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 < .02). In those with the risk allele at times of viral illness, there was increased expression of 4 coexpressed networks of genes including immune/Toll-like receptor signaling, and decreased expression of one network (ribosome). Subjects with the risk allele receiving mepolizumab with nonexacerbation viral illness had higher expression of eosinophil and mucus hypersecretion gene networks. In subjects with the risk allele receiving mepolizumab who experienced exacerbation, eosinophilic signaling networks were decreased, but gene networks involved in TGF-β/SMAD3 and perturbed epithelial integrity were increased compared to placebo. A number of drug-gene interactions were significant (P < .05, false discovery rate).

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.