CFH and Macular Degeneration
This web page was produced as an assignment for Gen677 at UW-Madison Spring 2010.
Genetic Evidence
In 2005, three separate studies found genetic evidence for CFH being a causal gene in AMD.
In the paper by Klein et al., the genomes of AMD patients and a control group of healthy patients were screened by genotyping for polymorphisms associated with AMD. 116,204 single nucleotide polymorphisms (SNP's) were genotyped. A polymorphism changing a tyrosine to a histodine at amino acid 402 in the CFH region was found to be associated with AMD. The polymorphism is located in a region of CFH that binds the C-reactive protein and heparin. Homozygous individuals with this variant had an increased risk of 7.4% of developing AMD (3).
Haines et al. also genotyped SNPs of AMD patients to find those associated with AMD. A haplotype containing CFH and five Complement Factor H-related genes was again found in 46% of the AMD cases studied and is therefore strongly associated with AMD. Individuals with this haplotype were then screened for sequences that potentially increased the risk of AMD. 11 total sequences were found, but one, T1277C, was found in 45 of the 48 cases with the haplotype (2).
Edwards et al., genotyped SNPs of AMD patients and found the same change from tyrosine to histodine at amino acid 402 in the CFH gene that Klein et al. discovered (1).
Inflammation has been associated with AMD and CFH moderates inflammation as part of the innate immune system. The polymorphism in the region that binds the C-reactive protein and heparin is thought to increase the affinity of CFH for C-reactive protein and heparin. Binding to both proteins then increases the affinity of CFH for the complement protein C3b. This in turn increases the down-regulation of complement's affect. AMD patients have been found to have elevated C-reactive protein levels and the drusen deposits contain proteins involved in the complement system (1,2,3).
- Complement Factor H Polymorphism in Age-Related Macular Degeneration by Klein et al.
- Complement Factor H Variant Increases the Risk of Age-Related Macular Degeneration by Haines et al.
- Complement Factor H Polymorphism and Age-Related Macular Degeneration by Edwards et al.
In the paper by Klein et al., the genomes of AMD patients and a control group of healthy patients were screened by genotyping for polymorphisms associated with AMD. 116,204 single nucleotide polymorphisms (SNP's) were genotyped. A polymorphism changing a tyrosine to a histodine at amino acid 402 in the CFH region was found to be associated with AMD. The polymorphism is located in a region of CFH that binds the C-reactive protein and heparin. Homozygous individuals with this variant had an increased risk of 7.4% of developing AMD (3).
Haines et al. also genotyped SNPs of AMD patients to find those associated with AMD. A haplotype containing CFH and five Complement Factor H-related genes was again found in 46% of the AMD cases studied and is therefore strongly associated with AMD. Individuals with this haplotype were then screened for sequences that potentially increased the risk of AMD. 11 total sequences were found, but one, T1277C, was found in 45 of the 48 cases with the haplotype (2).
Edwards et al., genotyped SNPs of AMD patients and found the same change from tyrosine to histodine at amino acid 402 in the CFH gene that Klein et al. discovered (1).
Inflammation has been associated with AMD and CFH moderates inflammation as part of the innate immune system. The polymorphism in the region that binds the C-reactive protein and heparin is thought to increase the affinity of CFH for C-reactive protein and heparin. Binding to both proteins then increases the affinity of CFH for the complement protein C3b. This in turn increases the down-regulation of complement's affect. AMD patients have been found to have elevated C-reactive protein levels and the drusen deposits contain proteins involved in the complement system (1,2,3).
1. Edwards, A. O., R. Ritter, K. J. Abel, A. Manning, C. Panhuysen, and L. A. Farrer. 2005. Complement Factor H Polymorphism and Age-Related Macular Degeneration. Science. 308:421-424.
2. Haines, J. L., M. A. Hauser, S. Schmidt, W. K. Scott, L. M. Olson, P. Gallins, K. L. Spencer, S. Y. Kwan, M. Noureddine, J. R. Gilbert, N. Schnetz-Boutaud, A. Agarwal, E. A. Postel, and M. A. Pericak-Vance. 2005. Complement Factor H Variant Increases the Risk of Age-Related Macular Degeneration. Science. 308:419-421.
3. Klein, R. J., C. Zeiss, E. Y. Chew, J. Tsai, R. S. Sackler, C. Haynes, A. K. Henning, J. P. SanGiovanni, S. M. Mane, S. T. Mayne, M. B. Bracken, F. L. Ferris, J. Ott, C. Barnstable, and J. Hoh. 2005. Complement Factor H Polymorphism in Age-Related Macular Degeneration. Science. 308:386-389.
