title: Genome-Wide Interaction Analysis of Air Pollution Exposure and Childhood Asthma with Functional Follow-up.
abstract: The evidence supporting an association between traffic-related air pollution exposure and incident childhood asthma is inconsistent and may depend on genetic factors.
  
  
  
  To identify gene-environment interaction effects on childhood asthma using genome-wide single-nucleotide polymorphism (SNP) data and air pollution exposure. Identified loci were further analyzed at epigenetic and transcriptomic levels.
  
  
  
  We used land use regression models to estimate individual air pollution exposure (represented by outdoor NO2levels) at the birth address and performed a genome-wide interaction study for doctors' diagnoses of asthma up to 8 years in three European birth cohorts (n = 1,534) with look-up for interaction in two separate North American cohorts, CHS (Children's Health Study) and CAPPS/SAGE (Canadian Asthma Primary Prevention Study/Study of Asthma, Genetics and Environment) (n = 1,602 and 186 subjects, respectively). We assessed expression quantitative trait locus effects in human lung specimens and blood, as well as associations among air pollution exposure, methylation, and transcriptomic patterns.
  
  
  
  In the European cohorts, 186 SNPs had an interaction P < 1 × 10-4and a look-up evaluation of these disclosed 8 SNPs in 4 loci, with an interaction P < 0.05 in the large CHS study, but not in CAPPS/SAGE. Three SNPs within adenylate cyclase 2 (ADCY2) showed the same direction of the interaction effect and were found to influence ADCY2 gene expression in peripheral blood (P = 4.50 × 10-4). One other SNP with P < 0.05 for interaction in CHS, rs686237, strongly influenced UDP-Gal:betaGlcNAc β-1,4-galactosyltransferase, polypeptide 5 (B4GALT5) expression in lung tissue (P = 1.18 × 10-17). Air pollution exposure was associated with differential discs, large homolog 2 (DLG2) methylation and expression.
  
  
  
