Discovery of HTRA1 Gene Provides Potential Marker for AMD

by Dan Roberts
October 2006
The protein Complement Factor H (CFH) has previously been found to play a role in the development of soft confluent drusen leading to AMD (see “CFH and CFB Proteins May Lead to AMD”). CFH has implicated inflammation as part of the AMD pathogenesis, and now, discovery of a new gene may complete the picture. Josephine Hoh (Department of Epidemiology and Public Health, Yale University) reported in the October 2006 issue of the journal Science (“HTRA1 Promoter Polymorphism in Wet Age-Related Macular Degeneration” by A. DeWan et al) that a single mutation in the gene HTRA1 on chromosome 10q26 is a major genetic risk factor for wet AMD.
Studies that genotyped 581 people with AMD and 309 without AMD in a Utah population confirmed suspicions of several research groups that the peak linkage and strongest associations with AMD are localized over the CFH gene and that if a person has a mutant copy of the HTRA1 gene, they have a significantly increased risk of developing AMD.
This provides a strong predictor for individuals who have family histories of the disease. A blood test to identify the mutant HTRA1 gene may now identify those who are up to seven times more likely to develop AMD than those with a normal gene. Not only will this allow such individuals to take preventative steps to lower their risk, but identification of the gene as a drug target can bring about new treatments for AMD and other retinal diseases brought on by drusen formation.
Such blood testing for gene typing, however, is expensive and time consuming, according to Gislin Dagnelie, Ph.D. (Johns Hopkins University). Traditionally, he says, gene-typing is done by amplifying a defective gene to make many copies. The genes are then matched one at a time to a specific template. Recently, “gene chip” technology has been developed that allows matching against many known defects simultaneously. This is still relatively uncommon, but within the next few years it will become the standard approach for diseases such as retinitis pigmentosa, where many different mutations may lead to similar disease processes. Multifactorial diseases like AMD may also benefit from this approach.