A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration (original) (raw)

Nature Genetics volume 38, pages 1173–1177 (2006)Cite this article

A Corrigendum to this article was published on 01 April 2007

This article has been updated

Abstract

Age-related macular degeneration (AMD; OMIM #603075) is the most frequent cause of visual impairment in the elderly population, with severe disease affecting nearly 10% of individuals of European descent over the age of 75 years. It is a complex disease in which genetic and environmental factors contribute to susceptibility. Complement factor H (CFH) has recently been identified as a major AMD susceptibility gene, and the Y402H polymorphism has been proposed as the likely causative factor. We genotyped polymorphisms spanning the cluster of CFH and five _CFH_-related genes on chromosome 1q23 in 173 individuals with severe neovascular AMD and 170 elderly controls with no signs of AMD. Detailed analysis showed a common haplotype associated with decreased risk of AMD that was present on 20% of chromosomes of controls and 8% of chromosomes of individuals with AMD. We found that this haplotype carried a deletion of CFHR1 and CFHR3, and the proteins encoded by these genes were absent in serum of homozygotes. The protective effect of the deletion haplotype cannot be attributed to linkage disequilibrium with Y402H and was replicated in an independent sample.

NOTE: In the version of this article initially published, the G and A alleles of rs1831281 in Figure 1 should be reversed, and the block 2 haplotypes in Figure 1, Table 2 and Supplementary Table 2 should be corrected to 1:AGGCGACG, 2:AGGCGAAG, 3:GTGCGGAG, 4:GTATGAAA and 5:GTGTAAAG. The error has been corrected in the HTML and PDF versions of the article.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 12 print issues and online access

$209.00 per year

only $17.42 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

Change history

In the version of this article initially published, the G and A alleles of rs1831281 in Figure 1 should be reversed, and the block 2 haplotypes in Figure 1, Table 2 and Supplementary Table 2 should be corrected to 1:AGGCGACG, 2:AGGCGAAG, 3:GTGCGGAG, 4:GTATGAAA and 5:GTGTAAAG. The error has been corrected in the HTML and PDF versions of the article.

References

  1. Mullins, R.F., Aptsiauri, N. & Hageman, G.S. Structure and composition of drusen associated with glomerulonephritis: implications for the role of complement activation in drusen biogenesis. Eye 15, 390–395 (2001).
    Article CAS Google Scholar
  2. Klein, R.J. et al. Complement factor H polymorphism in age-related macular degeneration. Science 308, 385–389 (2005).
    Article CAS Google Scholar
  3. Edwards, A.O. et al. Complement factor H polymorphism and age-related macular degeneration. Science 308, 421–424 (2005).
    Article CAS Google Scholar
  4. Haines, J.L. et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 308, 419–421 (2005).
    Article CAS Google Scholar
  5. Hageman, G.S. et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc. Natl. Acad. Sci. USA 102, 7227–7232 (2005).
    Article CAS Google Scholar
  6. Zareparsi, S. et al. Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration. Am. J. Hum. Genet. 77, 149–153 (2005).
    Article CAS Google Scholar
  7. Schouten, J.P. et al. Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res. 30, e57 (2002).
    Article Google Scholar
  8. Heinen, S. et al. De novo gene conversion in the RCA gene cluster (1q32) causes mutations in complement factor H associated with atypical hemolytic uremic syndrome. Hum. Mutat. 27, 292–293 (2006).
    Article Google Scholar
  9. Reid, K.B. et al. Complement system proteins which interact with C3b or C4b; a superfamily of structurally related proteins. Immunol. Today 7, 230–234 (1986).
    Article CAS Google Scholar
  10. DiScipio, R.G. Ultrastructures and interactions of complement factors H and I. J. Immunol. 149, 2592–2599 (1992).
    CAS PubMed Google Scholar
  11. Jozsi, M. et al. FHR-4A: a new factor H-related protein is encoded by the human FHR-4 gene. Eur. J. Hum. Genet. 13, 321–329 (2005).
    Article CAS Google Scholar
  12. Jakobsdottir, J. et al. Susceptibility genes for age-related maculopathy on chromosome 10q26. Am. J. Hum. Genet. 77, 389–407 (2005).
    Article CAS Google Scholar
  13. Rivera, A. et al. Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum. Mol. Genet. 14, 3227–3236 (2005).
    Article CAS Google Scholar
  14. van Leeuwen, R., Klaver, C.C., Vingerling, J.R., Hofman, A. & de Jong, P.T. The risk and natural course of age-related maculopathy: follow-up at 6 1/2 years in the Rotterdam study. Arch. Ophthalmol. 121, 519–526 (2003).
    Article Google Scholar
  15. The International ARM Epidemiological Study Group. An international classification and grading system for age-related maculopathy and age-related macular degeneration. Surv. Ophthalmol. 39, 367–374 (1995).
  16. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).
    Article CAS Google Scholar

Download references

Acknowledgements

We thank D. McGibbon for assistance with DNA extraction; J. Silvestri, V. McConnell, G. Wright, G. Meenagh and C. Benson for blood samples from their patients; P. Zipfel for antisera for use in protein blotting; C. Cardwell for statistical help and Illumina for discussions on choice of SNPs for typing. This work was supported by The Health Foundation.

Author information

Authors and Affiliations

  1. Department of Medical Genetics, Queen's University, Belfast, BT12 6BL, Belfast, UK
    Anne E Hughes, Nick Orr & Hossein Esfandiary
  2. Institute of Human Genetics, University of Newcastle upon Tyne, Newcastle upon Tyne, NE1 3BZ, UK
    Martha Diaz-Torres & Timothy Goodship
  3. Centre for Vision Science and Vascular Biology, Queen's University, Belfast, BT12 6BL, Belfast, UK
    Usha Chakravarthy

Authors

  1. Anne E Hughes
    You can also search for this author inPubMed Google Scholar
  2. Nick Orr
    You can also search for this author inPubMed Google Scholar
  3. Hossein Esfandiary
    You can also search for this author inPubMed Google Scholar
  4. Martha Diaz-Torres
    You can also search for this author inPubMed Google Scholar
  5. Timothy Goodship
    You can also search for this author inPubMed Google Scholar
  6. Usha Chakravarthy
    You can also search for this author inPubMed Google Scholar

Contributions

A.E.H., N.O. and H.E. designed the SNP association study, A.E.H. and N.O. analyzed SNP data, T.G. and M.D.-T. performed protein blotting experiments, U.C. provided clinical information and patient samples and A.E.H. performed all other experiments and wrote the paper.

Note: Supplementary information is available on the Nature Genetics website.

Corresponding author

Correspondence toAnne E Hughes.

Ethics declarations

Competing interests

The Queen's University of Belfast has applied for a patent related to research reported in this paper.

Supplementary information

Rights and permissions

About this article

Cite this article

Hughes, A., Orr, N., Esfandiary, H. et al. A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration.Nat Genet 38, 1173–1177 (2006). https://doi.org/10.1038/ng1890

Download citation

This article is cited by