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Progress in Understanding AMD Genetics

While a number of environmental and dietary risk factors have been linked with AMD, progress in identifying genetic components associated with the disease has been somewhat slower. However significant progress has been made over the last few years: up to six regions of the genome have been identified as potentially harboring AMD genes.

One region repeatedly linked to AMD in family based studies is located on chromosome 1. This year, several independent research teams reported a strong association of AMD with a chromosomal 1 gene that encodes the protein, complement factor H (CFH). A single base change in the CFH gene introduces a single amino acid change into the sequence of the variant CFH protein it produces, replacing the amino acid tyrosine with histidine. Understanding this simple genetic alteration - a change in a single unit of DNA out of the 3 billion or so units that make up our genetic blueprint - could hold future promise for those at risk for AMD. For now, the research findings are clarifying how AMD develops and how the disease is related to the immune system.

What is the Role of CHF?

The CHF protein helps regulate inflammation in part of the immune system that attacks diseased and damaged cells. CHF helps regulate complement - an arm of the immune system that provides rapid defense against microbes and clears out immune complexes & debris. When immune complexes, clusters of interlocking antigens and antibodies, aren't rapidly removed and continue to circulate they can be trapped in tissues or blood vessels where they can set off reactions that lead to inflammation. Phagocytic inflammatory cells such as macrophages can generate damaging reactive oxygen species. It appears that the abnormal CHF protein is less able to keep the complement system - and inflammation - under control.

AMD: Partly an "Immunogenetic" Disease?

The biological role of CFH as a modulator of inflammation through its regulation of complement makes it an attractive candidate gene for AMD susceptibility. Inflammation has repeatedly been implicated in the AMD disease process. For example, researchers have detected elevated levels of the inflammatory marker c-reactive protein in advanced AMD. They've also observed macrophages localized near neovascular lesions, and complement-related proteins contained in drusen deposits. In fact, some cell biologists believe that inflammation and difficulty in regulating the immune system play a causal role in forming drusen, a hallmark of AMD.

What Might the Future Hold?

The new gene findings could apply to many people. Two of the studies published earlier this year indicate that the CFH gene variant likely explains 43-50% of the overall risk of developing AMD in older adults. In another study the likelihood of having AMD was reportedly increased by a factor of 7.4 in people with the variant.

These findings may eventually lead to screening for the gene to assess a person's risk well before any symptoms develop. It also opens the door to developing new drug or gene therapies that might slow progress of the disease. The identification of CFH may also spur researchers to examine whether antioxidants, such as those used in the AREDS trial, or anti-inflammatory dietary strategies are helpful for those genetically susceptible to AMD.

Although the CHF gene has generated much excitement, we probably don't yet know the whole story. Genetic interactions are complex, many genes are involved, and environmental influences must be factored in as well. Yet 2005 will likely be remembered as a watershed year of progress toward understanding the basic causes of AMD.

References

1. Humphries P. Progress in understanding the genetics of AMD. AMD Alliance International Scientific Advisory Panel, 2005.
2. National Eye Institute Statement. Gene found to increase risk of the most common cause of blindness. March 10, 2005.
3. Klein RJ et al. Complement factor H polymorphism in age-related macular degeneration. Sci 308:385-89, 2005.
4. Haines JL et al. Complement factor H variant increases the risk of age-related AMD. Sci 308:419-21, 2005.
5. Edwards AO et al. Complement factor H polymorphism and age-related macular degeneration. Sci 308:421-24, 2005.
6. Hageman GS et al. A common haplotype in the complement regulatory gene, factor H, predisposes to ARMD. Proc Natl Sci Acad 102:7227-32, 2005.
7. Zareparsi S et al. Strong association of Y402H variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration. Am J Human Genetics 77:149-53, 2005.