Research
Urinary Proteomic Biomarkers in Coronary Artery Disease*

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Urinary proteomics is emerging as a powerful non-invasive tool for diagnosis and monitoring of variety of human diseases. We tested whether signatures of urinary polypeptides can contribute to the existing biomarkers for coronary artery disease (CAD). We examined a total of 359 urine samples from 88 patients with severe CAD and 282 controls. Spot urine was analyzed using capillary electrophoresis on-line coupled to ESI-TOF-MS enabling characterization of more than 1000 polypeptides per sample. In a first step a “training set” for biomarker definition was created. Multiple biomarker patterns clearly distinguished healthy controls from CAD patients, and we extracted 15 peptides that define a characteristic CAD signature panel. In a second step, the ability of the CAD-specific panel to predict the presence of CAD was evaluated in a blinded study using a “test set.” The signature panel showed sensitivity of 98% (95% confidence interval, 88.7–99.6) and 83% specificity (95% confidence interval, 51.6–97.4). Furthermore the peptide pattern significantly changed toward the healthy signature correlating with the level of physical activity after therapeutic intervention. Our results show that urinary proteomics can identify CAD patients with high confidence and might also play a role in monitoring the effects of therapeutic interventions. The workflow is amenable to clinical routine testing suggesting that non-invasive proteomics analysis can become a valuable addition to other biomarkers used in cardiovascular risk assessment.

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Published, MCP Papers in Press, October 19, 2007, DOI 10.1074/mcp.M700394-MCP200

*

This work was supported in part by the British Heart Foundation Chair and Programme Grant BHF PG/02/128, Wellcome Trust Cardiovascular Functional Genomics Initiative 066780/2/012, and European Union InGenious HyperCare Grant LSHM-CT-2006-037093 (to A. F. D. and H. M.); by the Joint Infrastructure Fund funding for the Sir Henry Wellcome Functional Genomics Facility; and by the Biotechnology and Biological Sciences Research Council and Engineering and Physical Sciences Research Council Radical Solutions for Researching the Proteome (RASOR) grant. H. Mischak is founder and co-owner of Mosaiques Diagnostics, which developed the CE-MS technology and the MosaiquesVisu software. E. Schiffer and P. Zürbig are employees of Mosaiques Diagnostics. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.mcponline.org) contains supplemental material.

b

Both authors contributed equally to this work.

c

Supported by Swiss National Science Foundation Grant PBBSB-105860 and the Lichtenstein-Stiftung, Basel, Switzerland. Present address: Medical Outpatient Dept., University Hospital, CH-8091 Zurich, Switzerland.

f

Supported by a National Institutes of Health predoctoral fellowship (Biotechnology Training Program Grant NIH 5T32GM08349).

l

Supported by a personal fellowship from the Deutsche Forschungsgemeinschaft (Grant DE 826/1-1).