Genome-wide protein QTL mapping identifies human plasma kallikrein as a post-translational regulator of serum uPAR levels
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 agg...
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| Format: | Article |
| Language: | English English English |
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Federation of American Society of Experimental Biology
2014
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| Online Access: | http://eprints.nottingham.ac.uk/32639/ http://eprints.nottingham.ac.uk/32639/ http://eprints.nottingham.ac.uk/32639/ http://eprints.nottingham.ac.uk/32639/1/Portelli%20FASEB%20J%202014.pdf http://eprints.nottingham.ac.uk/32639/2/Sayers%20FASEB%20SF1.pdf http://eprints.nottingham.ac.uk/32639/3/Sayers%20FASEB%20Supplementary%20Figure%202.pdf |
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nottingham-326392018-07-02T09:04:43Z http://eprints.nottingham.ac.uk/32639/ Genome-wide protein QTL mapping identifies human plasma kallikrein as a post-translational regulator of serum uPAR levels Portelli, Michael A. 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 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. Federation of American Society of Experimental Biology 2014-02 Article PeerReviewed application/pdf en cc_by http://eprints.nottingham.ac.uk/32639/1/Portelli%20FASEB%20J%202014.pdf application/pdf en cc_by http://eprints.nottingham.ac.uk/32639/2/Sayers%20FASEB%20SF1.pdf application/pdf en cc_by http://eprints.nottingham.ac.uk/32639/3/Sayers%20FASEB%20Supplementary%20Figure%202.pdf Portelli, Michael A. and Siedlinski, Mateusz and Stewart, Ceri E. and Postma, Dirkje S. and Nieuwenhuis, Maartje A. and Vonk, Judith M. and Nurnberg, Peter and Altmuller, Janine and Moffatt, M.F. and Wardlaw, Andrew J. and Parker, Stuart G. and Connolly, Martin J. and Koppelman, Gerard H. and Sayers, Ian (2014) Genome-wide protein QTL mapping identifies human plasma kallikrein as a post-translational regulator of serum uPAR levels. FASEB Journal, 28 (2). pp. 923-934. ISSN 0892-6638 http://dx.doi.org/10.1096/fj.13-240879 doi:10.1096/fj.13-240879 doi:10.1096/fj.13-240879 |
| repository_type |
Digital Repository |
| institution_category |
Local University |
| institution |
University of Nottingham Malaysia Campus |
| building |
Nottingham Research Data Repository |
| collection |
Online Access |
| language |
English English English |
| description |
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. |
| format |
Article |
| author |
Portelli, Michael A. 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 |
| spellingShingle |
Portelli, Michael A. 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 Genome-wide protein QTL mapping identifies human plasma kallikrein as a post-translational regulator of serum uPAR levels |
| author_facet |
Portelli, Michael A. 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 |
| author_sort |
Portelli, Michael A. |
| title |
Genome-wide protein QTL mapping identifies human plasma kallikrein as a post-translational regulator of serum uPAR levels |
| title_short |
Genome-wide protein QTL mapping identifies human plasma kallikrein as a post-translational regulator of serum uPAR levels |
| title_full |
Genome-wide protein QTL mapping identifies human plasma kallikrein as a post-translational regulator of serum uPAR levels |
| title_fullStr |
Genome-wide protein QTL mapping identifies human plasma kallikrein as a post-translational regulator of serum uPAR levels |
| title_full_unstemmed |
Genome-wide protein QTL mapping identifies human plasma kallikrein as a post-translational regulator of serum uPAR levels |
| title_sort |
genome-wide protein qtl mapping identifies human plasma kallikrein as a post-translational regulator of serum upar levels |
| publisher |
Federation of American Society of Experimental Biology |
| publishDate |
2014 |
| url |
http://eprints.nottingham.ac.uk/32639/ http://eprints.nottingham.ac.uk/32639/ http://eprints.nottingham.ac.uk/32639/ http://eprints.nottingham.ac.uk/32639/1/Portelli%20FASEB%20J%202014.pdf http://eprints.nottingham.ac.uk/32639/2/Sayers%20FASEB%20SF1.pdf http://eprints.nottingham.ac.uk/32639/3/Sayers%20FASEB%20Supplementary%20Figure%202.pdf |
| first_indexed |
2018-09-06T12:16:22Z |
| last_indexed |
2018-09-06T12:16:22Z |
| _version_ |
1610860391509786624 |