title: SERPINE1 -675 4G/5G polymorphism is associated with asthma severity and inhaled corticosteroid response.
abstract: Asthma is characterised by chronic airway inflammation and remodelling, which can be (partially) suppressed by inhaled corticosteroids (ICSs). Plasminogen activator inhibitor-1, encoded by the SERPINE1 gene, is the key inhibitor of the plasminogen activator system, which affects tissue repair and remodelling. We studied associations between a functional SERPINE1 -675 4G/5G promoter polymorphism and asthma development, severity and response to ICSs. Longitudinal cohorts of 281 asthmatics and their nonasthmatic spouses, and the general population (n=1,390) were studied. No significant associations were found with asthma development and immunoglobulin (Ig)E levels, or with forced expiratory volume in 1 s (FEV₁) in nonasthmatic controls. Asthmatic subjects carrying the SERPINE1 5G allele had higher IgE and lower lung function levels at follow-up, lower maximally attained lung function levels, and faster lung function decline compared with individuals with the 4G/4G genotype. ICS treatment showed an immediate improvement in FEV₁ in asthmatics carrying the 5G allele. However, these asthmatics still had the fastest rate of FEV₁ decline after initiating ICS treatment. Finally, the 5G allele was associated with a lower prevalence of complete asthma remission at follow-up. These findings suggest that SERPINE1 is not an asthma susceptibility gene, but rather affects the severity, progression and long-term ICS response in asthma.
authors.affiliation: Dept of Pulmonology, Center Groningen and University of Groningen, Groningen, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Dijkstra
authors.forename: D S
authors.initials: DS
authors.lastname: Postma
authors.forename: M
authors.initials: M
authors.lastname: Bruinenberg
authors.forename: C C
authors.initials: CC
authors.lastname: van Diemen
authors.forename: H M
authors.initials: HM
authors.lastname: Boezen
authors.forename: G H
authors.initials: GH
authors.lastname: Koppelman
authors.forename: W
authors.initials: W
authors.lastname: Timens
authors.forename: J M
authors.initials: JM
authors.lastname: Vonk
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D000368:Aged; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage*; D001249:Asthma / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D005260:Female; D005541:Forced Expiratory Volume; D005938:Glucocorticoids / Q000008:administration & dosage*; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011110:Polymorphism, Genetic; D012074:Remission Induction; D012129:Respiratory Function Tests
chemical_list: D018927:Anti-Asthmatic Agents; D005938:Glucocorticoids; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D007073:Immunoglobulin E