Thursday October 16 2008
Identification of markers of genetic susceptibility to asthma
A consortium of French research teams has just identified genetic markers highlighting an increased risk of developing asthma during early childhood that is further heightened by early exposure to tobacco smoke. These results were obtained through the EGEA Study (Epidemiological study on the Genetics and Environment of Asthma) and have been published in the 15 October 2008 online issue of the New England Journal of Medicine, together with editorial commentary. The major breakthrough in this research is the identification of interactions between genetic and environmental factors occurring at a very early stage of asthma development. These findings represent breakthrough insight into the pathophysiological mechanisms underpinning early-onset asthma, paving the way to targeted prevention strategies and new therapeutic treatments. The identification of gene-environment interactions is one of the major challenges in contemporary genetics research.
Asthma is an inflammatory respiratory system condition triggered by a number of complex events. The risk of developing asthma is compounded when associated with genetic susceptibility and exposure to environment and lifestyle-related factors. There are over 300 million asthma sufferers worldwide, 40% of whom are children. Asthma affects around 3.5 million people in France, causing around 2000 deaths every year.
The study that has just been published focused on a population of 372 French families including 1511 subjects, 651 of whom were asthma sufferers[2]. The researchers ran detailed, in-depth analyses on 36 gene variants (polymorphisms) located in a region of chromosome 17, called 17q21, in order to elucidate the functional role played by these variants in asthma onset and their relationship with exposure to environmental tobacco smoke.
The research teams drew on state-of-the-art statistical procedures to confirm the association between 17q21 polymorphisms and asthma. This association was demonstrated to be specific to the onset of asthma in infants aged 4 years old or earlier. The teams also pinpointed an interaction between these genetic polymorphisms and early-age exposure to tobacco smoke. Subjects homozygous for one of the genetic polymorphism variants (alleles) of the 17q21 region present a 1.7-fold higher risk of developing early-onset asthma compared to subjects presenting the other form of these polymorphisms. The risk is even higher – increasing at least 2.3-fold, and potentially 2.9-fold – with early-childhood exposure to environmental tobacco smoke.
These findings provide a greater understanding of the functional role of the 17q21 variants in the onset of asthma, and can help shape targeted prevention strategies and drive the development of novel therapeutic treatments.
These studies also illustrate the power of high-throughput genomewide association studies, which are capable of genotyping hundreds of thousands of genetic markers in tens of thousands of subjects in order to identify genes underlying predisposition to diseases catalogued as major public health issues. Research to characterize the factors driving genetic susceptibility is currently being pursued on an even wider scale, drawing in data from studies conducted worldwide. The Fondation Jean Dausset, the CEA's National Genotyping Centre, and the INSERM are all partners on this worldwide-scale project.
[1] A research consortium syndicating the INSERM; Fondation Jean Dausset-Human Polymorphism Research Centre, Paris; the French National Genotyping Centre(CEA-CNG), Evry; Evry-Val-d’Essonne University and Paris-Sud 11 University; and the University Teaching Hospitals at Paris (Necker, Trousseau, Cochin), Grenoble, Lyon, Marseille and Montpellier - all in France
[2] One of the strengths of this multicenter study, which was conducted through hospitals in five French cities (Grenoble, Lyon, Marseille, Montpellier, Paris), is that it included cases of asthma onset in childhood as well as in adults who were screened for a comprehensive range of clinical data, including exposure to environmental factors
Article reference :
“Effect of 17q21 Variants and Smoking Exposure in Early-Onset Asthma”
Emmanuelle Bouzigon, M.D., Ph.D, Eve Corda, M.S., Hugues Aschard, M.S., Marie-Hélène Dizier, Ph.D., Anne Boland, Ph.D., Jean Bousquet, M.D., Ph.D., Nicolas Chateigner, M.S., Frédéric Gormand, M.D., Jocelyne Just, M.D., Ph.D, Nicole Le Moual, Ph.D., Pierre Scheinmann, M.D., Valérie Siroux, Ph.D., Daniel Vervloet, M.D., Diana Zelenika, Ph.D., Isabelle Pin, M.D., Francine Kauffmann, M.D., Mark Lathrop, Ph.D, and Florence Demenais, M.D.
