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Age-related macular degeneration (AMD) is the commonest cause of blindness in developed countries, affecting some 1.5 million people in the UK alone. Treatment options are limited, so whilst neovascular (“wet”) AMD is to some extent treatable, there is no available treatment for the other form, called geographic atrophy or late “dry” AMD. A role for inflammation has been posited for at least twenty years and the finding from genetic evidence that an inherited fault in a protein called factor H (FH) was a strong risk factor for AMD focused attention on a part of the immune system called the complement system, a key driver of inflammation that FH helps to control.
The suggestion that AMD was caused by a failure of complement regulation in the eye has catalysed a rush to develop drugs that inhibit complement to treat geographic atrophy.
Designing the best drugs to fix this failure of control requires a comprehensive understanding of what has gone wrong. To this end, an international collaboration led by scientists in Tübingen, Manchester, Cardiff, London and Nijmegen tested whether other complement regulators were involved in the failure of control seen in AMD. One of these, a protein called factor H-related protein 4 (FHR4), was found to be present at higher levels in the blood of patients with AMD compared to age-matched individuals without the disease; this finding was highly significant in statistical analyses and was replicated in a total of 484 patient and 522 control samples from two independent collections. Next, analyses of eyes generously donated for research after life revealed that FHR4 protein was present in the AMD-affected parts of the eye where complement was being activated, suggesting that FHR4 contributes to loss of control of complement in AMD.
To discover whether the increased levels of FHR4 were a cause or consequence of AMD the team turned to genetics. All of the genes coding for FH, FHR4 and other so-called FH-family proteins are found together in a tight cluster on chromosome 1. Remarkably, a genome-wide association study, which is an investigation of a set of genetic variants across the genome, revealed that variants in this gene cluster have the biggest effect on FHR4 levels in blood and those variants highly overlap with the variants that determine the well-established genetic risk of AMD on chromosome 1.
The combined protein and genetic findings provide compelling evidence that FHR4 is a critical controller of complement in the eye and that genetically determined higher blood FHR4 levels lead to more FHR4 in the eye which in turn increase the risk of the uncontrolled complement activation that drives the disease. Apart from improving understanding of how AMD is caused, the work provides a way of predicting risk of the disease by simply measuring blood levels of FHR4 and a new route to treatment by reducing the blood levels of FHR4 to restore complement control in the eye.
University Hospital Tübingen
Institute for Ophthalmic Research
Prof. Simon J. Clark, Helmut Ecker Endowed Professor of AMD
Elfriede-Aulhorn-Straße 7, 72076 Tübingen
mail: simon.clark@uni-tuebingen.de
phone +49 7071 29 87894
Increased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration
Valentina Cipriani, Laura Lorés-Motta, Fan He, Dina Fathalla, Viranga Tilakaratna,
Selina McHarg, Nadhim Bayatti, İlhan E. Acar, Carel B. Hoyng, Sascha Fauser, Anthony T. Moore, John R.W. Yates, Eiko K de Jong, B. Paul Morgan, Anneke I. den Hollander, Paul N. Bishop & Simon J. Clark
https://doi.org/10.1038/s41467-020-14499-3
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