Identification of genetic variants predisposing to early-onset asthma and interacting with environmental exposure to tobacco-smoke in early life

October 16 2008

A research consortium of French scientists has identified the effect of genetic variants that confer increased risk of early-onset asthma. This risk is further enhanced by exposure to environmental tobacco smoke in early life.

These results were obtained as part of the French Epidemiological Study on the Genetics and Environment of Asthma (EGEA study)1 and are published online first at www.nejm.org on October 15, and will appear in the November 6 printed issue of the New England Journal of Medicine. The major interest of these findings is the identification of genes that play a role in the development of asthma at an early stage and interact with environmental factors. These findings provide a greater understanding of the functional role of the 17q21 genetic variants in the pathophysiology of asthma and can lead to the development of targeted therapy against asthma. It has also important implication for primary prevention of asthma. Altogether, the identification of interactions between genetic and environmental factors is one of the major challenges that genetic epidemiology is currently facing.

Asthma is a chronic inflammatory disease affecting the airways. It is characterized by recurrent attacks of breathlessness and wheezing, which vary in severity and frequency from person to person. Asthma is a complex and heterogeneous disease resulting from both genetic and environmental factors. More than 300 millions people suffer from asthma worldwide, among which 40% of children. In France, 3.5 millions people are affected with asthma and 2000 deaths are caused by asthma each year.

Following a genome-association study that identified genetic variants on chromosome 17q21 that are associated with the risk of asthma (Moffat et al, Nature, 2007,448:470-3), the goal of the present study published in the New England Journal of Medicine was to elucidate the relationship between this locus and asthma. The scientists tested 36 SNPs in the 17q21 region in 1511 subjects (691 asthmatics) from 372 EGEA families not only for an association with asthma but also for genetic heterogeneity according to age at the onset of asthma and exposure to environmental tobacco smoke in early life.

Based on state-of-the-art statistical methods, this study confirms that genetic variants covering a 113000 base-pair region on chromosome 17 are strongly associated with the risk of asthma. This study demonstrates that the increased risk of asthma conferred by these variants is restricted to early-onset asthma (onset at 4 years of age or younger) and that the risk is further increased by early-life exposure to environmental tobacco smoke. When smoking exposure is not taken into account, the overall risk of early-onset asthma is increased by a factor of 1.7 or more for subjects who are homozygotes for the asthma-associated alleles, as compared with those with other genotypes. This risk is higher (increased by a factor of 2.3 or more and even reaching 2.9) for homozygous subjects with early-life exposure to environmental tobacco smoke. The 17q21 genetic variants regulate the expression of at least two genes ORMDL3 and GSDML (also called GSDMB).

These findings provide a greater understanding of the functional role of the 17q21 variants in the pathophysiology of asthma and can lead to the development of targeted therapy against asthma. It has also important implication for primary prevention of asthma.

These results also illustrate the power of genomewide association studies that consist of genotyping hundreds of thousands of genetic markers in tens of thousands of subjects to identify genes underlying multifactorial diseases that raise major public health issues. Identification of genetic factors involved in asthma is being pursued within the Gabriel consortium that gathers large asthma studies at the European and international levels. The Fondation Jean Dausset-CEPH, the Centre National de Génotypage (CEA-CNG) and Inserm are part of this consortium.


(1) This consortium gathers research scientists and clinicians from Inserm, the Fondation Jean Dausset-Centre d’Etude du Polymorphisme Humain (CEPH) in Paris, the Centre National de Génotypage (CEA-CNG) in Evry, the Evry-Val-d’Essonne and Paris-Sud 11 Universities and French Clinical Centres from Paris (Necker, Trousseau, Cochin), Grenoble, Lyon, Marseille and Montpellier.


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References of the paper

“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.); Centre Hospitalier Universitaire de Grenoble, Grenoble (I.P.)

The research unit UMR-794 Inserm-Université d’Evry, entitled “Statistical methodology and genetic epidemiology of multifactorial diseases”, and located within the Fondation Jean Dausset-CEPH, is conducting a research programme to identify genes and gene-environment interactions in human diseases. 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 studies to better understand the origin and dissemination of genetic alterations across human populations. This research unit is involved in many consortiums at the national, European and international levels in which the UMR-794 scientists play a leading role at the statistical genetics, genetic epidemiology and population genetics levels.

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 at the international level by showing the feasibility of the Human Genome Project. In 2005, the CEPH activities focused on the preparation and distribution of biological specimen with the development of a high-throughput Biological Resource Center and on data distribution and analyses with the development of a bioinformatics and statistical analysis platform. The Fondation Jean-Dausset – CEPH is a partner of the French Cancer Genomics Programme launched by the Institut National du Cancer (INCa) and of several European programmes including one on asthma.

The Centre National de Génotypage (CNG), was created in 1997 as a GIP (Public Interest Group) gathering CEA, CNRS, INRA and Inserm and was integrated within the CEA in 2007 through the creation of the Institut de Génomique (Genomics Institute). It plays a leading role in France and at the international level in genetic research. The CNG is one of the biggest genotyping centre in Europe. The genetic studies conducted at CNG have led to the identification of molecular mechanisms that are involved in the pathophysiology of multifactorial diseases including asthma, Crohn’s disease, cardiovascular and infectious diseases. These studies open new routes for the development of new diagnostic tools and new therapies. Work carried out at CNG has led to identification of new genes that influence severity of diseases, notably in lung cancer as part of the INCa Cancer Genomics Programme.

The Epidemiological study on the Genetics and Environment of Asthma (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), has led to the collection of numerous clinical biological and environmental data (exposure to tobacco smoke, allergens, nutritional factors, job exposure, lifestyle factors…) in 372 families (including 1511 subjects of which 651 are affected with adult and childhood asthma). This study gathers research teams in epidemiology and genetics from Inserm, Evry and Paris-Sud 11 Universities, Fondation Jean Dausset-CEPH and CEA/CNG as well as clinicians from seven French clinical centres. The EGEA study has led to 44 publications and to more than 100 presentations at international meetings. This study is part of European consortiums (the GABRIEL Integrated Project and the GA2LEN Network of Excellence).


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Florence Demenais
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E-mail: florence.demenais@inserm.fr

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