Injuries, Trauma
Conditions
Keywords
Epigenetics, DNA methylation, Trauma
Brief summary
The objective of this study is to investigate potential early alterations in the DNA methylation profile after severe trauma and to investigate if the early marks persist.
Detailed description
Background: Severe trauma is an extreme physical exposure, which may have significant consequences for the patient. In addition to anatomical injury and hemodynamic compromise, severe trauma causes an immense and rapid systemic immune reaction. At the genomic level, trauma has been found to significantly increase gene expression in circulating leukocytes, and preliminary data is also emerging that trauma may even cause epigenetic (DNA methylation) alterations. Epigenetics, including DNA methylation, have been suggested as a mediator of genetic risk and to play a significant role in subsequent non-traumatic disease. Within the field of trauma DNA methylation has only been sparsely studied, but a few studies of traumatized animals have suggested that DNA methylation alterations may occur in relation to trauma. Even though DNA methylation is highly dynamic, some marks have been found to be stable over time, and thus may have long-term consequences. An increasing understanding of the role of epigenetics in disease development and response may pave the way for new treatment targets and modalities for multiple diseases including trauma. Research question: Does trauma induce immediate (\<4 hours) and persistent (30 days post-trauma) changes in the epigenome of peripheral blood cells, and do epigenetic changes correlate with patient recovery? Objectives: To identify potential early alterations in the DNA methylation profile after severe trauma AND to investigate if the early marks persist. Study design: A prospective, observational, cohort study of trauma patients admitted to RH's trauma center. The trauma cohort will be compared to a cohort of patients admitted for elective orthopedic surgery in terms of DNA methylation profile in blood cells pre-trauma/surgery, immediately post-trauma/surgery, and 30-45 days post-trauma/surgery. DNA methylation profiles will be assessed by array technique using Illumina's MethylationEPIC Bead-Chip. Primary outcome: Immediate (\<4 hours) post-trauma DNA methylation profile in blood cells. Secondary outcomes: Pre-trauma/surgery DNA methylation profile, change in DNA methylation from pre-trauma/surgery to immediately and 30 days post-trauma/surgery, occurrence of organ dysfunction, sepsis, septic shock, 30-day mortality, ICU admission \> 24 hours, ICU length of stay (LOS), hospital LOS.
Interventions
DIAGNOSTIC_TESTBlood samples for DNA methylation analysis
DNA from blood samples will be isolated and analyzed for genome-wide DNA methylation patterns using the Infinium HumanMethylationEPIC BeadChip (Illumina, San Diego, CA, USA).
Sponsors
Rigshospitalet, Denmark
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Age 18-65 years. * Trauma patients: Admitted to Rigshospitalet's trauma center generating a trauma team activation. * Surgical controls: Admitted for elective surgery (non-traumatic cause) at the orthopedics department AND * Only one surgical procedure planned from study day 0 to study day 45. * Expected procedure length of at least 60 minutes.
Exclusion criteria
* Not able to obtain informed consent and not possible to obtain consent from a next-of-kin. * Trauma patients: * Secondary transfers. * Pre-hospital blood transfusion OR blood transfusion in the trauma center before the first blood sample is obtained. * First blood sample taken later than 4 hours after the trauma. * Patients in cardiac arrest before/after hospital admission. * Additional traumatic exposure requiring hospital admission between the collection of the primary blood sample and the follow-up blood sample (will cause exclusion from follow-up blood sample). * Surgery not related to the trauma between the collection of the primary blood sample and the follow-up blood sample (will cause exclusion from follow-up blood sample). * Surgical controls: * Surgical procedures due to cancer or fractures. * Traumatic exposure requiring hospital admission between the collection of the primary blood sample and the follow-up blood sample (will cause exclusion from follow-up blood sample). * Additional, unplanned surgery between the collection of the primary blood sample and the follow-up blood sample (will cause exclusion from follow-up blood sample). * First post-operative blood sample taken later than 4 hours after surgical end time.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Immediate DNA methylation profile | Day of trauma/surgery | Immediate (\< 4 hours) post-trauma DNA methylation profile in blood cells compared to the pre-surgery (baseline) and immediate post-surgery (\< 4 hours) DNA methylation profile in blood cells. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Stability of DNA methylation profile | 30-45 days after trauma/surgery | Persistence of the DNA methylation profile in blood cells 30-45 days after the trauma compared to surgical patients. |
| Change in DNA methylation profile; pre-trauma/-surgery to post-trauma/-surgery | Day of trauma/surgery | Change in DNA methylation profile in blood cells from pre-trauma (if possible to obtain) to immediately post-trauma compared to surgical patients. |
| Change in DNA methylation profile; immediately post-trauma/-surgery to one month post-trauma/-surgery | 0 to 30-45 days after trauma/surgery | Change in DNA methylation profile in blood cells from immediately post-trauma to 30-45 days post-trauma compared to surgical patients. |
| Pre-trauma/-surgery DNA methylation profile | Pre-trauma/surgery | Pre-trauma (if possible to obtain from an existing biobank) DNA methylation profile in blood cells compared to pre-surgery. |
| Organ dysfunction | Day 30 after trauma/surgery | Occurrence of organ dysfunction (increase of ≥ 2 in SOFA-score) |
| Sepsis/septic shock | Day 30 after trauma/surgery | Occurrence of sepsis or septic shock |
| DNA methylation changes in relation to injury severity | Day 0-45 after trauma/surgery | Association of DNA methylation changes with injury severity. This will be done by comparing the DNA methylation profiles among patient with an injury severity score (ISS) \< 15 and patients with an ISS \> 15. |
Countries
Denmark
Outcome results
None listed