Gregory S Hageman1,2, Lisa S Hancox1, Andrew J Taiber1, Karen M Gehrs1, Don H Anderson2,3, Lincoln V Johnson2,3, Monte J Radeke2,3, David Kavanagh4, Anna Richards4, John Atkinson4, Seppo Meri5, Julie Bergeron6, Jana Zernant7, Joanna Merriam7, Bert Gold8, Rando Allikmets7,9, Michael Dean8. 1. a Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, Iowa. 2. b Center for the Study of Macular Degeneration, University of California, Santa Barbara, CA. 3. c Neuroscience Research Institute, University of California, Santa Barbara, CA. 4. d Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St Louis, MO. 5. e Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland. 6. f SAIC-Frederick, NCI-Frederick, Frederick, Maryland. 7. h Department of Ophthalmology, Columbia University, New York. 8. g Laboratory of Genomic Diversity, National Cancer Institute, NCI-Frederick, Frederick, Maryland. 9. i Department of Pathology and Cell Biology, Columbia University, New York.
Abstract
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.
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.
Authors: Karen Curtin; Lauren H Theilen; Alison Fraser; Ken R Smith; Michael W Varner; Gregory S Hageman Journal: Hypertens Pregnancy Date: 2019-04-12 Impact factor: 2.108
Authors: Sabine Hummert; Christina Glock; Stefan N Lang; Christian Hummert; Christine Skerka; Peter F Zipfel; Sebastian Germerodt; Stefan Schuster Journal: J R Soc Interface Date: 2018-05 Impact factor: 4.118
Authors: Richard B Pouw; Mieke C Brouwer; Anna E van Beek; Mihály Józsi; Diana Wouters; Taco W Kuijpers Journal: Front Immunol Date: 2018-04-17 Impact factor: 7.561
Authors: Richard B Pouw; Irene Gómez Delgado; Alberto López Lera; Santiago Rodríguez de Córdoba; Diana Wouters; Taco W Kuijpers; Pilar Sánchez-Corral Journal: Front Immunol Date: 2018-04-24 Impact factor: 7.561