Defect in immune system causes visual impairment in elderly

Ven van de, John

Visual impairment in the elderly is caused by a hereditary defect in the immune system, claim researchers at the Department of Ophthalmology in a recently published article in top journal Nature Genetics. 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 blocked causing damage to the retina. 

Johannes van de Ven and colleagues report a rare missense mutation inCFIencoding a p.Gly119Arg substitution that confers a high risk of AMD. Sera from AMD cases carrying the p.Gly119Arg variant mediate the degradation of C3b at a significantly lower level than sera from AMD cases without theCFIvariant. 

The findings have implications for both predictive testing and for the development of new AMD treatments. The first prognostic AMD tests, which are based on a small number of common variants, are currently being marketed. 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. 

Finally, 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. 

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 CFIgene confers a high risk of age-related macular degeneration. Nature Genetics,Published online: 19 May 2013 | doi:10.1038/ng.2640


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