by Dan Roberts
Updated October 2011
Two genes have been shown to lead to age-related macular degeneration (AMD) in recent studies.
In 2005, the first suspect protein was discovered by three separate research centers. Called Complement Factor H (CFH), it may be a cause of AMD in as many as 50% of cases. CFH helps to control the body’s immune response and inflammation. If the gene containing the code for this protein is deficient (mutated), that control can be diminished and may lead to some cases of macular degeneration. This discovery is in line with other recent research that has shown a possible connection between inflammation and AMD. (See C-reactive Protein Levels Connected to Macular Degeneration.)
One study was led by Dr. Albert O. Edwards at the University of Texas Southwestern Medical Center in Dallas. The second study was led by Dr. Pericak-Vance was at Duke and Vanderbilt, and the third was led by Dr. Josephine Hoh at Yale and included researchers from the National Eye Institute and the Rockefeller University. All three studies found that a single change in a letter of the genetic code led to a change of a single amino acid in the protein CFH. This protein limits the immune response and inflammation, but a defect in the gene that contains the code for CFH causes it to become less effective. The presence of the defective gene raises the risk of macular degeneration two to seven times, with the greatest risk occurring in people with both genes of the pair defective.
In Dr. Edwards’ study, 31.4 percent of the MD patients had two copies of the defective gene, and 21.5 percent had no copies. In the control group without MD, 13.7 percent had two copies, and 42.6 percent had no copies. The remainder of both groups had one copy of the defective gene. If, as it is beginning to appear, macular degeneration is related to the immune system, researchers may be able to develop drugs that focus on that particular response as a partial cure for the disease. Other causal factors, such as environment and nutrition, also need to be considered.
According to a report on a larger study published in the July 19, 2006 issue of the Journal of the American Medical Association, patients with two copies of a variant of the gene were at 11 times the risk of developing AMD compared to non-carriers. This was found by physicians at Erasmus Medical Center in Rotterdam. This more extensive confirmed the smaller studies by looking at 5,681 subjects who were 55 years or older when the study began in 1990. The researchers found that those who carried the gene variant had a 48 percent risk of developing AMD by age 95, compared to a 22 percent risk for non-carriers,.
In another study in 2005 conducted at Columbia University Medical Center and published in Nature Genetics, the question arose as to why 29% of the subjects who had a variation in Factor H did not develop AMD. This led to further analysis of 1,300 people and a breakthrough reported by Dr. Rando Allikmets, Ph.D., (the Acquavella Associate Professor in Ophthalmology, Pathology and Cell Biology). Dr, Allikmets’ team found a second gene, Factor B, to be the major reason for that analomy. While Factor H stops the immune response, Factor B activates it. The two opposites can, therefore, balance one another and prevent AMD from developing in some cases.
The two genes are now connected to development of AMD in three out of four people who have the disease. The next step is to learn how to control the body’s immune response that sets off inflammation. Once the viral or bacterial cause has been identified, that knowledge in combination with the newly-discovered genetic markers will make it possible to develop effective therapies for the prevention of the disease.
A later study (Johanna M Seddon, et al“Association of CFH Y402H and LOC387715 A69S With Progression of Age-Related Macular Degeneration,” JAMA, April 2007) showed that common variants of CFH and another gene, LOC387115, also linked to development of AMD, increased the risk of progression to advanced AMD. The variants, called Single Nucleotide Polymorphisms (SNP), independently increased the risk of progression from early or intermediate stages to advanced stages of AMD by 2.6 times (CHF) and 4.1 times (LOC387715). The presence of both risk genotypes, when combined with smoking and body mass index of 25+, increased the AMD progression risk 19-fold.
In October 2011, Seddon and investigators from Tufts Medical Center, Tufts University School of Medicine, and Brigham and Women’s Hospital, reported in Nature Genetics that they have identified a rare, high-risk mutation resulting in an arginine to cysteine substitution in the CFH protein. This mutation, called CFH R1210C, is associated with loss of function of the CFH protein, and its discovery suggests that loss of CFH function can drive AMD risk. The finding more clearly links CFH gene dysfunction to the disease and may lead to new and effective preventative treatments for high risk individuals.
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