Human Molecular Genetics Advance Access originally published online on December 15, 2007
Human Molecular Genetics 2008 17(7):971-977; doi:10.1093/hmg/ddm369
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Deletion of CFHR3 and CFHR1 genes in age-related macular degeneration
1 Center for Human Genetics Research and 2 Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN, USA 3 Center for Human Genetics and 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
* To whom correspondence should be addressed at: Center for Human Genetics Research, 519 Light Hall, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Tel: +1 6153435851; Fax: +1 6153438619; Email: jonathan{at}chgr.mc.vanderbilt.edu
Received October 9, 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 = 0.10–0.86). 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 0.39–1.04, 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.