OSTEO18, a novel urinary proteomic signature, associated with osteoporosis in heart transplant recipients
Yu-Ling Yu,
Qi-Fang Huang,
De-Wei An,
Julia Raad,
Dries S. Martens,
Agnieszka Latosinska,
Katarzyna Stolarz-Skrzypek,
Johan Van Cleemput,
Ying-Qing Feng,
Harald Mischak,
Karel Allegaert,
Peter Verhamme,
Stefan Janssens,
Tim S. Nawrot,
Jan A. Staessen
Affiliations
Yu-Ling Yu
The Research Unit Environment and Health, KU Leuven Department of Public Health and Primary Care, University of Leuven, Leuven, Belgium; Non-Profit Research Association Alliance for the Promotion of Preventive Medicine, Mechelen, Belgium
Qi-Fang Huang
Department of Cardiovascular Medicine, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
De-Wei An
The Research Unit Environment and Health, KU Leuven Department of Public Health and Primary Care, University of Leuven, Leuven, Belgium; Non-Profit Research Association Alliance for the Promotion of Preventive Medicine, Mechelen, Belgium; Department of Cardiovascular Medicine, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
Julia Raad
Mosaiques Diagnostics GmbH, Hannover, Germany
Dries S. Martens
Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium
Agnieszka Latosinska
Mosaiques Diagnostics GmbH, Hannover, Germany
Katarzyna Stolarz-Skrzypek
First Department of Cardiology, Interventional Electrocardiology and Hypertension, Jagiellonian University, Kraków, Poland
Johan Van Cleemput
Division of Cardiology, University Hospitals Leuven, Leuven, Belgium
Ying-Qing Feng
Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
Harald Mischak
Mosaiques Diagnostics GmbH, Hannover, Germany
Karel Allegaert
Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium; KU Leuven Department of Development and Regeneration, KU Leuven, Leuven, Belgium; Department of Hospital Pharmacy, Erasmus Medical Center, Rotterdam, the Netherlands
Peter Verhamme
Center for Molecular and Vascular Biology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium
Stefan Janssens
Division of Cardiology, University Hospitals Leuven, Leuven, Belgium
Tim S. Nawrot
The Research Unit Environment and Health, KU Leuven Department of Public Health and Primary Care, University of Leuven, Leuven, Belgium; Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium
Jan A. Staessen
Non-Profit Research Association Alliance for the Promotion of Preventive Medicine, Mechelen, Belgium; The Biomedical Sciences Group, Faculty of Medicine, University of Leuven, Leuven, Belgium; Corresponding author. Alliance for the Promotion of Preventive Medicine, Leopoldstraat 59, BE-2800 Mechelen, Belgium.
Background: Immunosuppressive treatment in heart transplant (HTx) recipient causes osteoporosis. The urinary proteomic profile (UPP) includes peptide fragments derived from the bone extracellular matrix. Study aims were to develop and validate a multidimensional UPP biomarker for osteoporosis in HTx patients from single sequenced urinary peptides identifying the parent proteins. Methods: A single-center HTx cohort was analyzed. Urine samples were measured by capillary electrophoresis coupled with mass spectrometry. Cases with osteoporosis and matching controls were randomly selected from all available 389 patients. In derivation case-control dataset, 1576 sequenced peptides detectable in ≥30 % of patients. Applying statistical analysis on these, an 18-peptide multidimensional osteoporosis UPP biomarker (OSTEO18) was generated by support vector modeling. The 2 replication datasets included 118 and 94 patients. For further validation, the whole cohort was analyzed. Statistical methods included logistic regression and receiver operating characteristic curve (ROC) analysis. Results: In derivation dataset, the AUC, sensitivity and specificity of OSTEO18 were 0.83 (95 % CI: 0.76–0.90), 74.3 % and 87.1 %, respectively. In replication datasets, results were confirmatory. In the whole cohort (154 osteoporotic patients [39.6 %]), the ORs for osteoporosis increased (p < 0.0001) across OSTEO18 quartiles from 0.39 (95 % CI: 0.25–0.61) to 3.14 (2.08–4.75). With full adjustment for known osteoporosis risk factors, OSTEO18 improved AUC from 0.708 to 0.786 (p = 0.0003) for OSTEO18 categorized (optimized threshold: 0.095) and to 0.784 (p = 0.0004) for OSTEO18 as continuously distributed classifier. Conclusion: OSTEO18 is a clinically meaningful novel biomarker indicative of osteoporosis in HTx recipients and is being certified as in-vitro diagnostic.
