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.
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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.
The Queen's University of Belfast has applied for a patent related to research reported in this paper.
Haploview plot of haplotype block structure of CFH region. (PDF 165 kb)
Breakpoint region of 1,620 bases. (PDF 11 kb)
Logistic regression analysis of rs1061170 (Y402H) and the presence or absence of deletion of CFHR1 and CFHR3. (PDF 8 kb)
Association of CFH rs1061170 and of block 2 haplotypes in replication group. (PDF 6 kb)
Primer information. (PDF 10 kb)
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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
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