PAI-1 gain-of-function genotype, factors increasing PAI-1 levels, and airway obstruction: The GALA II Cohort.
Sherenian MG, Cho SH, Levin AM, Min J, Oh SS, Hu D, Galanter J, Sen S, Huntsman S, Eng C, Rodriguez-Santana J, Serebrisky D, Avila PC, Kalhan R, Smith LJ, Borrell LN, Seibold MA, Williams KL, Burchard E, Kumar R. PAI-1 gain-of-function genotype, factors increasing PAI-1 levels, and airway obstruction: The GALA II Cohort.. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 2017; 47(9):1150-1158.
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology
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 whether 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 postbronchodilator lung function.
RESULTS: There was an interaction between asthma status and the PAI-1 polymorphism on FEV1 /FVC (P=.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=.006), but not in controls. Subjects with asthma and the AA/AG genotypes had a 5% decrease in FEV1 /FVC (P<.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=.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. As 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.
Medical Subject Headings
Adolescent; Adult; Airway Obstruction; Alleles; Asthma, Occupational; Child; Cohort Studies; Ethnic Groups; Female; Gain of Function Mutation; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Male; Odds Ratio; Plasminogen Activator Inhibitor 1; Polymorphism, Single Nucleotide; Respiratory Function Tests; Young Adult