A new paper from the Inouye lab and collaborators is out in Cell Systems:
Scott C. Ritchie, Peter Würtz, Artika P. Nath, Gad Abraham, Aki S. Havulinna, Liam G. Fearnley, Antti-Pekka Sarin, Antti J. Kangas, Pasi Soininen, Kristiina Aalto, Ilkka Seppälä, Emma Raitoharju, Marko Salmi, Mikael Maksimow, Satu Männistö, Mika Kähönen, Markus Juonala, Samuli Ripatti, Terho Lehtimäki, Sirpa Jalkanen, Markus Perola, Olli Raitakari, Veikko Salomaa, Mika Ala-Korpela, Johannes Kettunen*, Michael Inouye*, Cell Systems 2015. 1:1-9. doi:10.1016/j.cels.2015.09.007
GlycA is a composite biomarker that measures the total abundance of several inflammatory proteins within the blood stream, which has been shown to be predictive of 5-year risk of death, as well as 14-year cardiovascular disease risk, and 17-year type II diabetes risk.
In this study we examined the GlycA levels of more than 10,000 healthy adults in order to identify biological processes that lead to high GlycA in otherwise healthy adults. This is important for understanding why these individuals are at higher risk from not only premature death, but also other chronic illnesses like cardiovascular disease and type II diabetes, and will form a crucial foundation for future studies seeking to short-circuit this risk.
From literature, we knew that GlycA levels normally elevate and then return to normal as part of the ‘acute-phase’ response to external insults, like infections and physical injury. So the first thing we tested was whether there was a relationship between high GlycA and inflammation in healthy individuals. Our analyses showed that high GlycA associated with moderate increase of up to 29 cytokines—signalling molecules that play a role in inflammation and immune response—and the adults with high GlycA could have high GlycA up to a decade in the future. This suggests that high GlycA likely reflects a state of mild chronic inflammation in these adults, who were otherwise healthy.
Next, we inferred transcriptional networks of coexpressed genes from the blood of these individuals as a way of identifying biological processes associated with high GlycA in a “hypothesis-free” way. To make sure that the associated networks where not false positives we tested whether they replicated in an independent dataset.
The lead author on the paper, Scott Ritchie, a Ph.D. student in the Inouye Lab, had been working on a new method to quantify network replication in a statistically robust way, so we applied it to the networks we found associated with high GlycA. The tool, NetRep, is now publically available as an R package at https://github.com/InouyeLab/NetRep and a preprint for the method is now online at BiorXiv: http://www.biorxiv.org/content/early/2015/10/21/029553.
Although we found multiple networks associated with high GlycA, only one replicated in the independent dataset. In-depth analysis of its gene content revealed that this network indicated that individuals with high GlycA had abnormally high neutrophil function. We also found that these individuals had abnormally high white blood cell counts as well.
This lead us to the hypothesis that these individuals might have an overactive immune response, and therefore be at a higher risk of death and hospitalization from severe infections if and when they occur.
To test this hypothesis our colleague at the University of Oulu, Dr. Peter Würtz, analysed electronic hospital discharge and cause-of-death records for 7,599 adults randomly recruited from the working age population in Finland.
They found healthy adults whose GlycA levels were higher than the population average were at more than five times as likely to die from a non-localized bacterial infection, primarily septicemia, and more than 1.5 times as likely to die from a respiratory infection up to 14-years in the future.
Additional studies are needed to uncover the causal mechanisms linking GlycA, inflammation, and premature death before it can become clinically useful. In Australia, standard blood tests do not include GlycA levels, and even if one were to get their GlycA levels measured, it is not known how to reduce that risk if GlycA is abnormally high.
Ultimately, for interventions to reduce risk, one would need to know whether high GlycA is the result of a chronic, low-level microbial infection or an aberrant reaction of the body’s own inflammatory response, or a combination.
More details about the study can be found in the paper at http://dx.doi.org/10.1016/j.cels.2015.09.007