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Systems medicine links microbial inflammatory response with glycoprotein-associated mortality risk

Scott C Ritchie, Peter Würtz, Artika P Nath, Gad Abraham, Aki S Havulinna, Antti J Kangas, Pasi Soininen, Kristiina Aalto, Ilkka Seppälä, Emma Raitoharju, Marko Salmi, Mikael Maksimow, Satu Männistö, Mika Kähönen, Markus Juonala, Terho Lehtimäki, Sirpa Jalkanen, Markus Perola, Olli Raitakari, Veikko Salomaa, Mika Ala-Korpela, Johannes Kettunen, Michael Inouye
doi: https://doi.org/10.1101/018655
Scott C Ritchie
1Centre for Systems Genomics, School of Biological Sciences, The University of Melbourne, Parkville 3010, Victoria, Australia
2Department of Pathology, The University of Melbourne, Parkville 3010, Victoria, Australia
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Peter Würtz
3Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland
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Artika P Nath
1Centre for Systems Genomics, School of Biological Sciences, The University of Melbourne, Parkville 3010, Victoria, Australia
2Department of Pathology, The University of Melbourne, Parkville 3010, Victoria, Australia
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Gad Abraham
1Centre for Systems Genomics, School of Biological Sciences, The University of Melbourne, Parkville 3010, Victoria, Australia
2Department of Pathology, The University of Melbourne, Parkville 3010, Victoria, Australia
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Aki S Havulinna
4National Institute for Health and Welfare, Finland
5Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
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Antti J Kangas
3Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland
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Pasi Soininen
3Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland
6NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland
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Kristiina Aalto
7MediCity Research Laboratory, Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland
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Ilkka Seppälä
8Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere, School of Medicine, Tampere, Finland
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Emma Raitoharju
8Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere, School of Medicine, Tampere, Finland
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Marko Salmi
4National Institute for Health and Welfare, Finland
7MediCity Research Laboratory, Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland
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Mikael Maksimow
4National Institute for Health and Welfare, Finland
7MediCity Research Laboratory, Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland
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Satu Männistö
4National Institute for Health and Welfare, Finland
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Mika Kähönen
9Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere
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Markus Juonala
10Department of Medicine, University of Turku and Division of Medicine, Turku University Hospital, Turku, Finland
11Murdoch Childrens Research Institute, Parkville, Victoria, Australia
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Terho Lehtimäki
8Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere, School of Medicine, Tampere, Finland
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Sirpa Jalkanen
7MediCity Research Laboratory, Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland
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Markus Perola
4National Institute for Health and Welfare, Finland
5Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
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Olli Raitakari
12Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
13Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
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Veikko Salomaa
4National Institute for Health and Welfare, Finland
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Mika Ala-Korpela
3Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland
6NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland
14Oulu University Hospital, Oulu, Finland
15Computational Medicine, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom
16Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom
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Johannes Kettunen
3Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland
4National Institute for Health and Welfare, Finland
6NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland
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  • For correspondence: minouye@unimelb.edu.au johannes.kettunen@computationalmedicine.fi
Michael Inouye
1Centre for Systems Genomics, School of Biological Sciences, The University of Melbourne, Parkville 3010, Victoria, Australia
2Department of Pathology, The University of Melbourne, Parkville 3010, Victoria, Australia
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  • For correspondence: minouye@unimelb.edu.au johannes.kettunen@computationalmedicine.fi
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Summary

Integrative analyses of high-throughput omics data have elucidated the aetiology and pathogenesis for complex traits and diseases1–4, and the linking of omics information to electronic health records promises new insights into human health and disease. Recent nuclear magnetic resonance (NMR) spectroscopy biomarker profiling has implicated glycoprotein acetyls (GlycA) as a biomarker for cardiovascular risk5 and all-cause mortality6. To elucidate biological processes contributing to GlycA-associated mortality risk, we leveraged human omics data from three population-based cohorts together with nation-wide Finnish hospital and mortality records. Elevated GlycA was associated with myriad infection-related inflammatory processes. Within individuals, elevated GlycA levels were stable over long time periods, up to a decade, and chronically elevated GlycA was also associated with modest elevation of numerous cytokines. Individuals with elevated GlycA also showed increased expression of a transcriptional sub-network, the Neutrophil Degranulation Module (NDM), suggesting an increased activity of microbe-driven immune response. Subsequent analysis of nation-wide hospitalisation and death records was consistent with a microbial basis for GlycA-associated mortality, with each standard deviation increase in GlycA raising an individual’s future risk of hospitalization and death from non-localized infection by 40% and 136%, respectively. These results show that, beyond its established role in acute-phase response7–9, elevated GlycA is more broadly a biomarker for low-grade chronic inflammation and increased neutrophil activity. Further, increased risk of susceptibility to severe microbial-infection events in healthy individuals suggests this inflammation is a contributor to mortality risk. Taken together, this study demonstrates the power of an integrative approach that combines omics data and health records to delineate the biological processes underlying a newly discovered biomarker, providing a model strategy for future systems medicine studies.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted April 28, 2015.
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Systems medicine links microbial inflammatory response with glycoprotein-associated mortality risk
Scott C Ritchie, Peter Würtz, Artika P Nath, Gad Abraham, Aki S Havulinna, Antti J Kangas, Pasi Soininen, Kristiina Aalto, Ilkka Seppälä, Emma Raitoharju, Marko Salmi, Mikael Maksimow, Satu Männistö, Mika Kähönen, Markus Juonala, Terho Lehtimäki, Sirpa Jalkanen, Markus Perola, Olli Raitakari, Veikko Salomaa, Mika Ala-Korpela, Johannes Kettunen, Michael Inouye
bioRxiv 018655; doi: https://doi.org/10.1101/018655
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Systems medicine links microbial inflammatory response with glycoprotein-associated mortality risk
Scott C Ritchie, Peter Würtz, Artika P Nath, Gad Abraham, Aki S Havulinna, Antti J Kangas, Pasi Soininen, Kristiina Aalto, Ilkka Seppälä, Emma Raitoharju, Marko Salmi, Mikael Maksimow, Satu Männistö, Mika Kähönen, Markus Juonala, Terho Lehtimäki, Sirpa Jalkanen, Markus Perola, Olli Raitakari, Veikko Salomaa, Mika Ala-Korpela, Johannes Kettunen, Michael Inouye
bioRxiv 018655; doi: https://doi.org/10.1101/018655

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