Airway and peripheral uPAR is elevated in asthma, and identifies a severe, non-atopic subset of patients.

RATIONALE: Genetic polymorphisms in the asthma susceptibility gene, urokinase plasminogen activator receptor (uPAR/PLAUR) have been associated with lung function decline and uPAR blood levels in asthma subjects. Preliminary studies have identified uPAR elevation in asthma; however a definitive study regarding which clinical feature of asthma uPAR may be driving is currently lacking. OBJECTIVES: We aimed to comprehensively determine the uPAR expression profile in asthma and control subjects utilising bronchial biopsies and serum, and to relate uPAR expression to asthma clinical features. METHODS: uPAR levels were determined in control (n=9) and asthmatic (n=27) bronchial biopsies using immunohistochemistry, with a semi-quantitative score defining intensity in multiple cell types. Soluble cleaved (sc)uPAR levels were determined in serum through ELISA in UK (cases n=129; controls n=39) and Dutch (cases n=441; controls n=96) cohorts. MEASUREMENTS AND MAIN RESULTS: In bronchial tissue, uPAR was elevated in inflammatory cells in the lamina propria (P=0.0019), bronchial epithelial (P=0.0002) and airway smooth muscle cells (P=0.0352) of asthma patients, with uPAR levels correlated between the cell types. No correlation with disease severity or asthma clinical features was identified. scuPAR serum levels were elevated in asthma patients (1.5 fold; P=0.0008) and we identified an association between high uPAR serum levels and severe, non-atopic disease. CONCLUSIONS: This study provides novel data that elevated airway and blood uPAR in asthma is particularly related to severe, non-atopic asthma. The findings warrant further investigation and may provide a therapeutic opportunity for this refractory population

Study populations included in GWI study on active smoking and adult onset asthma.

<p>Study populations included in GWI study on active smoking and adult onset asthma.</p

Forest plots for the meta-analysis and replication study on the genetic effect of SNP rs5011804 on chromosome 12 in subjects exposed and non-exposed to ever active tobacco smoking (identified in second approach).

<p>The bottom forest plot presents the interaction meta-analysis and replication study for this SNP. ORs are calculated using a fixed effect model.</p

PRISMA flow diagram.

<p>PRISMA flow diagram.</p

Top SNPs that interact with active tobacco smoking in adult onset asthma identified in second approach (genetic effect in exposed)^#.

<p>Top SNPs that interact with active tobacco smoking in adult onset asthma identified in second approach (genetic effect in exposed)<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0172716#t003fn001" target="_blank">^#</a>.</p

Top SNPs that interact with active tobacco smoking in adult onset asthma identified in both approaches^#.

<p>Top SNPs that interact with active tobacco smoking in adult onset asthma identified in both approaches<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0172716#t004fn001" target="_blank">^#</a>.</p

Forest plots for the meta-analysis and replication study on the genetic effect of SNP rs9969775 on chromosome 9 in subjects exposed and non-exposed to ever active tobacco smoking (identified in first approach).

<p>The bottom forest plot presents the interaction meta-analysis and replication study for this SNP. ORs are calculated using a fixed effect model.</p

Top SNPs that interact with active tobacco smoking in adult onset asthma identified in first approach (overall interaction effect)^#.

<p>Top SNPs that interact with active tobacco smoking in adult onset asthma identified in first approach (overall interaction effect)<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0172716#t002fn001" target="_blank">^#</a>.</p

Forest plot for meta-analysis on the association between ever active tobacco smoking and adult onset asthma, without including the genetic effect.

<p>Forest plot for meta-analysis on the association between ever active tobacco smoking and adult onset asthma, without including the genetic effect.</p

Genetic effect of SNP rs5011804 following an additive model in the LifeLines cohort (N = 12,475), stratified by different tobacco smoke exposures.

<p>Genetic effect of SNP rs5011804 following an additive model in the LifeLines cohort (N = 12,475), stratified by different tobacco smoke exposures.</p