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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

Lookup NU author(s): Professor David KavanaghORCiD


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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. CONCLUSION: 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.

Publication metadata

Author(s): Hageman GS, Hancox LS, Taiber AJ, Gehrs KM, Anderson DH, Johnson LV, Radeke MJ, Kavanagh D, Richards A, Atkinson J, Meri S, Bergeron J, Zernant J, Merriam J, Gold B, Allikmets R, Dean M

Publication type: Article

Publication status: Published

Journal: Annals of Medicine

Year: 2006

Volume: 38

Issue: 8

Pages: 592-604

ISSN (print): 0785-3890

ISSN (electronic): 1365-2060

Publisher: Taylor & Francis AB


DOI: 10.1080/07853890601097030

Notes: Hageman, Gregory S Hancox, Lisa S Taiber, Andrew J Gehrs, Karen M Anderson, Don H Johnson, Lincoln V Radeke, Monte J Kavanagh, David Richards, Anna Atkinson, John Meri, Seppo Bergeron, Julie Zernant, Jana Merriam, Joanna Gold, Bert Allikmets, Rando Dean, Michael AMD Clinical Study Group N01-CO-12400/CO/United States NCI R01 EY011515-07S2/EY/United States NEI R01 EY011527-07/EY/United States NEI R01 EY013435-05/EY/United States NEI R01 EY11515/EY/United States NEI R01 EY11521/EY/United States NEI Z01 BC005652-15/BC/United States NCI Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Sweden Annals of medicine Ann Med. 2006;38(8):592-604.


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