PAI-1 genotype and regulation of airway PAI-1 in vivo: relationships with patterns of airway gene expression during illness
Recommended Citation
Schutt M, Gadd S, Senter J, Barrera L, Cho S, Pongracic J, 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, Becker P, Jackson D, Altman M, Kumar R. PAI-1 genotype and regulation of airway PAI-1 in vivo: relationships with patterns of airway gene expression during illness. J Allergy Clin Immunol 2025; 155(2):AB279.
Document Type
Conference Proceeding
Publication Date
2-1-2025
Publication Title
J Allergy Clin Immunol
Keywords
Allergy, Immunology
Abstract
Rationale: A functional promoter polymorphism (4G4G) in the Plasminogen Activator Inhibitor-1 (PAI-1) gene is associated with lower lung function, and more frequent asthma exacerbations. Genotype relationships with airway PAI-1 expression and asthma endotypes remain understudied. Methods: We included a subset of children aged 6–17 years with exacerbation-prone asthma who had baseline and illness nasal lavage samples, from the urban asthma MUPPITS-1 study. We examined the relationship of genotype with PAI-1 expression in bulk nasal lavage cells. eQTL analysis evaluated the association between gene expression and the PAI-1 genotype in illness samples. The top 3500 eQTL genes, by beta value, were selected for weighted gene co-expression network analysis (WCGNA). Results: We included 165 participants, 42% female, mean age 10.8 years with the following PAI-1 genotypes: 76 5G5G, 64 5G4G, and 25 4G4G. There were no differences by genotype in age, sex, race, ethnicity or BMI. In MUPPITS-1 baseline visits, PAI-1 airway gene expression was lower (P<0.002) in 4G4G than 5G5G or 4G5G participants. Conversely, during viral illnesses PAI-1 expression levels were highest in the 4G4G group (p<0.02). WCGNA analysis of the illness samples revealed 4 modules with increased expression, (protein metabolism, autophagy, immune/TLR signaling) and 3 that were decreased (epithelial development, ribosome/translation and DNA helicase activity) in the 4G4G genotype. Conclusions: The promoter polymorphism is associated with lower baseline airway PAI-1 expression, contrasting with prior reported associations with higher PAI-1 plasma levels. Genotype-specific increased PAI-1 expression during viral illnesses, and increased TLR signaling, may be relevant for worse asthma outcomes associated with the genotype.
Volume
155
Issue
2
First Page
AB279
