SERPINE1 promoter variants and differential airway responses to virus and biological therapy

Background A common functional promoter polymorphism (4G4G/4G5G) in the SERPINE1 gene, which encodes the plasminogen activator inhibitor 1 (PAI-1) protein, is associated with more frequent asthma exacerbations.Objective We examined genotype-specific airway transcriptomic responses during viral illness and how genotype modulates these responses in asthma exacerbations with and without mepolizumab treatment.Methods Nasal lavage samples from a subset of children aged 6-17 years with exacerbation-prone asthma from the type 2-enriched urban asthma MUPPITS-1 and MUPPITS-2 cohorts were used for RNA sequencing and genetic studies. Expression quantitative trait locus (eQTL) analysis and weighted gene coexpression network analysis were performed to determine PAI-1 genotype modulation of gene expression during viral illness and genotype associations with mean expression levels of coexpressed networks of genes (modules). Linear regression analysis was performed to evaluate interactions between mepolizumab and the PAI-1 promoter variants.Results Risk genotypes were associated with lower SERPINE1 expression at baseline but higher levels over the course of viral illness (P Conclusions Nasal lavage SERPINE1 transcripts increase during viral illness in children with asthma who have the risk allele but not in children without this allele. In asthma exacerbations, the risk allele is associated with augmentation of TGF-β/SMAD3 and epithelial pathways as well as a differential airway transcriptomic response to the type 2 modulator mepolizumab.