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Defect in immune system causes visual impairment in elderly

In a recently published article in Nature Genetics, the group of Dr. Anneke den Hollander (Nijmegen, the Netherlands) describes a hereditary defect in the immune system that causes visual impairment in the elderly.

Carriers of the defect have a 22 times higher risk of age-related macular degeneration, the leading cause of visual impairment in the elderly. Due to the defect, the immune system is insufficiently inhibited, causing damage to the retina.

The study reports a rare missense mutation in complement factor I (CFI) encoding a p.Gly119Arg substitution that confers a high risk of AMD. CFI plays an important role in the complement system, a part of our innate immunity. The role of the complement system is to eliminate pathogens, clear foreign substances and attract immune cells to the site of inflammation. However, the complement system can also injure our body’s own cells. CFI can protect our own cells from complement attack by inhibiting the complement system. Individuals with a defect in CFI can insufficiently inhibit the complement system, causing damage to the cells in the macula and eventually leading to macular degeneration. The researchers demonstrate that the complement system is indeed overactive in blood samples of patients carrying the CFI defect.

The findings have implications for both predictive testing and for the development of new AMD treatments. The first predictive AMD tests, which are based on a small number of common variants, are currently being offered directly to consumers on the internet. However, these tests are not reliable for individuals carrying rare variants that confer a high risk of developing AMD. It is therefore essential to understand the role of these rare variants in AMD before reliable genetic tests can be developed. These tests should not only be based on a small number of common variants but will also need to address rare, highly penetrant variants, particularly in the case of densely affected families.

New treatments are currently being developed to selectively inhibit complement activation in AMD. However, in recent phase 2 clinical trials, eculizumab, an inhibitor of complement component C5, seemed not to effectively restrict geographic atrophy or drusen area in patients with AMD. Complement inhibitors are likely to be more effective in individuals carrying rare variants that severely affect complement activation. Future research is warranted to unravel pathogenic mechanisms in various subgroups of AMD and to develop personalized treatments tailored to each patient's individual genetic makeup.

Original Publication:

Johannes P H van de Ven, Sara C Nilsson, Perciliz L Tan, Gabriëlle H S Buitendijk, Tina Ristau, Frida C Mohlin, Sander B Nabuurs, Frederieke E Schoenmaker-Koller, Dzenita Smailhodzic, Peter A Campochiaro, Donald J Zack, Maheswara R Duvvari, Bjorn Bakker, Codrut C Paun, Camiel J F Boon, Andre G Uitterlinden, Sandra Liakopoulos, B Jeroen Klevering, Sascha Fauser, Mohamed R Daha, Nicholas Katsanis, Caroline C W Klaver, Anna M Blom, Carel B Hoyng & Anneke I den Hollander. A functional variant in the CFI gene confers a high risk of age-related macular degeneration. Nature Genetics 45:813-817.