Abstract and Introduction
Abstract
Background Little is known about the role of most asthma susceptibility genes during human lung development. Genetic determinants for normal lung development are not only important early in life, but also for later lung function.
Objective To investigate the role of expression patterns of well-defined asthma susceptibility genes during human and murine lung development. We hypothesized that genes influencing normal airways development would be over-represented by genes associated with asthma.
Methods Asthma genes were first identified via comprehensive search of the current literature. Next, we analyzed their expression patterns in the developing human lung during the pseudoglandular (gestational age, 7–16 weeks) and canalicular (17–26 weeks) stages of development, and in the complete developing lung time series of 3 mouse strains: A/J, SW, C57BL6.
Results In total, 96 genes with association to asthma in at least two human populations were identified in the literature. Overall, there was no significant over-representation of the asthma genes among genes differentially expressed during lung development, although trends were seen in the human (Odds ratio, OR 1.22, confidence interval, CI 0.90–1.62) and C57BL6 mouse (OR 1.41, CI 0.92–2.11) data. However, differential expression of some asthma genes was consistent in both developing human and murine lung, e.g. NOD1, EDN1, CCL5, RORA and HLA-G. Among the asthma genes identified in genome wide association studies, ROBO1, RORA, HLA-DQB1, IL2RB and PDE10A were differentially expressed during human lung development.
Conclusions Our data provide insight about the role of asthma susceptibility genes during lung development and suggest common mechanisms underlying lung morphogenesis and pathogenesis of respiratory diseases.
Introduction
There is good evidence that genetic factors strongly influence the risk of asthma, and associations between numerous genes and asthma have been evaluated in the past decades. Recent genome wide association studies (GWAS) of asthma have identified several additional asthma susceptibility genes. Little is known about the role of most asthma susceptibility genes during human lung development.
The "developmental origins" hypothesis proposes that specific in utero events at critical periods during organogenesis and maturation result in long-term physiological or metabolic changes, ultimately contributing to disease in later life. Our group previously showed that Wnt signaling genes that were differentially expressed during fetal lung development were associated with impaired lung function in two cohorts of school-aged asthmatic children. These results suggest the importance of early life events in determining lung function. They also highlight the benefit of integrating gene expression and genetic association data to connect transcriptomic events in the early developing lung to genetic associations of lung function in later life.
Asthma is a disease characterized by both airway inflammation and smooth muscle contraction, leading to airway obstruction. Dendritic cells, mast cells, and T-lymphocytes, as well as airway smooth muscle cells, all begin to appear within the lung parenchyma during the pseudoglandular stage of lung development. We therefore hypothesized that genes influencing normal airways development, especially during the branching morphogenesis stage of human lung development, would be over-represented by genes associated with asthma. To test this hypothesis, we investigated the role of a well-defined set of asthma susceptibility genes during human and murine lung development. 96 asthma genes were first identified via comprehensive search of the current literature. Next, we analyzed their expression patterns in the developing human lung during the pseudoglandular (gestational age, 7-16 weeks) and canalicular (17-27 weeks) stages of development, and in the complete developing lung time series of 3 mouse strains: A/J, SW and C57BL6.
We show that overall, there was no over-representation of the asthma genes among genes differentially expressed during lung development, which may reflect the diverse ontological contexts of the asthma genes. However, some genes showed a consistent pattern of differential expression in all developing lung data sets, e.g. NOD1, EDN1, RORA, CCL5 and HLA-G, which suggests that these genes play a fundamental role in normal lung development.