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
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
Bianca Hermle | idw - Informationsdienst Wissenschaft
UCLA research could be step toward lab-grown eggs and sperm to treat infertility
07.02.2020 | University of California - Los Angeles Health Sciences
Fighting Against Multi-Resistant Bacteria
07.02.2020 | Julius-Maximilians-Universität Würzburg
At the end of December 2019, the first cases of pneumonia caused by a novel coronavirus were reported from the Chinese city of Wuhan. Since then, infections...
A team of researchers from Switzerland, the US and Poland have found evidence of a uniquely high density of hydrogen atoms in a metal hydride. The smaller spacings between the atoms might enable packing significantly more hydrogen into the material to a point where it could begin to superconduct at room temperature and ambient pressure.
The scientists conducted neutron scattering experiments at the Oak Ridge National Laboratory (ORNL) in the US on samples of zirconium vanadium hydride at...
An international research group with Dr. Longjian Xie from the Bavarian Research Institute of Experimental Geochemistry & Geophysics (BGI) of the University of Bayreuth has succeeded for the first time in measuring the viscosity that molten solids exhibit under the pressure and temperature conditions found in the lower earth mantle. The data obtained support the assumption that a bridgmanite-enriched rock layer was formed during the early history of the earth at a depth of around 1,000 kilometres – at the border to the upper mantle.
In addition, the data also provides indications that the lower mantle contains larger reservoirs of materials that originated in an early magma ocean and have...
According to Einstein's general relativity, the rotation of a massive object produces a dragging of space-time in its vicinity. This effect has been measured, in the case of the Earth’s rotation, with satellite experiments. With the help of a radio pulsar, an international team of scientists (with important contributions from scientists at the Max Planck Institute for Radio Astronomy in Bonn, Germany) were able to detect the swirling of the space-time around its fast-rotating white dwarf-companion star, and thus confirm the theory behind the formation of this unique binary star system.
In 1999, a unique binary system was discovered with the Australian Parkes Radio Telescope in the constellation Musca (the Fly), close to the famous Southern...
Scientists from the Physikalisch-Technische Bundesanstalt (PTB) and the Max Planck Institute for Nuclear Physics (MPIK) have carried out pioneering optical measurements of highly charged ions with unprecedented precision. To do this, they isolated a single Ar¹³⁺ ion from an extremely hot plasma and brought it practically to rest inside an ion trap together with a laser-cooled, singly charged ion. Employing quantum logic spectroscopy on the ion pair, they have increased the relative precision by a factor of a hundred million over previous methods. This opens up the multitude of highly charged ions for novel atomic clocks and further avenues in the search for new physics. [Nature, 29.01.2020]
Highly charged ions are—although seemingly exotic—a very natural form of visible matter. All the matter in our sun and in all other stars is highly ionized,...
16.01.2020 | Event News
15.01.2020 | Event News
07.01.2020 | Event News
07.02.2020 | Power and Electrical Engineering
07.02.2020 | Power and Electrical Engineering
07.02.2020 | Life Sciences