Gene-environment interaction for childhood asthma and exposure to farming in Central Europe - 10/08/11

Doi : 10.1016/j.jaci.2010.09.041

Markus J. Ege, MD ^a,^⁎ , David P. Strachan, MD ^b, William O.C.M. Cookson, MD, DPhil ^c, Miriam F. Moffatt, MD, DPhil ^c, Ivo Gut, PhD ^d, Mark Lathrop, PhD ^d,^e, Michael Kabesch, MD ^f, Jon Genuneit, MD ^g, Gisela Büchele, PhD ^g, Barbara Sozanska, MD ^h, Andrzej Boznanski, MD, PhD ^h, Paul Cullinan, MD ^c, Elisabeth Horak, MD ⁱ, Christian Bieli, MD ^j,^k, Charlotte Braun-Fahrländer, MD ^j,^k, Dick Heederik, PhD ^l, Erika von Mutius, MD ^a
GABRIELA Study Group
The members of the GABRIELA Study group are (listed in alphabetical order): Silvia Apprich, PhD,^s Andrzej Boznanski, MD, PhD,^v Charlotte Braun-Fahrländer, MD,^p,q Gisela Büchele, MPH,^o William Cookson, MD, DPhil,^m Paul Cullinan, MD,^m Hanna Danielewicz, MD,^v Anna Dębińska,^v Martin Depner, PhD,ⁿ Markus J. Ege, MD,ⁿ Urs Frey, MD, PhD,^w Oliver Fuchs, MD,^w Jon Genuneit,^o Dick Heederik, PhD,^r Elisabeth Horak, MD,^x Anne Hyvärinen, PhD,^t Sabina Illi, PhD,ⁿ Michael Kabesch, MD,^y Katalin Kovacs,^x Aleksandra Kosmęda, PhD,^v Wolfgang Kneifel, PhD,^s Philipp Latzin, MD, PhD,^w Roger Lauener, MD,^aa Georg Loss,^p,q Stephanie MacNeill, MSc,^m Bernhard Morass, MD,^x Anne-Cécile Normand,^u Ilka Noss, PhD,^r Renaud Piarroux, MD, PhD,^u Helena Rintala, PhD,^t Mascha K. Rochat, MD,^bb Nikolaos Sitaridis,^o Barbara Sozanska, MD,^v David Strachan, MD,^z Christine Strunz-Lehner, MPH,ⁿ Bertrand Sudre, MD, PhD,^u Erika von Mutius, MD, MSc,ⁿ Marco Waser, PhD,^p,q Juliane Weber, MD,ⁿ and Inge Wouters, PhD.^rFrom ^mthe National Heart and Lung Institute, South Kensington Campus, Imperial College London; ⁿthe University Children’s Hospital, LMU Munich; ^othe Institute of Epidemiology, Ulm University; ^pthe Swiss Tropical and Public Health Institute; ^qthe Institute of Social and Preventive Medicine, University of Basel; ^rthe Institute for Risk Assessment Sciences, Division of Environmental Epidemiology, Utrecht University; ^sthe Department of Food Science and Technology, University of Natural Resources and Applied Life Sciences, BOKU Vienna; ^tthe National Institute for Health and Welfare, THL Kuopio; ^uUMR 6249 Chrono-Environnement, Département de Parasitologie/Mycologie, Université de Franche-Comté, Besançon; ^vthe First Department of Pediatrics, Allergology and Cardiology, Wroclaw Medical University; ^wthe Division of Pulmonology, Department of Pediatrics, Bern University Hospital; ^xthe Department of Pediatrics and Adolescents, Division of Cardiology and Pulmonology, Innsbruck Medical University; ^ythe Clinic for Pediatric Pneumology and Neonatology, Hannover Medical School; ^zSt George’s, University of London; ^aathe High Mountain Hospital Davos, Davos-Wolfgang; and ^bbDépartement médico-chirurgical de pédiatrie, CHUV, Lausanne.London, United Kingdom, Munich, Ulm, and Hannover, Germany, Basel, Bern, Davos-Wolfgang, and Lausanne, Switzerland, Utrecht, The Netherlands, Vienna and Innsbruck, Austria, Kuopio, Finland, Besançon, France, and Wroclaw, Poland
^a University Children’s Hospital Munich, Munich, Germany
^b Division of Community Health Sciences, St George’s, University of London, London, United Kingdom
^c National Heart and Lung Institute, South Kensington Campus, Imperial College London, London, United Kingdom
^d Commissariat à L’Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France
^e Fondation Jean Dausset-CEPH, Paris, France
^f Clinic for Pediatric Pneumology and Neonatology, Hannover Medical School, Hannover, Germany
^g Institute of Epidemiology, Ulm University, Ulm, Germany
^h First Department of Paediatrics, Allergology and Cardiology Wroclaw Medical University, Wroclaw, Poland
ⁱ Department of Pediatrics and Adolescents, Division of Cardiology and Pulmonology, Innsbruck Medical University, Innsbruck, Austria
^j Swiss Tropical and Public Health Institute, Basel, Switzerland
^k University of Basel, Basel, Switzerland
^l Institute for Risk Assessment Sciences, Division of Environmental Epidemiology Utrecht University, Utrecht, The Netherlands

