title: Transient early wheeze and lung function in early childhood associated with chronic obstructive pulmonary disease genes.
abstract: BACKGROUND
  It has been hypothesized that a disturbed early lung development underlies the susceptibility to chronic obstructive pulmonary disease (COPD). Little is known about whether subjects genetically predisposed to COPD show their first symptoms or reduced lung function in childhood.
  
  
  OBJECTIVE
  We investigated whether replicated genes for COPD associate with transient early wheeze (TEW) and lung function levels in 6- to 8-year-old children and whether cigarette smoke exposure in utero and after birth (environmental tobacco smoke [ETS]) modifies these effects.
  
  
  METHODS
  The association of COPD-related genotypes of 20 single nucleotide polymorphisms in 15 genes with TEW, FEV1, forced vital capacity (FVC), and FEV1/FVC ratio was studied in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort (n = 1996) and replicated in the Child, parents and health: lifestyle and genetic constitution (KOALA) and Avon Longitudinal Study of Parents and Children (ALSPAC) cohorts.
  
  
  RESULTS
  AGER showed replicated association with FEV1/FVC ratio. TNS1 associated with more TEW in PIAMA and lower FEV1 in ALSPAC. TNS1 interacted with ETS in PIAMA, showing lower FEV1 in exposed children. HHIP rs1828591 interacted with cigarette smoke exposure in utero in PIAMA and with ETS in ALSPAC, with lower lung function in nonexposed children. SERPINE2, FAM13A, and MMP12 associated with higher FEV1 and FVC, and SERPINE2, HHIP, and TGFB1 interacted with cigarette smoke exposure in utero in PIAMA only, showing adverse effects of exposure on FEV1 being limited to children with genotypes conferring the lowest risk of COPD.
  
  
  CONCLUSIONS
  Our findings indicate relevant involvement of at least 3 COPD genes in lung development and lung growth by demonstrating associations pointing toward reduced airway caliber in early childhood. Furthermore, our results suggest that COPD genes are involved in the infant's lung response to smoke exposure in utero and in early life.
authors.affiliation: Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; GRIAC Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: m.kerkhof@umcg.nl.
authors.forename: Marjan
authors.initials: M
authors.lastname: Kerkhof
authors.affiliation: Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; GRIAC Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: H Marike
authors.initials: HM
authors.lastname: Boezen
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Raquel
authors.initials: R
authors.lastname: Granell
authors.affiliation: Centre for Prevention and Health Services Research, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
authors.forename: Alet H
authors.initials: AH
authors.lastname: Wijga
authors.affiliation: Institute for Risk Assessment Science, Utrecht University, Utrecht, The Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Bert
authors.initials: B
authors.lastname: Brunekreef
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Henriëtte A
authors.initials: HA
authors.lastname: Smit
authors.affiliation: Department of Pediatrics, Division of Respiratory Medicine, Erasmus University Medical Center/Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Johan C
authors.initials: JC
authors.lastname: de Jongste
authors.affiliation: Department of Epidemiology, Maastricht University School for Public Health and Primary Care CAPHRI, Maastricht, The Netherlands.
authors.forename: Carel
authors.initials: C
authors.lastname: Thijs
authors.affiliation: Department of Epidemiology, Maastricht University School for Public Health and Primary Care CAPHRI, Maastricht, The Netherlands.
authors.forename: Monique
authors.initials: M
authors.lastname: Mommers
authors.affiliation: Department of Epidemiology, Maastricht University School for Public Health and Primary Care CAPHRI, Maastricht, The Netherlands.
authors.forename: John
authors.initials: J
authors.lastname: Penders
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Henderson
authors.affiliation: Department of Paediatric Pulmonology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Gerard H
authors.initials: GH
authors.lastname: Koppelman
authors.affiliation: Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
mesh_terms: D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008168:Lung / Q000254:growth & development / Q000503:physiopathology*; D008297:Male; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000453:epidemiology* / Q000235:genetics*; D012119:Respiration / Q000235:genetics; D012129:Respiratory Function Tests; D012135:Respiratory Sounds / Q000235:genetics* / Q000503:physiopathology; D058258:Serpin E2 / Q000235:genetics / Q000378:metabolism; D014028:Tobacco Smoke Pollution / Q000009:adverse effects
chemical_list: D058258:Serpin E2; D014028:Tobacco Smoke Pollution
keywords: ALSPAC; Avon Longitudinal Study of Parents and Children; COPD; Child, parents and health: lifestyle and genetic constitution; Chronic obstructive pulmonary disease; ETS; Environmental tobacco smoke; FVC; Forced vital capacity; KOALA; OR; Odds ratio; PIAMA; Prevention and Incidence of Asthma and Mite Allergy; RAGE; Receptor for advanced glycation end products; SNP; Single nucleotide polymorphism; TEW; Transient early wheeze; in utero exposure; lung function growth; transient early wheeze