RT Journal Article
SR Electronic
T1 Systems medicine links microbial inflammatory response with glycoprotein-associated mortality risk
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 018655
DO 10.1101/018655
A1 Scott C Ritchie
A1 Peter Würtz
A1 Artika P Nath
A1 Gad Abraham
A1 Aki S Havulinna
A1 Antti J Kangas
A1 Pasi Soininen
A1 Kristiina Aalto
A1 Ilkka Seppälä
A1 Emma Raitoharju
A1 Marko Salmi
A1 Mikael Maksimow
A1 Satu Männistö
A1 Mika Kähönen
A1 Markus Juonala
A1 Terho Lehtimäki
A1 Sirpa Jalkanen
A1 Markus Perola
A1 Olli Raitakari
A1 Veikko Salomaa
A1 Mika Ala-Korpela
A1 Johannes Kettunen
A1 Michael Inouye
YR 2015
UL http://biorxiv.org/content/early/2015/04/28/018655.abstract
AB 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.