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Genome-wide protein QTL mapping identifies human plasma kallikrein as a post-translational regulator of serum uPAR levels

Portelli, Michael; Siedlinski, Mateusz; Stewart, Ceri E.; Postma, Dirkje S.; Nieuwenhuis, Maartje A.; Vonk, Judith M.; Nurnberg, Peter; Altmuller, Janine; Moffatt, M.F.; Wardlaw, Andrew J.; Parker, Stuart G.; Connolly, Martin J.; Koppelman, Gerard H.; Sayers, Ian

Authors

Mateusz Siedlinski

Ceri E. Stewart

Dirkje S. Postma

Maartje A. Nieuwenhuis

Judith M. Vonk

Peter Nurnberg

Janine Altmuller

M.F. Moffatt

Andrew J. Wardlaw

Stuart G. Parker

Martin J. Connolly

Gerard H. Koppelman



Abstract

The soluble cleaved urokinase plasminogen activator receptor (scuPAR) is a circulating protein detected in multiple diseases, including various cancers, cardiovascular disease, and kidney disease, where elevated levels of scuPAR have been associated with worsening prognosis and increased disease aggressiveness. We aimed to identify novel genetic and biomolecular mechanisms regulating scuPAR levels. Elevated serum scuPAR levels were identified in asthma (n=514) and chronic obstructive pulmonary disease (COPD; n=219) cohorts when compared to controls (n=96). In these cohorts, a genome-wide association study of serum scuPAR levels identified a human plasma kallikrein gene (KLKB1) promoter polymorphism (rs4253238) associated with serum scuPAR levels in a control/asthma population (P=1.17×10−7), which was also observed in a COPD population (combined P=5.04×10−12). Using a fluorescent assay, we demonstrated that serum KLKB1 enzymatic activity was driven by rs4253238 and is inverse to scuPAR levels. Biochemical analysis identified that KLKB1 cleaves scuPAR and negates scuPAR's effects on primary human bronchial epithelial cells (HBECs) in vitro. Chymotrypsin was used as a proproteolytic control, while basal HBECs were used as a control to define scuPAR-driven effects. In summary, we reveal a novel post-translational regulatory mechanism for scuPAR using a hypothesis-free approach with implications for multiple human diseases.

Citation

Portelli, M., Siedlinski, M., Stewart, C. E., Postma, D. S., Nieuwenhuis, M. A., Vonk, J. M., …Sayers, I. (2013). Genome-wide protein QTL mapping identifies human plasma kallikrein as a post-translational regulator of serum uPAR levels. FASEB Journal, 28(2), https://doi.org/10.1096/fj.13-240879

Journal Article Type Article
Publication Date Nov 18, 2013
Deposit Date May 30, 2014
Publicly Available Date May 30, 2014
Journal FASEB Journal
Print ISSN 0892-6638
Electronic ISSN 0892-6638
Publisher Federation of American Society of Experimental Biology
Peer Reviewed Peer Reviewed
Volume 28
Issue 2
DOI https://doi.org/10.1096/fj.13-240879
Keywords GWAS, Proteolysis, Respiratory disease, HBECs, Cellular proliferation and wound repair
Public URL http://eprints.nottingham.ac.uk/id/eprint/3171
Publisher URL http://www.fasebj.org/content/28/2/923.abstract

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