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University of Manchester researchers reveal clues to new genes behind rheumatoid

07 Jun 2007

Researchers at the University of Manchester have identified evidence of several new genes behind the chronic inflammatory disease rheumatoid arthritis (RA), which affects 387,000 people in the UK.

Professor Jane Worthington and her team at the University's arthritis research campaign (arc) Epidemiology Unit made their findings as part of the largest ever study of the genetics behind common diseases. The 9M Wellcome Trust Case Control Consortium (WTCCC), which today publishes its results in the journals Nature and Nature Genetics, has given a major boost to the understanding of genetics of seven common diseases, including RA. As well as providing insights into what leads some people to develop the diseases and offering new avenues for treatments, the success of the approach heralds exciting advances in the study of the genetics of disease. It has identified a wealth of genes implicated in coronary heart disease, type 1 and type 2 diabetes, Crohn's disease, bipolar disorder and hypertension, as well as RA. Some of these genes are novel whilst others were known about and have been confirmed by the current study. Professor Worthington and her team have implicated several genes in the development of RA for the first time. Previously two genes were known to explain 50% of genetically determined susceptibility. Now the team have replicated their results for one of the new genes and are working to validate others. RA is a chronic inflammatory disease that can affect nearly all joints in the body, particularly the hands and feet. Complications such as lung disease can occur. In addition, patients with RA are more likely to die from cardiovascular disease and some cancers. Some people respond well to treatment, but most suffer a lifetime of disability. The team will now carry out further work to validate the findings and understand how the variation within key genes influences the development of RA, the course of the disease and the response to treatment. Dr Anne Barton, a clinician on the team, said: "These are exciting results as RA is a complex, heterogeneous disease with some people suffering inflammation of the hands and feet which comes and goes whilst others develop a progressive form which can quite rapidly result in marked disability. We believe the genes we have found may determine who develops RA or how the severe the disease becomes. "We also hope that this study may help us to discover why 40-50% of people do not respond to therapy. This therapy is expensive - 8,000 per patient per year for the newest biologic agents that block the inflammatory mediator TNF - and this work could show whether someone would respond well or not in advance, rather than by costly trial and error." Professor Worthington said: "The WTCCC has been a fantastic example of collaborative effort in the UK. It has taken us to the place we are now, more rapidly and efficiently than if we had tried to undertake this study on our own. "We had 2,000 DNA samples from patients with RA. By contacting other RA clinicians and researchers in the UK, we now have a further 5,000 samples to take this work forward. "We are also indebted to the arthritis research campaign (arc), which provided the funding to collect the samples used. This was a huge investment, collecting samples from RA patients over two decades, but it was the sample collection which made it a high quality study." Professor Peter Donnelly, Chair of the WTCCC, based at the University of Oxford, said: "Many of the most common diseases are very complex, involving both 'nature' and 'nurture', genes interacting with our environment and lifestyles. By identifying the genes underlying these conditions, our study should enable scientists to understand better how disease occurs, which people are most at risk and, in time, to produce more effective, more personalised treatments." The 9 million WTCCC has been one of the UK's largest and most successful academic collaborations to date, involving 50 leading research groups and over 200 scientists in the field of human genetics from dozens of institutions. For these papers, part of a number of studies due to be published over the next year, the researchers analysed 17,000 DNA samples taken from people in the UK - two thousand patients for each disease and three thousand control samples - to identify common genetic variations for seven major diseases. Although the human genome is made up of more than three billion sub-units of DNA, called nucleotides (or bases), most of these show little in the way of differences between individuals. The International HapMap Consortium and related efforts demonstrated that a substantial part of the variation in DNA sequence between individuals is due to single-nucleotide polymorphisms (differences), also known as SNPs. There are approximately 8 million common SNPs in European populations. Fortunately, because SNPs that lie close together on chromosomes often tell quite similar stories, researchers in the WTCCC were able to explore this variation through analysing a subset of these SNPs (in fact approximately 500,000). "Human genetics has a chequered history of irreproducible results, but this landmark collaboration of scientists in Britain has shown conclusively that the new approach of analysing a large subset of genetic variants in large samples of patients and healthy individuals works," says Professor Donnelly. "We are now able to effectively scan most of the common variation in the human genome to look for variants associated with diseases. This approach will undoubtedly herald major advances in how we understand and tackle disease in the future." The findings have been welcomed by Dr Mark Walport, Director of the Wellcome Trust, the UK's largest medical research charity. The Wellcome Trust not only funded the WTCCC, but also co-funded the Human Genome Project and HapMap. "Just a few years ago it would have been thought wildly optimistic that it would be possible in the near future to study a thousand genetic variants in each of a thousand people," says Dr Mark Walport, Director of the Wellcome Trust, the UK's largest medical research charity, which funded the study. "What has been achieved in this research is the analysis of half a million genetic variants in each of seventeen thousand individuals, with the discovery of more than ten genes that predispose to common diseases. "This research shows that it is possible to analyse human variation in health and disease on an enormous scale. It shows the importance of studies such as the UK Biobank, which is seeking half a million volunteers aged between 40 and 69, with the aim of understanding the links between health, the environment and genetic variation. New preventive strategies and new treatments depend on a detailed understanding of the genetic, behavioural and environmental factors that conspire to cause disease." For more information or to arrange an interview with Professor Jane Worthington or Dr Anne Barton contact University of Manchester Media Relations Officer Mikaela Sitford on 0161 275 2111. For information on The Wellcome Trust Case Control Consortium (WTCCC) contact WT Media Officer Craig Brierley on 0207 611 7329. For information on the paper in Nature contact Assistant Press Officer at Nature Helen Jamison on 0207 843 4658 or h.jamison@nature.com. Notes for editors 1. The Wellcome Trust is the largest charity in the UK. It funds innovative biomedical research, in the UK and internationally, spending around 500 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing. http://www.wellcome.ac.uk The Wellcome Trust Case Control Consortium was supported by: the Medical Research Council, British Heart Foundation, Juvenile Diabetes Research Foundation, Diabetes UK, the Arthritis Research Campaign, the National Association for Colitis & Crohn's Disease and MDF The Bipolar Organisation 2. The University of Manchester Arthritis Research Campaign (arc) Epidemiology Unit aims to advance understanding of the major rheumatic and musculoskeletal disorders. The unit celebrated its 50th anniversary in 2004, and is one of the world-leading research groups in this field. Around 100 individuals work on a wide variety of different programmes and projects, and the size and strength of the unit permits it to undertake the very large scale, long-term prospective studies which are necessary to truly identify the cause of disease. Recent advances in genetics, molecular biology, biostatistics and computing have had major implications for the types of questions that can be answered using epidemiological methods.