This research project will use DNA sequencing technology to examine how the human genome, the inherited DNA sequence and modifications around DNA (known as the epigenome) impact on cellular functions during the perioperative period.
RELIEF Genomics is a substudy of a large ongoing trial known as RELIEF (REstrictive versus LIbEral Fluid therapy in major abdominal surgery). The RELIEF trial is an investigation into the impact of different intraoperative intravenous fluid therapy on short and long term outcomes in patients having major elective abdominal surgery. More specifically, the trial is assessing the long-term impacts of surgery on health and wellbeing, and includes patients who experience life threatening complications that relate to infection and a marked systemic inflammatory response.
The genomic analysis will investigate the changes in the activity of the genes in circulating inflammatory cells, known as peripheral blood mononucleocytes, in a selection of patients in the RELIEF trial who have either a minimal or marked inflammatory response after surgery. This will reveal the genes whose increased and decreased activity is related to the stress of the surgery. This analysis will provide novel insights into the mechanisms by which altered patterns of gene expression distinguish a marked response from a minimal response.
The investigators will also look at the potential impact of chemical modifications of DNA, known as DNA methylation, on those genes whose activity or inactivity appears to be central to either a minimal or marked inflammatory response. Currently little is known of the role DNA methylation plays in the inflammatory response to surgery. However, it is a form of epigenetic modification that has recently been demonstrated to play an important role in limiting gene expression in experimental models of the cellular immune response to infection.
Dr Chris Bain, Alfred Health, Melbourne
Associate investigators:
Professor Andrew Shaw, Vanderbilt University, USA
Professor Tomas Corcoran, Monash University and University of Western Australia
Dr Bozaoglu Kiymet, Baker IDI Heart and Diabetes Institute, Melbourne
The project was awarded two-year funding of $A139,849 through the ANZCA research grants program for 2015 and 2016.
The study explored how DNA and gene activity influence inflammation after major abdominal surgery. A sub-study of the ANZCA CTN-endorsed RELIEF trial (3,000 high risk patients), RELIEF Genomics investigated whether pre-existing DNA changes (DNA methylation) may affect gene expression, and how the body responds to the stress of surgery.
This study, the first multi-omic analysis of its type in perioperative medical research, provided new insights into why some patients experience excessive inflammation after surgery, leading to complications. The analysis provided the foundations for a model of how postoperative systemic inflammatory dysregulation (PSID) develops, and the potential utility of corticosteroids in modifying the host response. It has been re-presented widely, and re-validated with an analysis of over 2500 RELIEF trial patients investigating the association between inflammation and patient-centred outcomes after major abdominal surgery.
The research also confirmed that increased inflammation (measured by C-reactive protein levels) is linked to poor quality of recovery and persistent disability, and highlighted the importance of inflammation as an independent modifiable risk factor mediating clinical outcomes. The findings support personalised perioperative medicine, utilising biomarkers to individually tailor treatment interventions such as steroids and antibiotics.
The key study outcomes:
- Confirmed that pre-existing DNA changes influence post-operative inflammation, and that DNA patterns of DNA methylation changes occur after surgery. The study did not find a link between pre-existing gene activity and inflammation afterwards
- Identified and validated of a harmful state of PSID, a widespread immune system disturbance affecting hundreds of genes
- Found that certain genes predict PSID, and poor recovery outcomes, well before symptoms appeared.
- Explained why immune-suppressing treatments like steroids may not work alone in preventing complications.
Toner AJ, Corcoran TB, Vlaskovsky PS, Nierich AP, Bain CR, Dieleman JM. Inflammation risk before cardiac surgery and the treatment effect of intraoperative dexamethasone. Anaesthesia and Intensive Care (2024); 52: 28–36. doi:0.1177/0310057x231195098.