A role for Wnt signaling genes in the pathogenesis of impaired lung function in asthma

Abstract

Rationale: Animal models demonstrate that aberrant gene expression in utero can result in abnormal pulmonary phenotypes.

Objectives: 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.

Measurements and main 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.

Figure 1.

Significance analysis of microarray plot demonstrating differential expression of 1,776 genes across the pseudoglandular-to-canalicular periods of human fetal lung development. The genes shown in gray (n = 1,776) are differentially expressed at a false discovery rate = 0.10.

Figure 2.

Evidence of differential expression of Wnt genes between the pseudoglandular period to the canalicular stage of human fetal lung development (Wnt inhibitory factor 1 [WIF1] t test, P = 0.02; Wnt1-inducible signaling pathway protein 1 [WISP1] t test, P = 0.008; secreted frizzled-related protein 2 [sFRP2] t test, P = 0.007; sFRP5 t test, P = 0.002; Dickkopf 1 [DKK1] t test, P = 0.002). The horizontal black bar in the box plot represents the mean expression value for the gene. The whiskers represent the standard deviation in expression value.