  Our results indicated that gene-environment interactions are important for asthma development and provided supportive evidence for interaction with air pollution for ADCY2, B4GALT5, and DLG2.
authors.affiliation: 1 Institute of Environmental Medicine.
authors.forename: Anna
authors.initials: A
authors.lastname: Gref
authors.affiliation: 1 Institute of Environmental Medicine.
authors.forename: Simon K
authors.initials: SK
authors.lastname: Merid
authors.affiliation: 1 Institute of Environmental Medicine.
authors.forename: Olena
authors.initials: O
authors.lastname: Gruzieva
authors.affiliation: 2 European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, Université de Lyon, Lyon, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Ballereau
authors.affiliation: 3 Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Allan
authors.initials: A
authors.lastname: Becker
authors.affiliation: 1 Institute of Environmental Medicine.|4 Centre for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden.
authors.forename: Tom
authors.initials: T
authors.lastname: Bellander
authors.affiliation: 1 Institute of Environmental Medicine.|4 Centre for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Bergström
authors.affiliation: 5 Quebec Heart and Lung Institute and.|6 Department of Molecular Medicine, Laval University, Quebec City, Quebec, Canada.
authors.forename: Yohan
authors.identifier: 0000-0002-3067-3711
authors.initials: Y
authors.lastname: Bossé
authors.affiliation: 1 Institute of Environmental Medicine.
authors.forename: Matteo
authors.initials: M
authors.lastname: Bottai
authors.affiliation: 7 Department of Medicine.
authors.forename: Moira
authors.initials: M
authors.lastname: Chan-Yeung
authors.affiliation: 9 School of Population and Public Health.|8 Institute of Epidemiology I, Helmholtz Zentrum München - German Research Centre for Environmental Health, Neuherberg, Germany.
authors.forename: Elaine
authors.initials: E
authors.lastname: Fuertes
authors.affiliation: 10 Section of Paediatrics, Department of Medicine, Imperial College London, London, United Kingdom.|11 Department of Epidemiology.
authors.forename: Despo
authors.initials: D
authors.lastname: Ierodiakonou
authors.affiliation: 12 Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, and.
authors.forename: Ruiwei
authors.initials: R
authors.lastname: Jiang
authors.affiliation: 2 European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, Université de Lyon, Lyon, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Joly
authors.affiliation: 12 Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, and.
authors.forename: Meaghan
authors.initials: M
authors.lastname: Jones
authors.affiliation: 12 Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, and.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kobor
authors.affiliation: 1 Institute of Environmental Medicine.
authors.forename: Michal
authors.initials: M
authors.lastname: Korek
authors.affiliation: 13 Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Anita L
authors.initials: AL
authors.lastname: Kozyrskyj
authors.affiliation: 1 Institute of Environmental Medicine.|14 Department of Public Health Epidemiology, Unit of Chronic Disease Epidemiology, Swiss Tropical and Public Health Institute, University of Basel, Switzerland.
authors.forename: Ashish
authors.initials: A
authors.lastname: Kumar
authors.affiliation: 2 European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, Université de Lyon, Lyon, France.
authors.forename: Nathanaël
authors.initials: N
authors.lastname: Lemonnier
authors.affiliation: 9 School of Population and Public Health.|8 Institute of Epidemiology I, Helmholtz Zentrum München - German Research Centre for Environmental Health, Neuherberg, Germany.|15 Environmental and Occupational Health, Public Health Ontario, Toronto, Ontario, Canada.
authors.forename: Elaina
authors.initials: E
authors.lastname: MacIntyre
authors.affiliation: 2 European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, Université de Lyon, Lyon, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Ménard
authors.affiliation: 16 Merck & Co Inc, Rahway, New Jersey.
authors.forename: David
authors.initials: D
authors.lastname: Nickle
authors.affiliation: 17 Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Ma'en
authors.initials: M
authors.lastname: Obeidat
authors.affiliation: 2 European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, Université de Lyon, Lyon, France.
authors.forename: Johann
authors.initials: J
authors.lastname: Pellet
authors.affiliation: 8 Institute of Epidemiology I, Helmholtz Zentrum München - German Research Centre for Environmental Health, Neuherberg, Germany.
authors.forename: Marie
authors.initials: M
authors.lastname: Standl
authors.affiliation: 1 Institute of Environmental Medicine.
authors.forename: Annika
authors.initials: A
authors.lastname: Sääf
authors.affiliation: 18 Department of Biosciences and Nutrition.|19 Center for Innovative Medicine, and.|20 Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Cilla
authors.initials: C
authors.lastname: Söderhäll
authors.affiliation: 7 Department of Medicine.|21 Division of Metabolic Diseases and Nutritional Medicine, Ludwig-Maximilians-University of Munich, Dr. von Hauner Children's Hospital, Munich, Germany.
authors.forename: Carla M T
authors.initials: CMT
authors.lastname: Tiesler
authors.affiliation: 22 Department of Pulmonology.|23 Groningen Research Institute for Asthma and COPD.
authors.forename: Maarten
authors.initials: M
authors.lastname: van den Berge
authors.affiliation: 11 Department of Epidemiology.|23 Groningen Research Institute for Asthma and COPD.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Vonk
authors.affiliation: 24 Preventive Medicine, University of Southern California, Los Angeles, California.
authors.forename: Hita
authors.initials: H
authors.lastname: Vora
authors.affiliation: 22 Department of Pulmonology.|23 Groningen Research Institute for Asthma and COPD.|25 Department of Genetics.
authors.forename: Cheng-Jian
authors.initials: CJ
authors.lastname: Xu
authors.affiliation: 26 Centre for Research in Environmental Epidemiology, Barcelona, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Antó
authors.affiliation: 2 European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, Université de Lyon, Lyon, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Auffray
authors.affiliation: 9 School of Population and Public Health.
authors.forename: Michael
authors.initials: M
authors.lastname: Brauer
authors.affiliation: 27 CHU Montpellier, University of Montpellier, Montpellier, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Bousquet
authors.affiliation: 28 Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands; and.
authors.forename: Bert
authors.initials: B
authors.lastname: Brunekreef
authors.affiliation: 24 Preventive Medicine, University of Southern California, Los Angeles, California.
authors.forename: W James
authors.initials: WJ
authors.lastname: Gauderman
authors.affiliation: 8 Institute of Epidemiology I, Helmholtz Zentrum München - German Research Centre for Environmental Health, Neuherberg, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Heinrich
authors.affiliation: 18 Department of Biosciences and Nutrition.|19 Center for Innovative Medicine, and.
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.affiliation: 23 Groningen Research Institute for Asthma and COPD.|29 Pediatric Pulmonology and Pediatric Allerogology, Beatrix Children's Hospital, GRIAC Research Institute, and.
authors.forename: Gerard H
authors.initials: GH
authors.lastname: Koppelman
authors.affiliation: 22 Department of Pulmonology.|30 Department of Pulmonary Medicine and Tuberculosis, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Dirkje
authors.initials: D
authors.lastname: Postma
authors.affiliation: 7 Department of Medicine.
authors.forename: Christopher
authors.initials: C
authors.lastname: Carlsten
authors.affiliation: 1 Institute of Environmental Medicine.|4 Centre for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Pershagen
authors.affiliation: 1 Institute of Environmental Medicine.|4 Centre for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden.|31 Sachs Children's Hospital, Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Melén
mesh_terms: D000397:Air Pollution / Q000706:statistics & numerical data*; D001249:Asthma / Q000453:epidemiology* / Q000235:genetics; D002648:Child; D005060:Europe / Q000453:epidemiology; D005260:Female; D005500:Follow-Up Studies; D059647:Gene-Environment Interaction; D006801:Humans; D008297:Male; D009656:North America / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide; D001335:Vehicle Emissions
chemical_list: D001335:Vehicle Emissions
keywords: children; expression quantitative trait locus; gene expression; genome-wide interaction study; methylation