Expression analysis of asthma candidate genes during human and murine lung development

Thomas J Mariani,Vincent J Carey,Alvin T Kho,Erik Melén,Scott T Weiss,J Steven Leeder,Sunita Sharma,Kelan G Tantisira,Roger Gaedigk

doi:10.1186/1465-9921-12-86

Abstract

BackgroundLittle 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.ObjectiveTo 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.MethodsAsthma 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.ResultsIn 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.ConclusionsOur 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.

Highlights

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 [1,2]
There was no significant over-representation of the asthma genes among genes differentially expressed during lung development, trends were seen in the human (Odds ratio, OR 1.22, confidence interval, CI 0.90-1.62) and C57BL6 mouse data
Among the asthma genes identified in genome wide association studies, ROBO1, RORA, HLA-DQB1, IL2RB and PDE10A were differentially expressed during human lung development

Summary

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 [1,2]. 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 schoolaged asthmatic children [14]. These results suggest the importance of early life events in determining lung function. They 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. Genetic determinants for normal lung development are important early in life, and for later lung function

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Discussion

Conclusion