew J Taiber, Karen M Gehrs, Don H Anderson, Lincoln V Johnson, Monte J Radeke, David Kavanagh, Anna Richards, John Atkinson, Seppo Meri, Julie Bergeron, Jana Zernant, Joanna Merriam, Bert Gold, Rando Allikmets, Michael Dean, and AMD Clinical Study Group.
• 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
• Ann. Med. 2006 Jan 1; 38 (8): 592-604.

BackgroundVariants 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.ResultsWe 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.ConclusionThe 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.

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