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Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against

Gregory S Hageman1, Lisa S Hancox, Andrew J Taiber

  • 1Department 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

Annals of Medicine
|April 19, 2007
PubMed

Insights

A common deletion of complement factor H-related genes 1 and 3 (CFHR1/CFHR3) is linked to age-related macular degeneration (AMD). This finding sheds light on the genetic underpinnings of AMD and the role of complement genes in immunity.

Area of Science:

  • Genetics
  • Immunology
  • Ophthalmology

Background:

  • Complement factor H gene (CFH) variants are implicated in age-related macular degeneration (AMD).
  • The CFH gene and five related genes (CFHR1-5) are located in the regulators of complement activation (RCA) locus on chromosome 1q32.
  • Understanding the interplay between these genes and AMD is crucial.

Purpose of the Study:

  • To refine the understanding of structural and evolutionary relationships between CFH, CFHR genes, and AMD.
  • To investigate the impact of genetic variations within the RCA locus on AMD susceptibility.

Main Methods:

  • Employed a combined genetic, molecular, and immunohistochemical approach.
  • Identified and characterized a large deletion encompassing CFHR1 and CFHR3 genes.
  • Conducted genotyping analyses of AMD cases and controls from two independent cohorts.

Main Results:

  • A common deletion removing CFHR1 and CFHR3 was identified; individuals homozygous for this deletion lack CFHR1 protein.
  • Deletion homozygotes were found in 1.1% of AMD cases and 5.7% of controls, indicating a significant association (P=1.6 E-09).
  • CFHR1 and CFHR3 transcripts were abundant in the liver but not detected in the ocular retinal pigmented epithelium/choroid complex.

Conclusions:

  • The absence of CFHR1 and/or CFHR3 may explain the protective effects of certain CFH haplotypes.
  • High frequencies of the 402H allele and delCFHR1/CFHR3 alleles in African populations suggest ancient origins.
  • Genetic diversity at the RCA locus, potentially driven by selection, highlights the role of CFHR genes in innate immunity.
Abstract

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