title: The Early Development of Wheeze. Environmental Determinants and Genetic Susceptibility at 17q21.
abstract: BACKGROUND
  Growing up on a farm protects from childhood asthma and early wheeze. Virus-triggered wheeze in infancy predicts asthma in individuals with a genetic asthma risk associated with chromosome 17q21.
  
  
  OBJECTIVE
  To test environmental determinants of infections and wheeze in the first year of life, potential modifications of these associations by 17q21, and the implications for different trajectories of wheeze.
  
  
  METHODS
  We followed 983 children in rural areas of Europe from birth until age 6 years. Symptoms of wheeze, rhinitis, fever, and environmental exposures were documented with weekly diaries during year 1. Asthma at age 6 was defined as ever having a reported doctor's diagnosis. Single-nucleotide polymorphisms related to ORMDL3 (rs8076131) and GSDMB (rs7216389, rs2290400) at 17q21 were genotyped.
  
  
  RESULTS
  Early wheeze was positively associated with presence of older siblings among carriers of known asthma risk alleles at 17q21 (e.g., rs8076131) (adjusted odds ratio [aOR], 1.53; 95% confidence interval [CI], 1.16-2.01). Exposure to farm animal sheds was inversely related to wheeze (aOR, 0.44; 95% CI, 0.33-0.60). Both effects were similarly observed in children with transient wheeze up to age 3 years without subsequent development of asthma (aOR, 1.71 [95% CI, 1.09-2.67]; and aOR, 0.48 [95% CI, 0.30-0.76], respectively).
  
  
  CONCLUSIONS
  These findings suggest that the chromosome 17q21 locus relates to episodes of acute airway obstruction common to both transient wheeze and asthma. The previously identified asthma risk alleles are the ones susceptible to environmental influences. Thus, this gene-environment interaction reveals two faces of 17q21: The same genotype constitutes genetic risk and allows for environmental protection, thereby providing options for prospective prevention strategies.
authors.affiliation: 1 Dr. von Hauner Children's Hospital, Ludwig Maximilians University Munich, Munich, Germany.|2 Department of Pediatrics, University of California, San Diego, La Jolla, California.
authors.forename: Georg J
authors.initials: GJ
authors.lastname: Loss
authors.affiliation: 1 Dr. von Hauner Children's Hospital, Ludwig Maximilians University Munich, Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Depner
authors.affiliation: 1 Dr. von Hauner Children's Hospital, Ludwig Maximilians University Munich, Munich, Germany.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Hose
authors.affiliation: 3 Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany.
authors.forename: Jon
authors.identifier: http://orcid.org/0000-0001-5764-1528
authors.initials: J
authors.lastname: Genuneit
authors.affiliation: 4 Department of Health Protection, National Institute for Health and Welfare, Kuopio, Finland.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Karvonen
authors.affiliation: 4 Department of Health Protection, National Institute for Health and Welfare, Kuopio, Finland.
authors.forename: Anne
authors.initials: A
authors.lastname: Hyvärinen
authors.affiliation: 5 Children's Hospital, University of Zürich, Zürich, Switzerland.|6 Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland.
authors.forename: Caroline
authors.initials: C
authors.lastname: Roduit
authors.affiliation: 7 Department of Pediatric Pneumology and Allergy, KUNO Children's University Hospital Regensburg, Regensburg, Germany.|8 Clinic for Pediatric Pneumology and Neonatology, Hannover Medical School, Hannover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kabesch
authors.affiliation: 6 Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland.|9 Children's Hospital of Eastern Switzerland, St. Gallen, Switzerland.
authors.forename: Roger
authors.initials: R
authors.lastname: Lauener
authors.affiliation: 10 Comprehensive Biomaterial Bank Marburg CBBM, Center for Tumor Biology and Immunology, Faculty of Medicine, Philipp University of Marburg, Marburg, Germany.|11 German Center for Lung Research, Giessen, Germany.
authors.forename: Petra Ina
authors.initials: PI
authors.lastname: Pfefferle
authors.affiliation: 4 Department of Health Protection, National Institute for Health and Welfare, Kuopio, Finland.|12 Department of Public Health, University of Helsinki, Helsinki, Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Pekkanen
authors.affiliation: 13 Department of Respiratory Disease, University of Besançon, University Hospital, Besançon, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Dalphin
authors.affiliation: 14 Children's Hospital Schwarzach, Schwarzach, Austria.|15 Teaching Hospital of Paracelsus Private Medical University of Salzburg, Salzburg, Austria.
authors.forename: Josef
authors.initials: J
authors.lastname: Riedler
authors.affiliation: 16 Swiss Tropical and Public Health Institute, Basel, Switzerland.|17 University of Basel, Basel, Switzerland; and.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Braun-Fahrländer
authors.affiliation: 1 Dr. von Hauner Children's Hospital, Ludwig Maximilians University Munich, Munich, Germany.|18 German Center for Lung Research, Comprehensive Pneumology Center Munich, Munich, Germany.
authors.forename: Erika
authors.initials: E
authors.lastname: von Mutius
authors.affiliation: 1 Dr. von Hauner Children's Hospital, Ludwig Maximilians University Munich, Munich, Germany.|18 German Center for Lung Research, Comprehensive Pneumology Center Munich, Munich, Germany.
authors.forename: Markus J
authors.identifier: http://orcid.org/0000-0001-6643-3923
authors.initials: MJ
authors.lastname: Ege
mesh_terms: D000483:Alleles; D001249:Asthma / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D005060:Europe; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012135:Respiratory Sounds / Q000235:genetics*; D012307:Risk Factors; D012424:Rural Population / Q000706:statistics & numerical data
keywords: 17q21 locus; childhood asthma; epidemiology; farming; infant wheeze