UNITED KINGDOM–(ENEWSPF)–9 July 2012. The biological role of a gene variant implicated in multiple sclerosis (MS) has been determined by researchers at Oxford University. The finding explains why MS patients do badly on a set of drugs used successfully in other autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel disease – something that has been a puzzle for over 10 years.
The study illustrates that understanding the details of how some changes in the DNA code are linked to common diseases can inform clinical practice and guide the treatments that people receive so as to prevent adverse side effects.
The Oxford University team, along with German, Danish and US colleagues, has published the findings in the journal Nature. They were funded through the MRC Human Immunology Unit, part of the MRC Weatherall Institute of Molecular Medicine, and the Wellcome Trust.
‘The hope has been that analyses of the whole human genome would lead to findings that are clinically relevant,’ says Professor Lars Fugger of the Nuffield Department of Clinical Neurosciences at Oxford University, who led the work. ‘We show that this is possible. It’s one of the first such examples, certainly in autoimmune disease.’
Gene scientists in recent years have been successful at identifying hundreds of individual changes, slips and alterations in our DNA that can be reliably linked to the risk of many common diseases such as MS, diabetes and heart disease.
But it has been difficult to determine which of these DNA changes are causal and what biological role they play in disease. In addition, most of the gene variants only have small effects, each on their own accounting for little of the genetic contribution to disease.
This has led some to question the worth of these very large genetic studies, or to suggest that the assumption that decoding the human genome would change medicine has been oversold.
‘Some people say that genomic association studies haven’t delivered on the promise of decoding the human genome,’ says Professor Fugger. ‘But the postgenomic era has only just started.’The researchers investigated one particular genetic variant – found in a gene called TNFRSF1A – which has previously been associated with the risk of developing MS.
The Oxford-led research team used a battery of genetic, molecular, cell biology and biophysical techniques to show that the TNFRSF1A gene variant results in the production of an altered, shortened version of the TNFR1 protein encoded by the gene.
The long version of the TNFR1 protein normally sits at the surface of cells and binds TNF, an important signalling molecule involved in a number of biological pathways in the body. In contrast, the shortened form lacks an anchor to keep it at the cell surface and is instead released outside of the cell.
The researchers showed that the free, shortened protein can mop up TNF, preventing it from triggering signalling. This is essentially the same thing TNF blocking drugs do.
Drugs that block TNF are effective treatments in rheumatoid arthritis, inflammatory bowel disease and other autoimmune disorders. Yet a clinical trial over 10 years ago found the drugs make MS patients significantly worse and exacerbate the disease.
‘Now we know that the functional effect of the TNFRSF1A gene variant mirrors that of TNF blocking drugs, and this promotes MS risk,’ says Mr Adam Gregory, one of the joint first authors of the paper from the Nuffield Department of Clinical Neurosciences at Oxford University. ‘Had we known this prior to the clinical trial of TNF blockers in MS patients, this could have helped to predict the poor outcome,’ notes Dr Calliope Dendrou, the other joint first author from the same department.
Professor Fugger says the results are a ‘proof of concept’ that understanding the biological details of how gene variants are associated with a disease can direct which patients should or should not receive specific drugs.
‘Whilst the TNFRSF1A gene variant is linked to a modest risk of developing MS, the drug that mimics the effect of the variant has a considerably greater impact. The effects of genetic variants influencing disease risk or resistance can be amplified by drugs. This has often been completely overlooked but will be critical for using genetic findings in a medical context.’
- The paper ‘TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis’ by Adam Gregory, Calliope Dendrou and colleagues is to be published in the journal Nature on Sunday 8 July 2012.
- The Oxford University researchers have applied for a patent on gene and protein tests connected to anti-TNF therapies through Isis Innovation, the University of Oxford’s technology transfer company.
- The study was funded by the MRC Human Immunology Unit, part of the MRC Weatherall Institute of Molecular Medicine, and the Wellcome Trust.
- For almost 100 years the Medical Research Council has improved the health of people in the UK and around the world by supporting the highest quality science. The MRC invests in world-class scientists. It has produced 29 Nobel Prize winners and sustains a flourishing environment for internationally recognised research. The MRC focuses on making an impact and provides the financial muscle and scientific expertise behind medical breakthroughs, including one of the first antibiotics penicillin, the structure of DNA and the lethal link between smoking and cancer. Today MRC funded scientists tackle research into the major health challenges of the 21st century. www.mrc.ac.uk
- The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust’s breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests. www.wellcome.ac.uk
- Oxford University’s Medical Sciences Division is one of the largest biomedical research centres in Europe, with over 2,500 people involved in research and more than 2,800 students. The University is rated the best in the world for medicine, and it is home to the UK’s top-ranked medical school.From the genetic and molecular basis of disease to the latest advances in neuroscience, Oxford is at the forefront of medical research. It has one of the largest clinical trial portfolios in the UK and great expertise in taking discoveries from the lab into the clinic. Partnerships with the local NHS Trusts enable patients to benefit from close links between medical research and healthcare delivery.A great strength of Oxford medicine is its long-standing network of clinical research units in Asia and Africa, enabling world-leading research on the most pressing global health challenges such as malaria, TB, HIV/AIDS and flu. Oxford is also renowned for its large-scale studies which examine the role of factors such as smoking, alcohol and diet on cancer, heart disease and other conditions.