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

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.

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

“…The AG and AA groups were combined for primary analysis to increase precision of estimates even if these estimates would be more conservative. Notably, there was a clear dose effect for the A allele that remained statistically significant in our prior paper . This was also noted in our current sensitivity analyses for the relative associations of the AA and AG genotypes on the FEV 1 /FVC ratio (data not shown).…”

“…We recently demonstrated that a gain‐of‐function polymorphism in the PAI‐1 promoter region leads to an increased risk of asthma and reduced lung function in asthmatic subjects in the context of severe early life lower respiratory infection . Our group, among others, has also found that PAI‐1 is associated with altered lung function and increased odds of hospitalization/ER utilization in subjects with asthma . However, based on the biological action of PAI‐1, we expected to see that any genotype effect would be modified by asthma status as healthy controls would not have ongoing airway inflammation.…”

“…Lower respiratory tract viral illness in the first 2 years of life—This was based on parent report of a medical illness requiring medical attention in the first years of life …”

“…While lower socio‐economic status (SES) is correlated with decreased pulmonary function in children and with greater rates of decline in adulthood, genetic ancestry is associated with lung function in admixed populations even after accounting for SES . These genetic associations may be population specific or dependent on environmental factors to affect lung disease and phenotypes . We recently studied a gain‐of‐function polymorphism in PAI‐1, which is a variant whose frequency varies by African ancestry .…”

“…7 These genetic associations may be population specific 8 or dependent on environmental factors to affect lung disease and phenotypes. 9,10 We recently studied a gainof-function polymorphism in PAI-1, which is a variant whose frequency varies by African ancestry. 11 We found a joint effect of the PAI-1 polymorphism at the rs2227631 promoter region and early life infection, which was associated with reduced FEV 1 and FEV 1 /FVC ratio in children with asthma.…”