PAI-1 Gain-of-function Genotype, Factors Increasing PAI-1 Levels, and Airway Obstruction: The GALA II Cohort

Authors

M. G. Sherenian, Northwestern University
S. H. Cho, University of South Florida
A. Levin, Henry Ford Health System
J-Y. Min, Northwestern University
S. S. Oh, University of California
D. Hu, University of California
J. Galanter, University of California
S. Sen, Department of Preventive Medicine
S. Huntsman, University of California
C. Eng, University of California
J. R. Rodriguez-Santana, Centro de Neumologia Pediatrica
D. Serebrisky, Jacobi Medical Center
P. C. Avila, Northwestern University
R. Kalhan, Northwestern University
L. J. Smith, Northwestern University
L. N. Borrell, Lehman College
M. A. Seibold, National Jewish Health
L. Keoki Williams, Henry Ford Health System
E. G. Burchard, University of California
R. Kumar, Northwestern University

Document Type

Article

Publication Date

2017

Keywords

asthma, epidemiology, PAI-1, pediatrics

Digital Object Identifier (DOI)

https://doi.org/10.1111/cea.12958

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 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.

Was this content written or created while at USF?

Yes

Citation / Publisher Attribution

Clinical & Experimental Allergy, v. 47, issue 9, p. 1150-1158

Scholar Commons Citation

Sherenian, M. G.; Cho, S. H.; Levin, A.; Min, J-Y.; Oh, S. S.; Hu, D.; Galanter, J.; Sen, S.; Huntsman, S.; Eng, C.; Rodriguez-Santana, J. R.; Serebrisky, D.; Avila, P. C.; Kalhan, R.; Smith, L. J.; Borrell, L. N.; Seibold, M. A.; Williams, L. Keoki; Burchard, E. G.; and Kumar, R., "PAI-1 Gain-of-function Genotype, Factors Increasing PAI-1 Levels, and Airway Obstruction: The GALA II Cohort" (2017). Internal Medicine Faculty Publications. 203.
https://digitalcommons.usf.edu/intmed_facpub/203