How does genetic make-up affect the risk of AMD?
- Type of funding: Project Grant
- Grant Holder: Professor Paul Bishop
- Institute: University of Manchester
- Region: North West
- Start date: September 2014
- End Date: June 2018
- Priority: Causes
- Eye Category: AMD
Age-related macular degeneration (AMD) is a condition that affects light-sensitive cells in the macula – the central part of the retina, at the back of the eye. Lifestyle factors such as smoking and diet have been linked to the risk of getting AMD and recent research has also shown that our genes play an important role. We know that genes are a cell’s instruction manual for making proteins. But we don’t yet understand how changes in these genes increase the risk of AMD.In this study the researchers are using eye tissue from human donors that comes from a part of the eye near the macula, called Bruch’s membrane. They will analyse the tissue for genetic changes that are known to make people at higher risk or lower risk of AMD. They will then look for the proteins contained in Bruch’s membrane and compare them between the high and low risk tissue. The aim is to find out what difference these genetic changes make to the make-up of tissue around the macula in AMD. The results will give us important information for identifying future targets for treatment.
Elucidation of molecular mechanisms underpinning disease initiation and progression in age-related macular degeneration.Recent studies have demonstrated that genetics plays a major role in determining AMD risk. In particular, genetic variations on chromosome 1 in a region containing genes encoding complement factor H (CFH), a splice variant called FHL-1, and the five complement factor H related proteins (CFHR 1-5) have a major effect in modifying AMD risk. There is a second important locus on chromosome 10 (the ARMS2/HTRA1 locus). However, there is currently very limited understanding of how, at a biochemical level, these genetic variations modify risk.
The team is addressing these questions using two strategies. Firstly, they are investigating how genetic variations across the chromosome 1 locus affect the levels of synthesis by the retinal pigment epithelium of CFH, FHL-1 and the 5 CFHR proteins. Secondly, as they believe Bruch’s membrane is central to AMD pathology, they are undertaking untargeted proteomic studies of macular Bruch’s membrane extracts from subjects who had extreme genotypes i.e. high risk just at chromosome 1, high risk just at chromosome 10 and low risk. They are using iTRAQ technology to compare the proteomes between these groups and compare within the groups the proteomes before and after AMD pathology has developed.
These experiments are designed to determine whether the biochemical pathways involved in chromosome 1 and chromosome 10 associated AMD are the same or different, and what biochemical pathways are involved in disease initiation and progression. This will be important for the future design of therapeutics for preventing AMD or slowing down disease progression.