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A Role for Wnt Signaling Genes in the Pathogenesis of Impaired Lung Function in Asthma

¹ Channing Laboratory, Center for Genomic Medicine, and ² Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; ³ Harvard Medical School, Boston, Massachusetts; ⁴ Division of Pediatric Pulmonology, Hospital Nacional de Niños, San José, Costa Rica; ⁵ University of Rochester Medical Center, Rochester, New York; ⁶ Children's Mercy Hospital, Kansas City, Missouri; ⁷ University of California Los Angeles, Los Angeles; and ⁸ Saban Research Institute, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, California

Correspondence and requests for reprints should be addressed to Sunita Sharma, M.D., Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115. E-mail: resss{at}channing.harvard.edu

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 (FEV₁, FVC, and FEV₁/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 FEV₁ (combined P = 0.0005) and FVC (combined P = 0.0004), and Wnt inhibitory factor 1 with FVC (combined P = 0.003) and FEV₁/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.

Key Words: asthma • lung development • lung function • genetic variation • gene expression

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The trajectory of lung function growth appears to be set early in life. Animal models demonstrate that abnormal in utero expression of genes implicated in normal lung development can result in abnormal pulmonary phenotypes after birth. What This Study Adds to the Field Gene expression profiling of early human fetal lung development can be used to identify novel genes and pathways that influence lung function in subjects with asthma.