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

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, Jill Hageman, Jamal Hoballah, Heather StockmanIlkka Immonen, Matti Laine, Hanna Jarva, Irma Järvelä, Sanna Seitsonen, Gaetano Barile, Stanley Chang, John C. Merriam, R. Theodore Smith, Lawrence A. Yannuzzi

Research output: Contribution to journalArticle

179 Scopus citations

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.

Original languageEnglish
Pages (from-to)592-604
Number of pages13
JournalAnnals of Medicine
Volume38
Issue number8
DOIs
StatePublished - Dec 1 2006

Keywords

  • Age-related macular degeneration
  • Alternative pathway
  • Complement
  • Deletion
  • Evolution
  • Factor H
  • Factor H-related
  • Haplotype
  • Vision

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    Hageman, G. S., Hancox, L. S., Taiber, A. J., Gehrs, K. M., Anderson, D. H., Johnson, L. V., Radeke, M. J., Kavanagh, D., Richards, A., Atkinson, J., Meri, S., Bergeron, J., Zernant, J., Merriam, J., Gold, B., Allikmets, R., Dean, M., Hageman, J., Hoballah, J., ... Yannuzzi, L. A. (2006). 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. Annals of Medicine, 38(8), 592-604. https://doi.org/10.1080/07853890601097030