In the most comprehensive genetic study of asthma yet several new genes that predispose to asthma have been discovered. Some of these genes are in pathways that tell the immune system when the lining of the airways, the mucosa, has been damaged. Other genes may control the rate of healing of the airways after they have been damaged. The study was performed by the European based GABRIEL consortium, a collaboration of 164 scientists from 19 different countries. In essence, the GABRIEL genome-wide association study highlights mucosal targets for effective asthma therapies. Professor Erika von Mutius at Ludwig-Maximilians-Universität (LMU) Munich and co-coordinator of GABRIEL said “The puzzle now is to work out what is causing the damage to the airway lining in asthma.” The GABRIEL team also looked at the genes which control levels of allergy causing antibodies known as Immunoglobulin E or IgE. Surprisingly, these genes did not have much effect on the presence of asthma, and the asthma genes had little effects on the levels of Immunoglobulin E. This means that the allergies which accompany many cases of asthma are likely to be a consequence of the asthma rather than its cause. (New England Journal of Medicine online, 23 September 2010)
The GABRIEL consortium studied over 10,000 asthmatics and 16,000 normal subjects matched for each country of origin. In total the consortium carried out over 15 billion individual genetic tests that covered all genes in the human genome. They discovered several new genes that predispose to asthma. The GABRIEL team also looked at the genes which control levels of antibodies that cause allergies (known as Immunoglobulin E or IgE). Surprisingly, these genes did not have much effect on the presence of asthma, and the asthma genes had little effects on the levels of Immunoglobulin E. This means that the allergies which accompany many cases of asthma are likely to be a consequence of the asthma rather than its cause.
The study showed that genetic effects are weaker in adults, and that the most important gene in children (known as ORMDL3/GSDMB) does not seem to have effects on patients who developed asthma after they had grown up. The GABRIEL scientists found that the new genes affected more than a third of children with asthma in their study, and that the genes had strong effects on cases of severe asthma. They suggested that concentrating on these genes would lead (eventually) to better therapies for the illness. The scientists found that genetic testing would be of no value in predicting early in life which children might eventually develop the disease.
This indicates that environmental factors are also very important in causing asthma to develop. The GABRIEL consortium are still working together to identify environmental exposures that could protect against the illness. Professor Miriam Moffatt, Professor of Human Genetics at Imperial College London and one of the leaders of the study said, “It has been enormously gratifying to work with such a group of dedicated scientists from so many countries. This genetic study has taken five years from planning until completion, but it builds on many earlier years of work in which all the 26,000 volunteers were recruited and studied in great detail. The study would therefore not have been possible without the contribution of all of the GABRIEL members.”
Although large multi-national collaborations are becoming the norm with the study of many complex genetic diseases, the GABRIEL study is uniquely in that nearly all of the 15 billion genetic tests were performed in a single institution, the Centre National de Genotypage near Paris. Professor Mark Lathrop, the Director of the CEA-CNG and the Scientific Director of the Fondation Jean Dausset–Centre d’Etude du Polymorphisme Humain (CEPH) , pointed out the crucial role of an integrated large-scale infrastructure like CEA-CNG which has the capacity to perform all the steps from receiving the biological samples, to high throughput genotyping, quality control and data analysis. The Fondation Jean Dausset – CEPH was also a major player in this study.
Professor Ivo Gut, former Deputy Director of the CEA-CNG and now Director of the Centro Nacional de Análisis Genómico in Barcelona said “These results constitute a huge leap forward in the understanding of asthma that will lead to major advances in the treatment and quality of life of people suffering from the disease. It has been an immense effort to get this far but is well worth it. The generous support from the funding agencies, the kind donation of DNA by the research subjects and the huge personal dedication of the collaborators of the Gabriel consortium, have made this study possible.”
Professor Florence Demenais, Director of the Genetic Variation and Human Diseases laboratory in Paris (UMR-946 Inserm-Université Paris Diderot, Fondation Jean Dausset), who led the statistical analysis that combined all of the data said, ” Large scale genetic studies, such as this one, provide a powerful tool to decipher the genetic mechanisms underlying asthma and to unravel different types of disease that make up the asthma syndrome”.
Professor David Strachan, Professor of Epidemiology at St Georges Hospital in London said “Asthma has often been considered a single disease, but our genetic findings suggest that childhood-onset asthma may differ biologically from asthma that is acquired in adult life. The GABRIEL consortium is now investigating whether the causes of asthma differ between people with and without these newly discovered genetic variants.”
Professor Moffatt said “As a result of genetic studies we now know that allergies may be secondary to defects of the lining of the airways in asthma, and indeed to the barrier of the skin in children with eczema. This does not mean that allergies are not important, but it does mean that concentrating therapies only on allergy will not effectively treat the whole disease”.
Professor William Cookson, Director of Respiratory Sciences at Imperial College London and one of the co-ordinators of the GABRIEL project said “One of the problems with asthma research has been choosing where to intervene in the networks of complex immune pathways that are activated in the disease. The GABRIEL genome-wide association study now highlights targets for effective asthma therapies, and suggests that therapies against these targets will be of use to large numbers of asthmatics in the population”.
Professor Erika von Mutius at LMU Munich and co-coordinator of GABRIEL said “The puzzle now is to work out what is causing the damage to the airway lining in asthma. The GABRIEL study has also been busy looking for clues as to the environmental causes of asthma, particularly by dissecting the strong protective effects of living on a farm. In the next year we will be combining the results from the genetic and environmental wings of the GABRIEL study, and we are greatly looking forward to what we may find”. (GABRIEL/suwe)
The study was primarily funded by the European Community, The French Ministry for Higher Education and Research, Asthma UK and the Wellcome Trust. The contributing authors and centres are listed on the GABRIEL website at www.cng.fr/gabriel).
“A GABRIEL consortium Large-Scale Genome-Wide Association Study of Asthma”
Miriam F. Moffatt et.al
New England Journal of Medicine online, 23 September 2010
Professor Dr med. Erika von Mutius
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