International team delivers research breakthrough for leading cause of blindness

7 February 2020
Source: Queen Mary University of London

Researchers have identified a new protein linked to age-related macular degeneration (AMD) that could offer new hope for the diagnosis and treatment of the disease, which affects over 600,000 people in the UK alone.

The research team, made up of scientists from Queen Mary University of London, the University of Manchester, Cardiff University, and Radboud University Medical Center, Nijmegen, found significantly higher levels of a protein called factor H-related protein 4 (FHR-4) in the blood of AMD patients.

Further investigation, using eye tissue donated for medical research, showed the presence of the FHR-4 protein within the macula – the specific region of the eye affected by the disease.

The results of this study open up new routes for the early diagnosis, by measuring FHR-4 levels in the blood, and suggests therapies targeting this protein could provide promising future treatment options for the disease.

FHR-4 regulates the complement system, part of the immune system, which plays a critical role in inflammation and the body’s defence against infection.

Previous studies have linked the complement system to AMD showing that genetically inherited faults in key complement proteins are strong risk factors for the condition.

Top left: Example of impaired central vision of a patient affected by advanced AMD. Top right: Drawing of the DNA helix. Bottom right: Accumulation (in yellow) of the protein FHR-4 in the human macula – the specific region of the eye affected by the disease. Bottom left: Retinal fundus photo of a patient affected by ‘dry’ AMD (geographic atrophy.)

In this study, the researchers used a genetic technique, known as a genome-wide association study, to identify specific changes in the genome related to the increased levels of FHR-4 found in AMD patients.

They found higher blood FHR-4 levels were associated with changes to genes that code for proteins belonging to the factor H family, which clustered together within a specific region of the genome. The identified genetic changes also overlapped with genetic variants first found to increase the risk of AMD over 20 years ago.

Together, the findings suggest that inherited genetic changes can lead to higher blood FHR-4 levels, which results in uncontrolled activation of the complement system within the eye and drive disease.

Blood levels of FHR4 were measured in 484 patients and 522 age-matched control samples using two independent, established collections of AMD patient data, the Cambridge AMD study, led by Professor Anthony Moore from Moorfields Eye Hospital and UCL Institute of Ophthalmology (now at the University of California San Francisco) and Professor John Yates from Cambridge University, and the European Genetic Database (EUGENDA), led by Professor Anneke den Hollander and Professor Carel Hoyng from Radboud University Medical Center.

There are two main types of AMD – “wet” AMD and “dry” AMD. Whilst some treatment options exist for ‘wet’ AMD, there is currently no available treatment for “dry” AMD.

Dr Valentina Cipriani, who jointly led the statistical data analysis with Dr. Laura Lorés-Motta from the Radboud University Medical Center and is an expert in ophthalmic statistical genetics at Queen Mary University of London, and member of the International AMD Genomics Consortium (IAMDGC), said: “By unveiling FHR-4 as a novel, key molecular player for AMD, our study was able to dissect further the genetic disease predisposition at the factor H region. This is one of the most established genetic associations in the field of complex genetics. We hope our findings will accelerate interest from the wider research community in the involvement of the complement system in AMD, with the ultimate goal of uncovering the role of the whole ‘complementome’ in the disease.”

Professor Simon Clark, a specialist in the regulation of the complement system in health and disease at the University of Manchester, said: “This study really is a step-change in our understanding of how complement activation drives this major blinding disease. Up until now, the role played by FHR proteins in disease has only ever been inferred. But now we show a direct link and, more excitingly, become a tangible step closer to identifying a group of potential therapeutic targets to treat this debilitating disease.”

Professor Paul Bishop, an ophthalmologist and AMD expert at the University of Manchester, said: “The combined protein and genetic findings provide compelling evidence that FHR-4 is a critical controller of that part of the immune system which affects the eyes. Apart from improving understanding of how AMD is caused, this work also provides a way of predicting risk of the disease by simply measuring blood levels of FHR-4 and also provides a new route to treatment by reducing the blood levels of FHR-4 to restore immune system function in the eyes.”

Professor Paul Morgan, an expert in complement biology at Cardiff University, and leader in the development of the antibodies and assays that underpinned this work said: “The collaboration between experts in complement biology, eye disease and genetics across Europe has enabled the accumulation of a robust body of evidence that genetically dictated FHR-4 levels in plasma are an important predictor of risk of developing AMD. The unique antibodies and assays we have developed have potential not only for contributing to risk prediction but also to new ways of treating this common and devastating disease.”

Notes to editors:

  • Research paper: ‘Increased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration’ V Cipriani et al. Nature Communications DOI: 10.1038/s41467-020-14499-3
  • For a copy of the paper, please contact:
    Sophie McLachlan
    Faculty Communications Manager (Science & Engineering)
    Queen Mary University of London
    Email: sophie.mclachlan@qmul.ac.uk
    Tel: 020 7882 3787

About Queen Mary University of London

At Queen Mary University of London, we believe that a diversity of ideas helps us achieve the previously unthinkable.

In 1785, Sir William Blizard established England’s first medical school, The London Hospital Medical College, to improve the health of east London’s inhabitants. Together with St Bartholomew’s Medical College, founded by John Abernethy in 1843 to help those living in the City of London, these two historic institutions are the bedrock of Barts and The London School of Medicine and Dentistry.

Today, Barts and The London continues to uphold this commitment to pioneering medical education and research. Being firmly embedded within our east London community, and with an approach that is driven by the specific health needs of our diverse population, is what makes Barts and The London truly distinctive.

Our local community offer to us a window to the world, ensuring that our ground-breaking research in cancer, cardiovascular and inflammatory diseases, and population health not only dramatically improves the outcomes for patients in London, but also has a far-reaching global impact.

This is just one of the many ways in which Queen Mary is continuing to push the boundaries of teaching, research and clinical practice, and helping us to achieve the previously unthinkable.

About Cardiff University

Cardiff University is recognised in independent government assessments as one of Britain’s leading teaching and research universities and is a member of the Russell Group of the UK’s most research intensive universities. The 2014 Research Excellence Framework ranked the University 5th in the UK for research excellence. Among its academic staff are two Nobel Laureates, including the winner of the 2007 Nobel Prize for Medicine, Professor Sir Martin Evans. Founded by Royal Charter in 1883, today the University combines impressive modern facilities and a dynamic approach to teaching and research. The University’s breadth of expertise encompasses: the College of Arts, Humanities and Social Sciences; the College of Biomedical and Life Sciences; and the College of Physical Sciences and Engineering, along with a longstanding commitment to lifelong learning.

About Radboud University Medical Center Nijmegen, the Netherlands

Radboud university medical center specializes in patient care, scientific research, teaching and training. Our mission is to have a significant impact on health care. We aim to be pioneers in shaping the health care of the future. We do this in a person-centered and innovative way and in close collaboration with our network.

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