The most prevalent form of adult blindness is most likely caused by a failure of at least one of five proteins that regulate the immune system, according to a team of scientists from the University of Manchester.
The finding might pave the way for groundbreaking therapies for age-related macular degeneration (AMD), which affects 600,000 individuals in the United Kingdom alone.
The study was published in the American Journal of Human Genetics and was funded by the Medical Research Council and a partnership between scientists in Manchester, London, and Tübingen, Germany.
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Inflammation in the rear of the eye has long been linked to AMD.
Previous study identified a set of genes considered to control the complement system, a crucial component in our immunological response against infections, as potential risk factors for the illness.
The function of these genes, Complement Factor H (CFH) and Complement Factor H-Related 1 to 5 (CFHR-1 to CFHR-5), was unknown until recently.
However, using mass spectrometry to examine the amounts of these genes’ products—FH and FHR-1 through FHR-5 proteins—in 604 blood plasma samples, the researchers were able to establish for the first time that all five FHR proteins are at higher levels in persons with AMD than in those without.
The complement pathway, which is part of the innate immune system, provides our first line of defence against infections, designating injured cells for death and attracting and activating other immune cells.
A dysfunctional complement pathway in the back of the eye causes a harmful inflammation response in AMD.
Dr. Richard Unwin from The University of Manchester’s Stoller Biomarker Discovery Center said:
This is a hugely important study for people with AMD. Measuring the levels of these FHR proteins has been a big challenge over the last few years and is technically quite challenging as they are present at low levels in the blood and are very similar to each other.
By using state-of-the-art mass spectrometry methods we can now confidently measure these proteins and show for the first time what is an important, if not the most important, factor in how AMD develops.
This opens up whole new areas for improving patient care, through the development of new treatments targeted at these proteins or in simply monitoring levels to discover who has higher levels of complement activation and as such will benefit from complement-modifying treatments.
It’s important to stress that studies over time need to be carried out before we can say with authority that these proteins are able to predict risk—and that will take time.
We’re confident about our results: a second study by Dr. Laura Lorés-Motta and Prof Anneke den Hollander at Radboud University in the Netherlands has in parallel arrived to the same conclusion about FHR proteins using a different measuring technique.
AMD damages the back of the eye, creating deposits, which leads to two types of AMD: moist and dry AMD. Early intervention, however, may be able to halt its spread.
Dr Valentina Cipriani, a Lecturer in Statistical Genomics at Queen Mary University of London who led the data analysis said:
For more than 15 years the focus for AMD has been on Complement Factor H and its protein FH. Our analysis clearly points beyond FH.
By using an approach called a genome-wide association study that looks at genetic variants across the genomes of people with and without the disease, we were able to identify genetic variants that determine both higher FHR protein levels and increased risk of AMD.
Prof Simon Clark, Helmut Ecker Endowed Professor of AMD at Eberhard Karls University of Tübingen who co-supervised the work said:
This really marks a step-change in our understanding around the driving mechanisms behind specific types of AMD.
It follows on from our original discovery last year around FHR-4, but while all higher levels of at least one of the five FHR proteins are now known to be associated with AMD risk not all patients will have their disease driven by this route.
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Therefore, being able to measure these proteins in patients’ blood will be vital in identifying patients who will react to FHR-targeting therapies sometime in the future.
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