Effect of Intrauterine Smoke Exposure on microRNA-15a Expression in Human Lung Development and Subsequent Asthma Risk

Background: In utero smoke (IUS) exposure is associated with asthma susceptibility. Objective: We sought to test the hypothesis that changes in miRNA expression by IUS exposure during human lung development is associated with asthma susceptibility. Methods: Gene expression was profiled from 53 IUS unexposed and 51 IUS exposed human fetal lung tissues. We tested for the differential expression of miRNAs across post-conception age and by IUS using linear models with covariate adjustment. We tested the IUS-associated miRNAs for association with their gene expression targets using pair-wise inverse correlation. Using our mouse model, we investigated the persistence of the IUS-associated miRNA signature using RT-PCR from the lungs of mouse pups with and without IUS at postnatal day 14. MiRNAs were then tested for association with asthma and exacerbations using whole blood gene expression profiles from Asthma BRIDGE. Results: Five miRNAs were differentially expressed across post-conception age (adjusted p < 0.0002) including two that were differentially expressed by IUS exposure in human fetal lung (p < 0.05). MiR-15a was differentially expressed by post-conception age (p = 0.00002), IUS exposure in human fetal lung (p = 0.005), and in the post-natal mouse lung (p = 0.01). MiR-15a was also associated with the in utero expression of GSDMB (adjusted p = 0.0002), a known childhood asthma gene and with asthma exacerbations (p = 0.0009) in Asthma BRIDGE. Thus, miR-15a is expressed during human lung development, is impacted by IUS exposure, regulates the intrauterine expression of asthma genes, and is associated with asthma severity. Conclusions: These results provide evidence for the role of miR-15a in the fetal origin of asthma.