Trauma regulates genes that predict survival

Genome Advance of the Month

Trauma regulates genes that predict survival

September 2011

By Jonathan Gitlin, Ph.D.
Science Policy Analyst

Examining a patient's genome seems logical when dealing with, for example, an inherited disease, or a cancer. This month's Genome Advance takes a genomics approach to one of the world's leading causes of death, in this case one that we don't usually associate with genomics — trauma. Traumatic injuries — car accidents, falls, blows, etc. — are the leading cause of death for Americans under the age of 44. Critically injured patients often succumb to multiple organ failure, usually after dealing with infections and the resulting inflammatory response.

A study, published in the journal PLoS Medicine, was conducted by the Inflammation and the Host Response to Injury Large-Scale Collaborative Research Program, and involved a prospective clinical trial that followed 168 severe blunt-force trauma patients at the Massachusetts General Hospital in Boston and leading trauma centers in the United States. The study created "within-patient" gene expression profiles for each patient over a 28-day period following the injury. Blood samples were taken at regular intervals, and these were assayed to see which genes and pathways were being turned on or off over time.

Using the Marshall Multiple organ dysfunction score (which is used in critical care medicine to describe complex clinical outcomes), investigators divided the patients into five subgroups, from those who recovered quickly to those who succumbed to multiple organ failure. With the patients grouped by outcome, the investigators then looked for common patterns of gene expression that might be related to how those patients fared in the ICU.

Several gene pathways did show different patterns of regulation over time between the different groups. These gene pathways are involved in controlling immune function, and in mounting the inflammatory response to infection. Multiple organ failure usually results after the patient contracts an infection that then leads to sepsis, where a localized infection becomes systemic. One such gene pathway, the Toll-like receptor (TLR) signaling pathway, was the subject of this year's Nobel Prize in Medicine.

In particular, two gene pathways stood out following the analysis. Patients who showed an early activation of an important immunological pathway called MHC-II (major histocompatibility complex class II) had the best clinical outcomes. Conversely, in the subgroup of patients with the worst clinical outcome, this gene pathway is rapidly shut down.

Likewise, those patients that recovered quickly had an early suppression of another pathway called p38 MAPK, which was activated in the subgroup with the worst clinical outcome. Both of these pathways, as well as the other ones that showed significant alterations in their level of activity, demonstrated that differences between the subgroups were greatest between 40 and 80 hours after injury, suggesting the possibility of using them as biomarkers in critical care medicine to identify at-risk individuals. It may even prove possible to manage these inflammatory pathways with medications before the patient suffers multi-organ system failure.

Although we're still several years away from using a technique like this clinically, this study is one of the first to show that taking a genome-wide approach (instead of just looking at individual genes) might pay dividends even in fields of medicine where such an approach may not seem obvious.

The study, called Dissecting inflammatory complications in critically injured patients by within-patient gene expression changes: a longitudinal clinical genomics study. Desai KH, Tan CS, Leek JT, Maier RV, Tompkins RG, Storey JD; and the Inflammation and the Host Response to Injury Large-Scale Collaborative Research Program. PLoS Medicine, Sep;8(9):e1001093. 2011. [PubMed], was funded by the National Institute of General Medical Sciences, one of the 27 institutes and centers at the National Institutes of Health.