Association of a PAI-1 Gene Polymorphism and Early Life Infections with Asthma Risk, Exacerbations, and Reduced Lung Function.

Seong H Cho,Harold J Farber,Denise Serebrisky,Sam S Oh,Pedro C Avila,Rajesh Kumar,Esteban G Burchard,Donglei Hu,L Keoki Williams,Scott Huntsman,Celeste Eng,Max A Seibold,Luisa N Borrell,William Rodríguez-Cintrón ,María Pino-Yanes ,José Rodríguez‐Santana ,Śaunak Sen ,William D Dupont ,Dong Young Kim,Shannon Thyne ,Jin Young Min ,Dara Torgerson

doi:10.1371/journal.pone.0157848

Abstract

BackgroundPlasminogen activator inhibitor-1 (PAI-1) is induced in airways by virus and may mediate asthmatic airway remodeling. We sought to evaluate if genetic variants and early life lower respiratory infections jointly affect asthma risk.MethodsWe included Latino children, adolescents, and young adults aged 8–21 years (1736 subjects with physician-diagnosed asthma and 1747 healthy controls) from five U.S. centers and Puerto Rico after excluding subjects with incomplete clinical or genetic data. We evaluated the independent and joint effects of a PAI-1 gain of function polymorphism and bronchiolitis / Respiratory Syncytial Virus (RSV) or other lower respiratory infections (LRI) within the first 2 years of life on asthma risk, asthma exacerbations and lung function.ResultsRSV infection (OR 9.9, 95%CI 4.9–20.2) and other LRI (OR 9.1, 95%CI 7.2–11.5) were independently associated with asthma, but PAI-1 genotype was not. There were joint effects on asthma risk for both genotype-RSV (OR 17.7, 95% CI 6.3–50.2) and genotype-LRI (OR 11.7, 95% CI 8.8–16.4). A joint effect of genotype-RSV resulted in a 3.1-fold increased risk for recurrent asthma hospitalizations. In genotype-respiratory infection joint effect analysis, FEV1% predicted and FEV1/FVC % predicted were further reduced in the genotype-LRI group (β -2.1, 95% CI -4.0 to -0.2; β -2.0, 95% CI -3.1 to -0.8 respectively). Similarly, lower FEV1% predicted was noted in genotype-RSV group (β -3.1, 95% CI -6.1 to -0.2) with a trend for lower FEV1/FVC % predicted.ConclusionsA genetic variant of PAI-1 together with early life LRI such as RSV bronchiolitis is associated with an increased risk of asthma, morbidity, and reduced lung function in this Latino population.

Highlights

Genes & Environments Study of African Americans (II) (Asthma) affects more than 25 million people in the United States including 9.3% of all US children, with $56 billion in annual healthcare and indirect costs.[1]
There were joint effects on asthma risk for both genotype-Respiratory Syncytial Virus (RSV) and genotypeLRI
In genotype-respiratory infection joint effect analysis, forced expiratory volume in 1 second (FEV1)% predicted and FEV1/Forced Vital Capacity (FVC) % predicted were further reduced in the genotype-lower respiratory infections (LRI) group (β -2.1, 95% CI -4.0 to -0.2; β -2.0, 95% CI -3.1 to -0.8 respectively)

Summary

Introduction

Asthma affects more than 25 million people in the United States including 9.3% of all US children, with $56 billion in annual healthcare and indirect costs.[1]. The plasmin and fibrinolytic pathway may be relevant in airway remodeling and upper respiratory infection is associated with increased fibrinogenic activities in subjects with recurrent wheezing or asthma.[12,13] plasminogen activator inhibitor-1 (PAI-1) promotes fibrosis, [14,15] and blocking of this enzyme prevents extracellular matrix (ECM) deposition.[16,17] URI increases airway PAI-1 levels, with virus inducing PAI-1 production in human airway epithelial cells.[12] PAI-1 promoter site genetic variants are strongly associated with plasma PAI-1 levels,[18] and with increased risk of asthma, decreased forced expiratory volume in 1 second (FEV1), and airway hyperreactivity.[19] [20]. We sought to evaluate if genetic variants and early life lower respiratory infections jointly affect asthma risk

Methods

Results

Conclusion