A role for Wnt signaling genes in the pathogenesis of impaired lung function in asthma.
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.
Sharma
Sunita
S
Channing Laboratory, Center for Genomic Medicine, 181 Longwood Avenue, Boston, MA 02115, USA. resss@channing.harvard.edu
Tantisira
Kelan
K
Carey
Vincent
V
Murphy
Amy J
AJ
Lasky-Su
Jessica
J
Celedón
Juan C
JC
Lazarus
Ross
R
Klanderman
Barbara
B
Rogers
Angela
A
Soto-Quirós
Manuel
M
Avila
Lydiana
L
Mariani
Thomas
T
Gaedigk
Roger
R
Leeder
Stephen
S
Torday
John
J
Warburton
David
D
Raby
Benjamin
B
Weiss
Scott T
ST
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*
D051153:Wnt Proteins