Abstract
BackgroundWe have previously identified Urokinase Plasminogen Activator Receptor (PLAUR) as an asthma susceptibility gene. In the current study we tested the hypothesis that PLAUR single nucleotide polymorphisms (SNPs) determine baseline lung function and contribute to the development of Chronic Obstructive Pulmonary Disease (COPD) in smokers.Methods25 PLAUR SNPs were genotyped in COPD subjects and individuals with smoking history (n = 992). Linear regression was used to determine the effects of polymorphism on baseline lung function (FEV1, FEV1/FVC) in all smokers. Genotype frequencies were compared in spirometry defined smoking controls (n = 176) versus COPD cases (n = 599) and COPD severity (GOLD stratification) using logistic regression.ResultsFive SNPs showed a significant association (p < 0.01) with baseline lung function; rs2302524(Lys220Arg) and rs2283628(intron 3) were associated with lower and higher FEV1 respectively. rs740587(-22346), rs11668247(-20040) and rs344779(-3666) in the 5'region were associated with increased FEV1/FVC ratio. rs740587 was also protective for COPD susceptibility and rs11668247 was protective for COPD severity although no allele dose relationship was apparent. Interestingly, several of these associations were driven by male smokers not females.ConclusionThis study provides tentative evidence that the asthma associated gene PLAUR also influences baseline lung function in smokers. However the case-control analyses do not support the conclusion that PLAUR is a major COPD susceptibility gene in smokers. PLAUR is a key serine protease receptor involved in the generation of plasmin and has been implicated in airway remodelling.
Highlights
We have previously identified Urokinase Plasminogen Activator Receptor (PLAUR) as an asthma susceptibility gene
Smoking is associated with an increased decline in forced expiratory volume in 1 second (FEV1) and is a major risk factor for the development of Chronic Obstructive Pulmonary Disease (COPD) [11] we investigated the role of PLAUR single nucleotide polymorphisms (SNPs) in smokers
In addition to dichotomous trait analyses based on post bronchodilator spirometry we investigated the role of PLAUR SNPs in determining baseline lung function, FEV1 and FEV1/FVC ratio in the entire population (n = 992) (Figure 2 and Additional file 2)
Summary
We have previously identified Urokinase Plasminogen Activator Receptor (PLAUR) as an asthma susceptibility gene. In the current study we tested the hypothesis that PLAUR single nucleotide polymorphisms (SNPs) determine baseline lung function and contribute to the development of Chronic Obstructive Pulmonary Disease (COPD) in smokers. PLAUR plays a key role in the formation of the serine protease plasmin by interacting with urokinase plasminogen activator (PLAU) [4] and has been implicated in many processes including; cell differentiation, proliferation and migration [5]. From the known biology of PLAUR, this protease receptor is potentially involved in these processes due to its role in matrix metalloproteinase (MMP) and transforming growth factor (TGF)β1 activation and tissue fibrosis [5]
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