Reprint requests: Markus J. Ege, MD, Dr von Haunersche Kinderklinik, Lindwurmstrasse 4, 80337 Munich, Germany.

Abstract

Background

Asthma is a disease in which both genetic and environmental factors play important roles. The farming environment has consistently been associated with protection from childhood asthma and atopy, and interactions have been reported with polymorphisms in innate immunity genes.

Objective

To detect gene-environment interactions for asthma and atopy in the farming environment.

Methods

We performed a genome-wide interaction analysis for asthma and atopy by using 500,000 genotyped single nucleotide polymorphisms (SNPs) and farm-related exposures in 1708 children from 4 rural regions of Central Europe. We also tested selectively for interactions between farm exposures and 7 SNPs that emerged as genome-wide significant in a large meta-analysis of childhood asthma and 5 SNPs that had been reported previously as interacting with farm exposures for asthma or atopy.

Results

Neither the asthma-associated SNPs nor the SNPs previously published for interactions with asthma showed significant interactions. The genome-wide interaction study did not reveal any significant interactions with SNPs within genes in the range of interacting allele frequencies from 30% to 70%, for which our study was well powered. Among rarer SNPs, we identified 15 genes with strong interactions for asthma or atopy in relation to farming, contact with cows and straw, or consumption of raw farm milk.

Conclusion

Common genetic polymorphisms are unlikely to moderate the protective influence of the farming environment on childhood asthma and atopy, but rarer variants, particularly of the glutamate receptor, metabotropic 1 gene, may do so. Given the limited statistical power of our study, these findings should be interpreted with caution before being replicated in independent farm populations.

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Key words : Childhood asthma, atopy, GWAS, gene-by-environment interaction, candidate genes

Abbreviations used : aOR, GAS7, GE, GRM1, GWAS, IOR, logOR, OR, SNP, TLR

Plan

Methods

Population

Questionnaires and IgE measurements

Environmental exposures

Interactions with asthma-associated SNPs

Interactions with previously reported SNPs

Genome-wide interaction analysis

Supported by the European Commission as part of GABRIEL (a multidisciplinary study to identify the genetic and environmental causes of asthma in the European Community) contract number 018996 under the Integrated Program LSH-2004-1.2.5-1. M.J.E received the Stephan-Weiland Fellowship of the GABRIEL consortium.

Disclosure of potential conflict of interest: M. J. Ege has received research support from the European Union, the German Research Foundation (DFG), and the Behring-Röntgen Foundation. I. Gut has received research support from the European Commission (through Project GABRIEL) and the Wellcome Trust. M. Kabesch has received remuneration in the form of grants, honoraria, or consulting fees from Roxall, Glaxo Wellcome, Novartis, Sanofi-Aventis, MSD, and Allergopharma and has received research support from the DFG, Bundesministerium für Bildung und Forschung, and the European Union. D. Heederik has received research support from the European Union. E. von Mutius has consulted for Novartis, GlaxoSmithKline, Protectimmun, and UCB and has received research support from Airsonett AB. M. Depner has received research support from the European Commission. R. Lauener has received research support from the European Union and the Kühne Foundation. J. Weber has received research support from the European Commission. The rest of the authors have declared that they have no conflict of interest.

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Vol 127 - N° 1

P. 138 - janvier 2011 Retour au numéro

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Gene-environment interaction for childhood asthma and exposure to farming in Central Europe - 10/08/11

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