Association of PAI-1 promoter polymorphisms with airway gene expression during illnesses in children with exacerbation-prone asthma
Recommended Citation
Thames A, Schutt M, Gadd S, Barrera L, Cho S, Wentworth-Sheilds W, Liu A, Gruchalla R, Kercsmar C, Hershey GK, Zoratti E, Johnson C, Teach S, Kattan M, Bacharier L, O'Connor G, Gern J, Visness C, Coleman A, Gergen P, Kumar R. Association of PAI-1 promoter polymorphisms with airway gene expression during illnesses in children with exacerbation-prone asthma. J Allergy Clin Immunol 2026; 157(2):AB194.
Document Type
Conference Proceeding
Publication Date
2-10-2026
Publication Title
J Allergy Clin Immunol
Keywords
mepolizumab, placebo, plasminogen activator inhibitor 1, transforming growth factor beta, allele, asthma, child, cold, conference abstract, controlled study, diagnosis, etiology, expression quantitative trait locus, female, gene expression, gene regulatory network, genotype, human, major clinical study, male, nasal lavage, preschool child, promoter region, ribosome, squamous epithelium, weighted gene co-expression network analysis
Abstract
Rationale: A common, promoter polymorphism in the SERPINE1 gene, which encodes Plasminogen Activator Inhibitor-1 is associated with asthma exacerbations. We examined genotype specific airway transcriptomic responses to respiratory illness, and how genotype modulates these responses in asthma exacerbations, with and without mepolizumab. Methods: Genotype-stratified analyses were performed using nasal-lavage RNA samples from a subset of exacerbation-prone children with asthma, aged 6–17 years with genotype, expression, and illness data from the urban asthma MUPPITS-1 (n=165) and MUPPITS-2 (n=228) studies. Expression quantitative trait loci analysis and weighted gene co-expression network analysis (WGCNA) were performed to determine the association of genotype with mean expression of gene modules. Linear regression analysis was performed to evaluate interactions between mepolizumab and the PAI-1 promoter variants. Results: In risk-allele positive children, WGCNA analysis of cold samples (MUPPITS1) revealed 4 modules with increased expression (including immune/TLR signaling) and one module with decreased expression (ribosome), compared to children with no risk allele. Only in risk-allele positive children on mepolizumab (MUPPITS2), eosinophil associated gene modules had an increase in expression in cold illness, decrease in early exacerbation, and increase in late exacerbation compared to placebo (p-interaction for treatment by genotype <0.05, <0.1 and <0.05 respectively by FDR). Squamous epithelial and TGFβ/SMAD3 modules increased only in risk-allele positive children on mepolizumab compared to placebo in early and late exacerbation samples (p-interaction<0.1 and <0.05 respectively by FDR). Conclusions: During exacerbations, the risk-allele is associated with a differential transcriptomic response to mepolizumab, with increased expression of the TGFβ/SMAD3 module and epithelial modules previously associated with exacerbation.
Volume
157
Issue
2
First Page
AB194
