PAI-1 gain of function genotype and airway obstruction in asthma

Rationale: A gain of function promoter polymorphism in Plasminogen Activator Inhibitor -1 (PAI-1) modulates airway remodeling. We sought to determine if this polymorphism is associated with greater airway obstruction in children with asthma. Methods: We studied 2070 Latino children (8-21y) from the GALA II cohort with genotypic and pulmonary function data. The rs2227631 snp was categorized as wild-type (AA) or any risk allele (AG, GG). We examined the association of the polymorphism with asthma and airway obstruction within asthmatics (FEV1/FVC <80%) via multivariate logistic regression. We estimated the relationship of the PAI-1 risk allele with FEV1/FVC by multivariate linear regression, stratified by asthma status. We replicated associations in the SAPPHIRE cohort of African American adults (n=1056). Results: There was an interaction between asthma and the PAI-1 polymorphism on FEV1/FVC (p=0.03). The genotype was associated with lower FEV1/FVC in subjects with asthma (β=-1.25,SE=0.45, p=0.006), but not in normal controls (β=-0.38,SE=0.69, p=0.58). Compared to non-asthmatic subjects without the polymorphism, subjects with asthma and the genotype had an approximately 5% decrease in FEV1/FVC (β= -5.18, SE=0.79, p=0.000). The presence of the polymorphism in asthmatics was associated with a 75% increase in risk of clinical obstruction defined as FEV1/FVC < 80%-predicted (OR=1.76, SE=0.45, p =0.03). All findings were replicated in the SAPPHIRE cohort. Conclusions: The PAI-1 gain of function mutation was only associated with decreased FEV1/FVC ratio in asthmatic subjects, with a 75% increased odds of airway obstruction. Further research is needed to determine if PAI-1 modifies the progression of airway obstruction in asthmatic subjects.