title: A role for Wnt signaling genes in the pathogenesis of impaired lung function in asthma.
abstract: BACKGROUND
  Animal models demonstrate that aberrant gene expression in utero can result in abnormal pulmonary phenotypes.
  
  
  OBJECTIVE
  We sought to identify genes that are differentially expressed during in utero airway development and test the hypothesis that variants in these genes influence lung function in patients with asthma.
  
  
  METHODS
  Stage 1 (Gene Expression): Differential gene expression analysis across the pseudoglandular (n = 27) and canalicular (n = 9) stages of human lung development was performed using regularized t tests with multiple comparison adjustments. Stage 2 (Genetic Association): Genetic association analyses of lung function (FEV(1), FVC, and FEV(1)/FVC) for variants in five differentially expressed genes were conducted in 403 parent-child trios from the Childhood Asthma Management Program (CAMP). Associations were replicated in 583 parent-child trios from the Genetics of Asthma in Costa Rica study.
  
  
  RESULTS
  Of the 1,776 differentially expressed genes between the pseudoglandular (gestational age: 7-16 wk) and the canalicular (gestational age: 17-26 wk) stages, we selected 5 genes in the Wnt pathway for association testing. Thirteen single nucleotide polymorphisms in three genes demonstrated association with lung function in CAMP (P < 0.05), and associations for two of these genes were replicated in the Costa Ricans: Wnt1-inducible signaling pathway protein 1 with FEV(1) (combined P = 0.0005) and FVC (combined P = 0.0004), and Wnt inhibitory factor 1 with FVC (combined P = 0.003) and FEV(1)/FVC (combined P = 0.003).
  
  
  CONCLUSIONS
  Wnt signaling genes are associated with impaired lung function in two childhood asthma cohorts. Furthermore, gene expression profiling of human fetal lung development can be used to identify genes implicated in the pathogenesis of lung function impairment in individuals with asthma.
authors.affiliation: Channing Laboratory, Center for Genomic Medicine, 181 Longwood Avenue, Boston, MA 02115, USA. resss@channing.harvard.edu
authors.forename: Sunita
authors.initials: S
authors.lastname: Sharma
authors.forename: Kelan
authors.initials: K
authors.lastname: Tantisira
authors.forename: Vincent
authors.initials: V
authors.lastname: Carey
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Murphy
authors.forename: Jessica
authors.initials: J
authors.lastname: Lasky-Su
authors.forename: Juan C
authors.initials: JC
authors.lastname: Celedón
authors.forename: Ross
authors.initials: R
authors.lastname: Lazarus
authors.forename: Barbara
authors.initials: B
authors.lastname: Klanderman
authors.forename: Angela
authors.initials: A
authors.lastname: Rogers
authors.forename: Manuel
authors.initials: M
authors.lastname: Soto-Quirós
authors.forename: Lydiana
authors.initials: L
authors.lastname: Avila
authors.forename: Thomas
authors.initials: T
authors.lastname: Mariani
authors.forename: Roger
authors.initials: R
authors.lastname: Gaedigk
authors.forename: Stephen
authors.initials: S
authors.lastname: Leeder
authors.forename: John
authors.initials: J
authors.lastname: Torday
authors.forename: David
authors.initials: D
authors.lastname: Warburton
authors.forename: Benjamin
authors.initials: B
authors.lastname: Raby
authors.forename: Scott T
authors.initials: ST
authors.lastname: Weiss
mesh_terms: D000293:Adolescent; D001249:Asthma / Q000196:embryology / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D015331:Cohort Studies; D005260:Female; D005541:Forced Expiratory Volume / Q000235:genetics; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D005865:Gestational Age; D006801:Humans; D008168:Lung / Q000196:embryology / Q000503:physiopathology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014797:Vital Capacity / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics*
chemical_list: D051153:Wnt Proteins