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B-cell Lymphoma 2 (BCL2) Single Nucleotide Polymor ...
B-cell Lymphoma 2 (BCL2) Single Nucleotide Polymorphism (rs17759659) Is Associated With Intracranial Hypertension
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Video Transcription
Hello, everyone. My name is Hanson Dame, and I'm a neurosurgery resident at the University of Pittsburgh. It's a privilege to share with you my research on the association between B-cell lymphoma 2 gene and increased intracranial pressure after severe traumatic brain injury in patients. When patients present to the emergency department with a heterogeneous spectrum of severe traumatic brain injury, over the course of several hours, we begin to observe the onset of various secondary sequelae that worsens prognosis and alters their outcomes. Despite the optimal management that we can provide using the tools that are currently available to us, we've all seen patients who present with similar injuries, such as a GCS who ultimately have ICP variability and experience divergent outcomes in their hospital stay. For this reason, there is growing interest in understanding the role for genetic factors that can alter the onset of secondary injury and contribute to individual variability as well as clinical management. Research from experimental models in rats showed that TPI activates apoptosis in neuronal and glial cells, which is an active and genetically driven pathway that are facilitated by caspase. This is different from brain necrosis that is a result of prior mechanical trauma following brain injury. On the other hand, we know that the BCL2 gene encodes the main pro-survival protein that can protect cells from traumatic and ischemic stimuli in order to allow pericontusional brain tissue to survive despite being injured. Compared to controls without neurotrauma, in patients with TBI, we see that BCL2 expression is upregulated in the CSF as well as the brain tissue. For this reason, we hypothesize that the BCL2 gene, specifically polymorphisms, can be associated with changes in the ICP as well as the development of edema and clinical management following severe TBI. In the current study, we looked at patients with severe TBI who present to a single level one trauma center in the United States. Over the course from years 2000 to 2014, patients with GCS of four to eight between the age of 16 and 80 years old were included. Also included in the study were measurements of at least 24 hours of ICP monitoring in these patients. And blood samples were collected in order to allow for genotyping and further analysis of biomarkers in these patients. In a previous candidate gene study of 17 BCL2 SNPs, findings from the study identified the SNP RS17759659, which is a SNP located on the intron of the BCL2 gene to be a predictor of outcomes after severe TBI. In these patients, possession of the variant allele of the BCL2 SNP had worse functional outcomes at three months post-injury. In our study of 264 patients, the mean age was 39 years old and 78% were male. The mean ICP for the homozygous wild type AA patients were 11 compared to 13 in the heterozygous patients, AG. And lastly, it was 14 for the homozygous variant patients, GG. In addition to increased ICPs, there were also more spikes in the ICP over 20 as well as over 25 for patients who possessed the variant allele of the BCL2 SNP. The table on the left demonstrates the patient and clinical characteristics that are included in the study. In this figure, ICP differences are captured in accordance to BCL2 SNP genetic variability over the course of 120 hours. The graph in green represents homozygous variant patients, while in red reflect the heterozygous BCL2 patients, and in blue were the homozygous wild type BCL2 SNP patients. Multivariant analysis in our study demonstrated that the mean ICP was 2.7 higher in patients who were homozygous variant compared to the homozygous wild type BCL2 patients. There were also a 10% increase in ICP spikes over 20 in the same patients. As the second and third graphs from the right demonstrate, patients with the variant allele were also more likely to have radiographic edema identified during their hospital course as well as require the need for surgical decompression. In conclusion, we know from rat models as well as other experimental studies on BCL2 that expression is upregulated nearly 15-fold in the cortical neurons that are injured but could possibly survive after neurotrauma. Likely due to increased apoptosis, patients with both variant alleles of the BCL2 SNP are also at increased risk of developing cerebral edema. We found that BCL2 RS17759659 polymorphism was associated with elevated mean ICP spikes over 20 in severe TBI patients during the five days post-trauma period. We also found that the presence of both variant alleles can carry greater risk of developing edema as well as a higher need for surgical decompression. Limitations to the present study include the retrospective design of the study and in terms of the future direction, that includes direct quantification of BCL2 expression levels in the CSF samples that were obtained in the study. I want to thank these mentors for their guidance. Thank you very much for your time. Thank you.
Video Summary
The video features Hanson Dame, a neurosurgery resident at the University of Pittsburgh, discussing his research on the association between the B-cell lymphoma 2 (BCL2) gene and increased intracranial pressure (ICP) after severe traumatic brain injury (TBI). The study analyzed patients with severe TBI and found that possession of the variant allele of the BCL2 SNP RS17759659 resulted in worse functional outcomes at three months post-injury. Patients with the variant allele had higher mean ICP, more spikes in ICP over 20, increased risk of radiographic edema, and a higher need for surgical decompression. The study suggests that BCL2 polymorphisms may impact ICP and edema development following severe TBI.
Keywords
Hanson Dame
neurosurgery resident
B-cell lymphoma 2 gene
intracranial pressure
traumatic brain injury
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