Inserm, Unité 794, Paris (E.B., E.C., H.A., N.C., F.D.); Fondation Jean Dausset-Centre d'Etude du Polymorphisme Humain (CEPH), Paris (E.B., E.C., H.A., N.C., M.L., F.D.); Université d’Evry, Evry (E.B., H.A., N.C., F.D.); Inserm, Unité 535, Villejuif (M.-H.D.); Université Paris–Sud 11, Villejuif (M.-H.D., N.L.M., F.K.); Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry (A.B., D.Z., M.L.); Hôpital Arnaud de Villeneuve, Montpellier (J.B.); Centre Hospitalier Lyon-Sud, Pierre Bénite (F.G.); Hôpital d’Enfants Armand Trousseau, Paris (J.J.); Inserm, Unité 780, Villejuif (N.L.M., F.K.); Hôpital Necker, Paris (P.S.); Inserm Unité 823, Grenoble (V.S., I.P.);Hôpital Sainte-Marguerite, Marseille (D.V.); and Centre Hospitalier Universitaire de Grenoble, Grenoble (I.P.)
The research unit UMR-794 Inserm-Evry University, entitled “Statistical methodology and epidemiology of multifactorial diseases” and based at the Fondation Jean Dausset-CEPH, is conducting a research programme to identify the genes and gene-environment interactions underlying human disease. This programme combines genetic epidemiology studies of common diseases (asthma, cancers, neuro-psychiatric diseases), development of statistical methodologies to detect genes, model their effects and their interactions with environmental factors, and population genetics research to better understand the origin and dissemination of genetic alterations across human populations. This research unit is involved in many national, European and international consortiums, in which the UMR-794 teams provide key leadership input on statistical genetics, genetic epidemiology and population genetics.
The Centre d’Etude du Polymorphisme Humain (CEPH) was created in 1984 and became Fondation Jean Dausset - CEPH in 1993. It played a major historical role by demonstrating the feasibility of the international Human Genome Project. In 2005, the CEPH refocused its activities on preparing and distributing biological specimens with the development of a high-throughput biological resources centre, and on data distribution and analyses with the development of a bioinformatics and statistical analysis platform. The Fondation Jean Dausset-CEPH is a partner on the French Cancer Genomics Programme launched by the National Cancer Institute (INCa) as well as on several other European-scale programmes, including one on asthma.
The National Genotyping Centre (CNG) was created in 1997 as a Public Interest Group syndicating the CEA, the CNRS, the INRA and the INSERM, and was integrated into the CEA in 2007 through the creation of the Institut de Génomique (Genomics Institute). It plays a leading genetic research role in France and the international arena. The CNG is Europe’s biggest genotyping centre. These CNG-based genetic studies have led to the identification of the molecular mechanisms underpinning the pathophysiology of diseases like asthma, Crohn's disease (a chronic inflammatory intestinal disease), and cardiovascular and infectious diseases. These studies open new routes for the development of new diagnostic tools and novel therapeutic strategies. This research has led to the identification of genes that influence disease severity, especially in lung cancer, under the INCa Cancer Genomics Programme.
The Epidemiological study on the Genetics and Environment of Asthma (the EGEA study) aims at identifying genetic and environmental factors involved in asthma and asthma-related phenotypes. This study, conducted in clinical centres of five French cities (Grenoble, Lyon, Marseille, Montpellier, Paris), was able to collect a vast array of clinical and biological data and environmental factors (exposure to tobacco smoke, allergens, nutritional factors, work-related factors, lifestyle factors, and more) in a study population of 372 families (totalling 1511 children and adults, 651 of which are asthma sufferers). The study has syndicated genetics and epidemiology research teams from the INSERM and affiliated Universities (Evry, Paris-Sud 11), plus the Fondation Jean Dausset-CEPH and the CEA/CNG as well as clinicians from seven French clinical centres. The EGEA study has already spawned 44 publications and over 100 presentations at international congresses. The EGEA is an integral part of European consortiums and excellence clusters (the GABRIEL integrated project, GA2LEN excellence cluster).