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A large-scale, consortium-based genomewide association study of asthma

Moffatt, M. F. and Gut, I. G. and Demenais, F. and Strachan, D. P. and Bouzigon, E. and Heath, S. and von Mutius, E. and Farrall, M. and Lathrop, M. and Cookson, W. O. and Imboden, M. and Liu, L. J. and Künzli, N. and Schindler, C. and Rochat, T. and Gerbase, M. and Curjuric, I. and Thun, G. A. and Probst-Hensch, N. and Braun-Fahrländer, C.. (2010) A large-scale, consortium-based genomewide association study of asthma. The New England journal of medicine, Vol. 363, H. 13. pp. 1211-1221.

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Official URL: http://edoc.unibas.ch/dok/A6002085

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Abstract

BACKGROUND: Susceptibility to asthma is influenced by genes and environment; implicated genes may indicate pathways for therapeutic intervention. Genetic risk factors may be useful in identifying subtypes of asthma and determining whether intermediate phenotypes, such as elevation of the total serum IgE level, are causally linked to disease. METHODS: We carried out a genomewide association study by genotyping 10,365 persons with physician-diagnosed asthma and 16,110 unaffected persons, all of whom were matched for ancestry. We used random-effects pooled analysis to test for association in the overall study population and in subgroups of subjects with childhood-onset asthma (defined as asthma developing before 16 years of age), later-onset asthma, severe asthma, and occupational asthma. RESULTS: We observed associations of genomewide significance between asthma and the following single-nucleotide polymorphisms: rs3771166 on chromosome 2, implicating IL1RL1/IL18R1 (P=3x10(-9)); rs9273349 on chromosome 6, implicating HLA-DQ (P=7x10(-14)); rs1342326 on chromosome 9, flanking IL33 (P=9x10(-10)); rs744910 on chromosome 15 in SMAD3 (P=4x10(-9)); and rs2284033 on chromosome 22 in IL2RB (P=1.1x10(-8)). Association with the ORMDL3/GSDMB locus on chromosome 17q21 was specific to childhood-onset disease (rs2305480, P=6x10(-23)). Only HLA-DR showed a significant genomewide association with the total serum IgE concentration, and loci strongly associated with IgE levels were not associated with asthma. CONCLUSIONS: Asthma is genetically heterogeneous. A few common alleles are associated with disease risk at all ages. Implicated genes suggest a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation. Variants at the ORMDL3/GSDMB locus are associated only with childhood-onset disease. Elevation of total serum IgE levels has a minor role in the development of asthma. (Funded by the European Commission and others.)
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Epidemiology and Public Health (EPH) > Biostatistics > Biostatistics Frequentist Modelling
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Former Units within Swiss TPH > Environmental Exposures (Liu)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Former Units within Swiss TPH > Microbial Exposure & Childhood Allergies (Braun-Fahrländer)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Epidemiology and Public Health (EPH) > Chronic Disease Epidemiology > Genetic Epidemiology of Non-Communicable Diseases (Probst-Hensch)
03 Faculty of Medicine > Departement Public Health > Sozial- und Präventivmedizin > Genetic Epidemiology of Non-Communicable Diseases (Probst-Hensch)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Epidemiology and Public Health (EPH) > Chronic Disease Epidemiology > Air Pollution and Health (Künzli)
03 Faculty of Medicine > Departement Public Health > Sozial- und Präventivmedizin > Air Pollution and Health (Künzli)
03 Faculty of Medicine > Departement Public Health > Sozial- und Präventivmedizin
UniBasel Contributors:Braun-Fahrländer, Charlotte and Curjuric, Ivan and Liu, Lee-Jane S. and Künzli, Nino and Probst Hensch, Nicole and Schindler, Christian
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Massachusetts Medical Society
ISSN:1533-4406
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:08 Nov 2012 16:08
Deposited On:11 Oct 2012 15:28

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