Researchers at Yale University and Rockefeller University have discovered a genetic mutation that predicts a patient?s likelihood to develop age-related macular degeneration (AMD), the leading cause of blindness in the elderly. By understanding the genetic causes of AMD, researchers hope to now develop new screens for early-detection and new therapies for improved treatment.

Fifteen million people in the United States currently suffer from age-related macular degeneration, and as the baby boomer population ages, this number is expected to double. Patients with severe AMD lose vision in the center of the eye, making it difficult to do simple daily activities like driving, reading or even recognizing a familiar face. While scientists know that high blood pressure, smoking, and family history are risk factors, they have never found a common genetic link that could account for development of AMD in most patients. Because they understand so little about the disease genetics, it's been difficult for researchers to develop any broadly effective treatments. What they needed was a way to scan through the three billion bases of the human genome in enough detail to find the mutations responsible for AMD.

As reported in the April 15, 2005 issue of Science, Dr. Josephine Hoh of Yale and her colleagues at the Laboratory of Statistical Genetics at Rockefeller University used genome-mapping microarrays, capable of simultaneously scanning 100,000 genetic variations called SNPs, to do just that. They compared each of the 100,000 SNPs between 50 healthy people and 96 AMD patients and found that the AMD patients shared a SNP genetic variation that was not present in the healthy group. That SNP turned out to be in the Complement Factor H (CFH) gene, and having it puts a person at nearly eight times greater risk of developing the disease.

After using SNPs to pinpoint the CFH gene, scientists sequenced CFH from both groups and found that the SNP they discovered most likely changes the structure of the CFH protein, causing the immune system to misbehave and ultimately deteriorate the retina. Scientists know that CFH inhibits certain immune proteins, called complement proteins, that are involved in inflammation and that help destroy invading microorganisms during an infection. However, the CFH mutation may make it impossible to control complement activation, resulting in chronic inflammation and damage to healthy tissues. The research group found both CFH and complement protein deposits in the retina and surrounding damaged eye tissue of AMD patients.

To identify CFH, the researchers used the Affymetrix GeneChip® Mapping 100K Set, which allowed them to analyze over 100,000 SNPs — a number large enough to cover the entire human genome with an average spacing of one SNP every 23.6 kilobases. Hoh's study is one of the first successful whole-genome association studies, since previously, scientists could only look at a few hundred markers at a time, making it impossible to scan the genome with enough detail to find a handful of genes.

Understanding the role of CFH and uncontrolled inflammation plays in AMD may help doctors design new therapies and genetic screens for at-risk patients sooner. Early detection, new treatments, and life-style changes — such as avoiding smoking, changing the diet, or taking zinc supplements — may prevent or stop AMD, helping a growing number of seniors preserve healthy vision.