Genetic Factors May Explain Divergent Outcomes in Severe TBI

Nancy A. Melville

July 07, 2020

A variation of the gene that encodes the B-cell lymphoma 2 (Bcl-2) protein increases the risk for intracranial pressure (ICP), cerebral edema, and need for surgical intervention after traumatic brain injury (TBI), new research suggests.

A novel prospective study of more than 200 patients with severe TBI showed the presence of the Bcl-2 rs17759659 polymorphism was significantly associated with increased ICP.

"Given the heterogeneity of TBI and complexity of neurocritical care, there are no other known clinical investigations of genetic alleles to be associated with ICP changes in TBI patients while controlling for various patient and injury characteristics," lead author Hansen Deng, MD, Department of Neurological Surgery, University of Pittsburgh Medical Center, Pennsylvania, told Medscape Medical News.

"These findings may provide new insights into the role for genetic factors to account for variability of secondary sequelae after severe TBI," Deng added.

The results were presented at the virtual American Association of Neurological Surgeons (AANS) 2020 Annual Meeting and were published online June 9 in the Journal of Neurotrauma.

Divergent Outcomes

It is often challenging to understand the causes behind significant differences in outcomes that can occur from similar TBIs, Deng noted.

"Despite the optimal management that we can provide [in TBI] with the tools that are available to all of us, we have all seen patients who present with similar injuries who ultimately have ICP variability and divergent outcomes in their hospital stay," he said.

Regarding the potential role of genetic factors, preclinical studies have pointed to the potential of one factor in particular. Bcl-2 is an antiapoptotic protein and a key modulator of programmed cell death.

Previous research has shown Bcl-2 expression to be upregulated nearly 15-fold in cortical neurons that are injured but that could survive after neurotrauma, said Deng.

"We know that Bcl-2 encodes a prosurvival protein with a neuroprotective role that can protect cells from traumatic and ischemic stimuli to allow pericontusional brain tissue to survive despite being injured. We see it is upregulated in pericontusional brain and in cerebrospinal fluid in TBI, representing a potential diagnostic and therapeutic target," he noted.

To determine whether the BCL2 gene is associated with changes in ICP and can potentially play a role in clinical management following TBI, the investigators evaluated prospective data on 264 patients with severe TBI at the University of Pittsburgh Brain Trauma Research Center from 2000 to 2014.

All had a Glasgow Coma Scale score of 4 to 8 and had undergone at least 24 hours of intracranial pressure monitoring.

The mean age of the patients was 39 years; 78% were men. The most common mechanisms of injury were motor vehicle accidents (44.7%) and falls (22.7%).

The BCL2 polymorphism rs1759659 was grouped by major allele (A) and minor allele (G). In addition, 39.8% of the participants were homozygous wild-type (AA), 48.1% were heterozygous (AG), and 12.1 had the homozygous variant genotype (GG).

Genotype Differences

Results showed significant differences in mean levels of ICP in the 5 days post trauma according to genotype. For participants with AA genotype, the mean ICP was 11.4 ± 4.3 mmHg. For those with heterozygous genotype, the mean ICP was 12.8 ± 6.3 mmHg. The mean ICP was highest, at 14.3 ± 6.6 mmHg (P = .023), for those with GG genotype.

Among patients carrying the variant allele of rs17759659, there were significantly more episodes of ICP spikes higher than 20 mmHg (P = .017) and spikes higher than 25 mmHg (P = .048) in comparison with patients who did not have the allele.

After multivariate adjustment controlling for patient and injury parameters, the presence of the rs17759659 variant allele was significantly associated with increased ICP (P = .005).

In addition, those with the GG genotype had a nearly four times' increased risk for surgical decompression compared with the patients with the AA genotype (odds ratio [OR], 3.7; P = .004). The genotype was also linked to significantly higher ICP (P = .015) and edema (OR, 2.5; P = .04).

"In the first investigation to our knowledge that involves a large cohort of severe TBI patients at the University of Pittsburgh Brain Trauma Research Center, we find that the Bcl-2 rs17759659 polymorphism is associated with elevated ICP in the acute period post trauma," Deng said.

"Ultimately, this can contribute to the onset of secondary injury resulting in edema and the need for craniectomy," he added.

Deng noted that it is easy to screen for these alleles and that "targeted screening and genotype-based therapies may further improve risk stratification and outcome following severe TBI."

New Insight Into an Overlooked Issue

Commenting on the study for Medscape Medical News, Uzma Samadani, MD, PhD, neurosurgeon at the Minneapolis VA Medical Center and Centracare, Minneapolis, Minnesota, agreed with the investigators that the findings shed important light on an often overlooked issue.

"This is a well-conducted and impactful study and an important step forward for treatment of brain injury," said Samadani, who was not involved with the research.

"Understanding genetics of susceptibility is absolutely critical to improving outcomes after brain injury, and the current standard of care provided at most hospitals does not account for differential genetics," she added.

She noted several study limitations, including that ICP, cerebral edema, and the need for craniectomy are all short-term proxy measures of outcome, rather than functional outcome measures, such as the ability to live without deficit.

"It would be ideal to show correlation with both objective short-term proxy measures and long-term functional outcome," she said. She noted that future studies, such as those proposed by the researchers, may show such correlations.

Another limitation was that 90% of the participants were white, and 78% were men.

"Women are more likely to suffer chronic effects of neurotrauma, and people of color are less likely to have resources enabling them to recover fully," Samadani noted.

"Generalizability of this study to populations other than white men would need to be shown for it to be truly impactful for all," she said.

The study was partly funded by the National Institutes of Health. Deng has reported no relevant financial relationships. Samadani has relationships with Abbott Diagnostic Laboratories, Integra Corp, Medtronic Corp, the Minnesota Brain Injury Alliance, the National Football League, Oculogica Inc, OssDsign, and others.

American Association of Neurological Surgeons (AANS) 2020 Annual Meeting: Abstract 414.

J Neurotrauma. Published online June 9, 2020. Abstract

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