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Human Molecular Genetics Advance Access published online on December 15, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm369
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Deletion of CFHR3 and CFHR1 Genes in Age-Related Macular Degeneration

Kylee L. Spencer1, Michael A. Hauser2, Lana M. Olson1, Silke Schmidt2, William K. Scott5, Paul Gallins5, Anita Agarwal3, Eric A. Postel4, Margaret A. Pericak-Vance5 and Jonathan L. Haines1,*

1 Center for Human Genetics Research, Vanderbilt University, Nashville, TN USA 2 Center for Human Genetics, Duke University, Durham, NC USA 3 Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN USA 4 Duke University Eye Center and Department of Ophthalmology, Duke University Medical Center, Durham, NC USA 5 Miami Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL USA

* Corresponding author: Jonathan L. Haines, Ph.D., Center for Human Genetics Research, 519 Light Hall, Vanderbilt University Medical Center, Nashville, TN 37232. Ph: (615) 343-5851, Fax: (615) 343-8619 Email: Jonathan{at}chgr.mc.vanderbilt.edu

Received October 9, 2007; Revised December 11, 2007; Accepted December 11, 2007

Age-related macular degeneration (AMD) impairs vision for ~7.5 million Americans. Both susceptibility variants and protective haplotypes in the complement factor H (CFH) gene modulate risk for AMD. Recently, deletion of the "CFH-related" genes CFHR1 and CFHR3 was found to be segregating with a particular CFH haplotype, which reduced the risk of AMD. We tested the deletion for association in a Caucasian population of 780 cases and 265 controls and examined its effect in the context of known AMD risk factors. The deletion did not segregate perfectly with any one SNP, as previously suggested. CFH haplotype P2 was the most frequent haplotype in deletion homozygotes (47%), and the majority (14/16) of these individuals were homozygous for the non-risk allele of Y402H. Overall, deletion homozygosity was significantly more frequent in controls than cases (2.6% controls, 0.8% cases, p=0.025, OR=0.29, 95% CI= 0.10 to 0.86). After controlling for age, Y402H, smoking, and LOC387715 A69S, the protective effect of the deletion was no longer statistically significant (p=0.27). However, using a CFH haplotype that all deletion homozygotes share as a surrogate for the deletion, this marker remained modestly associated with AMD after adjustment for known risk factors (OR=0.63, 95% CI 0.39 to 1.04, p=0.07). Therefore, deletion of CFHR1 and CFHR3 may account for a small portion of the protection from AMD associated with particular haplotypes in CFH. The presence of protective haplotypes in CFH that do not carry the deletion, suggests that other protective variants in this region have yet to be discovered.


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