Asthma

Shaw, Dominick; Portelli, Michael A.; Sayers, Ian

doi:10.1016/b978-0-12-386882-4.00028-1

Cited by 2 publications

(2 citation statements)

References 122 publications

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“…Therefore, we set out to determine whether serum scuPAR is elevated, and by inference involved in, a specific subset of patients with asthma. Asthma is a heterogeneous obstructive lung disease comprised of different disease subsets which have markedly different presenting symptoms and degrees of severity, some of which may have greater association with circulating scuPAR. Therefore, we hypothesized that there may be a ‘uPAR driven’ subset of patients with asthma.…”

Section: Discussionmentioning

confidence: 53%

“…Asthma, a chronic inflammatory airway disorder, is known to cause widespread variable airflow obstruction that is often reversible, spontaneously or with treatment, and presents with airway hyperresponsiveness . The urokinase plasminogen activator receptor (uPAR) is a glycosylphosphatidylinositol (GPI)‐anchored membrane protein translated from the gene PLAUR .…”

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confidence: 99%

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Airway and peripheral urokinase plasminogen activator receptor is elevated in asthma, and identifies a severe, nonatopic subset of patients

Portelli

Moseley

Stewart

et al. 2016

Allergy

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peripheral urokinase plasminogen activator receptor is elevated in asthma, and identifies a severe, nonatopic subset of patients. AbstractRationale: 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 features of asthma uPAR may be driving is currently lacking. Objectives: We aimed to comprehensively determine the uPAR expression profile in asthma and control subjects utilizing 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 = 514; 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 patients with asthma, 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 patients with asthma (1.5-fold; P = 0.0008), and we identified an association between high uPAR serum levels and severe, nonatopic disease. Conclusions: This study provides novel data that elevated airway and blood uPAR is a feature of asthma and that blood uPAR is particularly related to severe, nonatopic asthma. The findings warrant further investigation and may provide a therapeutic opportunity for this refractory population.Asthma, a chronic inflammatory airway disorder, is known to cause widespread variable airflow obstruction that is often reversible, spontaneously or with treatment, and presents with airway hyperresponsiveness (1). The urokinase plasminogen activator receptor (uPAR) is a glycosylphosphatidylinositol (GPI)-anchored membrane protein (2-4) translated from the gene PLAUR (4). uPAR has been associated with asthma at the biological and cellular level (5-8), with elevated uPAR Allergy 72 (2017) 473-482

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Section: Discussionmentioning

confidence: 53%

mentioning

confidence: 99%

Airway and peripheral urokinase plasminogen activator receptor is elevated in asthma, and identifies a severe, nonatopic subset of patients

Portelli

Moseley

Stewart

et al. 2016

Allergy

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Genome‐Wide Association Studies in Asthma

Portelli

Sayers

2016

Encyclopedia of Life Sciences

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Asthma is a complex respiratory disease, with both genetic and environmental factors contributing to disease susceptibility. Genome‐wide association studies (GWAS) have now identified novel risk alleles and loci associated with asthma diagnosis and more recently with clinical subgroups of disease. However, while providing insight into potential disease mechanisms these risk alleles have modest effect sizes and account for a small proportion of the anticipated heritability of asthma. In this article we provide an overview of GWAS in asthma to date including reproducible associations and advances in our understanding of the biology of asthma. In addition we discuss ancestry‐specific findings and how genetics may contribute to the development of multiple allergic conditions known as the ‘atopic march’. Finally, we outline the strengths and weaknesses of GWAS and look to future approaches including a greater focus to functional variation and assessment of gene–gene and gene–environment interactions. Key Concepts Asthma is a common respiratory disease that is heterogeneous with respect to its underlying pathology and clinical presentation. Susceptibility to develop asthma involves both genetic and environmental risk factors. Genome‐wide association is the current method of choice to identify genetic factors underlying complex, multifactorial diseases such as asthma. GWAS of asthma have identified several genetic risk factors and genes with confidence, for example IL33, IL1RL1, ORMDL3 loci. Replication of findings remains the gold standard. GWAS of subgroups of asthma, for example, childhood‐onset disease have identified specific genetic risk factors. The effect sizes identified in GWAS are typically modest for single variants. GWAS have provided a unique insight into the altered biology of asthma including changes in innate and adaptive immune responses, altered airway smooth muscle function and epithelial barrier/function abnormalities. While GWAS of asthma have been successful there remains a large missing heritability. Future approaches include better clinical definition of asthma and greater interrogation of genetic factors not currently addressed, for example, regulatory variants, rare variants, copy number variants and greater attention to gene–environment interactions, gene–gene interactions and epigenetic mechanisms.

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Asthma

Cited by 2 publications

References 122 publications

Airway and peripheral urokinase plasminogen activator receptor is elevated in asthma, and identifies a severe, nonatopic subset of patients

Airway and peripheral urokinase plasminogen activator receptor is elevated in asthma, and identifies a severe, nonatopic subset of patients

Genome‐Wide Association Studies in Asthma

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