PAI‐1 gain‐of‐function genotype, factors increasing PAI‐1 levels, and airway obstruction: The GALA II Cohort

Abstract

Background PAI-1 gain of function variants promote airway fibrosis, and are associated with asthma and with worse lung function in subjects with asthma. Objective We sought to determine if the association of a gain-of-function polymorphism in Plasminogen Activator Inhibitor −1 (PAI-1) with airway obstruction is modified by asthma status, and whether any genotype effect persists after accounting for common exposures that increase PAI-1 level. Methods We studied 2070 Latino children (8–21y) with genotypic and pulmonary function data from the GALA II cohort. We estimated the relationship of the PAI-1 risk allele with FEV1/FVC by multivariate linear regression, stratified by asthma status. We examined the association of the polymorphism with asthma and airway obstruction within asthmatics via multivariate logistic regression. We replicated associations in the SAPPHIRE cohort of African Americans (n=1056). Secondary analysis included the effect of the at-risk polymorphism on post bronchodilator lung function. Results There was an interaction between asthma status and the PAI-1 polymorphism on FEV1/FVC (p=0.03). The gain-of-function variants, genotypes (AA/AG), were associated with lower FEV1/FVC in subjects with asthma (β=−1.25, CI:−2.14,−0.35, p=0.006), but not in controls. Subjects with asthma and the AA/AG genotypes had a 5% decrease in FEV1/FVC (p<0.001). In asthmatics, the risk genotype (AA/AG) was associated with a 39% increase in risk of clinically relevant airway obstruction (OR=1.39, CI:1.01, 1.92, p=0.04). These associations persisted after exclusion of factors that increase PAI-1 including tobacco exposure and obesity. Conclusions and Clinical Relevance The decrease in the FEV1/FVC ratio associated with the risk genotype was modified by asthma status. The genotype increased the odds of airway obstruction by 75% within asthmatics only. Since exposures known to increase PAI-1 levels did not mitigate this association, PAI-1 may contribute to airway obstruction in the context of chronic asthmatic airway inflammation.

The Intrinsically Disordered Loop in the USF1 bHLHZ Domain Modulates Its DNA-Binding Sequence Specificity in Hereditary Asthma

“…Another member of the dimeric bHLHZ transcription factor family is USF1 (upstream stimulatory factor 1), − which binds to the E-box motif that governs transcription of PAI-1 (plasminogen activator inhibitor-1). , Transcription of PAI-1 is elevated in the airways of those who suffer from heritable asthma, suggesting that PAI-1 induces allergic inflammation and tissue remodeling. − Two different alleles exist with the embedded E-box that controls PAI-1 transcription; the alleles are termed “4G” and “5G” based on the length of the G tract flanking the E-box (G tract starts with the 5′ G of the E-box, Figure B). USF1 binds both the 4G and 5G E-boxes associated with the PAI-1 promoter, with the 4G E-box being preferentially bound by USF1. , The PAI-1 gene and 4G/5G polymorphism may play a role in asthma, as the 4G allele is more frequently observed in asthmatic children, and those with the 4G/4G genotype have the highest plasma levels of PAI-1, followed by 4G/5G then 5G/5G. − …”