Towards an SI-Traceable Reference Measurement System for Seven Serum Apolipoproteins Using Bottom-Up Quantitative Proteomics: Conceptual Approach Enabled by Cross-Disciplinary/Cross-Sector Collaboration

Clinical Chemistry, vol. 67, pp. 478–489

Abstract

Current dyslipidemia management in patients with atherosclerotic cardiovascular disease (ASCVD) is based on traditional serum lipids. Yet, there is some indication from basic research that serum apolipoproteins A-I, (a), B, C-I, C-II, C-III, and E may give better pathophysiological insight into the root causes of dyslipidemia. To facilitate the future adoption of clinical serum apolipoprotein (apo) profiling for precision medicine, strategies for accurate testing should be developed in advance. Recent discoveries in basic science and translational medicine set the stage for the IFCC Working Group on Apolipoproteins by Mass Spectrometry. Main drivers were the convergence of unmet clinical needs in cardiovascular disease (CVD) patients with enabling technology and metrology. First, the residual cardiovascular risk after accounting for established risk factors demonstrates that the current lipid panel is too limited to capture the full complexity of lipid metabolism in patients. Second, there is a need for accurate test results in highly polymorphic and atherogenic apolipoproteins such as apo(a). Third, sufficient robustness of mass spectrometry technology allows reproducible protein quantification at the molecular level. Fourth, several calibration hierarchies in the revised ISO 17511:2020 guideline facilitate metrological traceability of test results, the highest achievable standard being traceability to SI. This article outlines the conceptual approach aimed at achieving a novel, multiplexed Reference Measurement System (RMS) for seven apolipoproteins based on isotope dilution mass spectrometry and peptide-based calibration. This RMS should enable standardization of existing and emerging apolipoprotein assays to SI, within allowable limits of measurement uncertainty, through a sustainable network of Reference Laboratories.

Authors 17

1. Christa M. Cobbaert corresponding Aachen Department of Clinical Chemistry Laboratory Medicine

   Leiden University Medical Center

   Affiliation as printed

   Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands

2. Harald Althaus
   Affiliation as printed

   Siemens Healthcare Diagnostics Products GmbH, Marburg, Germany

3. Ilijana Begcevic Brkovic

   University Hospital Leipzig · Leipzig University

   Affiliation as printed

   Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig,Germany

   LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany

4. Uta Ceglarek

   University Hospital Leipzig · Leipzig University

   Affiliation as printed

   Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig,Germany

   LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany

5. Stefan Coassin

   Innsbruck Medical University · Universität Innsbruck

   Affiliation as printed

   Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Innsbruck, Austria

6. Vincent Delatour

   Laboratoire National de Métrologie et d'Essais

   Affiliation as printed

   Laboratoire National de Métrologie et d’Essais, Paris, France

7. Liesbet Deprez

   European Commission · Joint Research Center

   Affiliation as printed

   European Commission, Joint Research Centre (JRC), Geel, Belgium

8. Ioannis Dikaios

   European Commission · Joint Research Center

   Affiliation as printed

   European Commission, Joint Research Centre (JRC), Geel, Belgium

9. Julia Dittrich

   University Hospital Leipzig · Leipzig University

   Affiliation as printed

   Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig,Germany

   LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany

10. Andrew N. Hoofnagle

    University of Washington

    Affiliation as printed

    Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA

11. Gerhard Max Kostner

    Medical University of Graz

    Affiliation as printed

    Gottfried Schatz Research Center (for Cell Signaling, Metabolism and Aging), Division of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria

12. Florian Kronenberg

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Innsbruck, Austria

13. Zsusanna Kuklenyik

    Centers for Disease Control and Prevention

    Affiliation as printed

    Division of Laboratory Sciences, Centers for Disease Control and Prevention, Atlanta, GA

14. Urban Prinzing
    Affiliation as printed

    Roche Diagnostics GmbH, Penzberg, Germany

15. Hubert W. Vesper

    Centers for Disease Control and Prevention

    Affiliation as printed

    Division of Laboratory Sciences, Centers for Disease Control and Prevention, Atlanta, GA

16. Ingrid Zegers

    Laboratoire National de Métrologie et d'Essais

    Affiliation as printed

    Laboratoire National de Métrologie et d’Essais, Paris, France

17. L. Renee Ruhaak Aachen Department of Clinical Chemistry Laboratory Medicine

    Leiden University Medical Center

    Affiliation as printed

    Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands