The pharmacogenomics of Severe Traumatic Brain Injury

Sm, Adams; Conley, Yvette P.; Wagner, Amy K.; Jha, Ruchira M.; Clark, Robert S. B.; Poloyac, Samuel M.; Kochanek, Patrick M.; Empey, Philip E.

doi:10.2217/pgs-2017-0073

Cited by 15 publications

(10 citation statements)

References 95 publications

(120 reference statements)

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“…Further, recovery after brain injury is associated with a complex interaction among cellular, host, treatment, and environmental factors (Adams et al, 2017; Kenzie et al, 2017, 2018). Thus, to move toward a true precision medicine approach, an improved understanding how genetic and other biologic factors interact with other host, injury-related, treatment, and environmental factors to influence recovery will be critical.…”

Section: Discussionmentioning

confidence: 99%

Genetic Influences on Behavioral Outcomes After Childhood TBI: A Novel Systems Biology-Informed Approach

et al. 2019

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Objectives: To test whether genetic associations with behavioral outcomes after early childhood traumatic brain injury (TBI) are enriched for biologic pathways underpinning neurocognitive and behavioral networks. Design: Cross-sectional evaluation of the association of genetic factors with early (~ 6 months) and long-term (~ 7 years) post-TBI behavioral outcomes. We combined systems biology and genetic association testing methodologies to identify biologic pathways associated with neurocognitive and behavior outcomes after TBI. We then evaluated whether genes/single nucleotide polymorphism (SNPs) associated with these biologic pathways were more likely to demonstrate a relationship (i.e., enrichment) with short and long-term behavioral outcomes after early childhood TBI compared to genes/SNPs not associated with these biologic pathways. Setting: Outpatient research setting. Participants: 140 children, ages 3–6:11 years at time of injury, admitted for a TBI or orthopedic injury (OI). Interventions: Not Applicable. Main Outcome Measures: Child behavior checklist total problems T score. Results: Systems biology methodology identified neuronal systems and neurotransmitter signaling (Glutamate receptor, dopamine, serotonin, and calcium signaling), inflammatory response, cell death, immune systems, and brain development as important biologic pathways to neurocognitive and behavioral outcomes after TBI. At 6 months post injury, the group (TBI versus OI) by polymorphism interaction was significant when the aggregate signal from the highest ranked 40% of case gene associations was compared to the control set of genes. At ~ 7 years post injury, the selected polymorphisms had a significant main effect after controlling for injury type when the aggregate signal from the highest ranked 10% of the case genes were compared to the control set of genes Conclusions: Findings demonstrate the promise of applying a genomics approach, informed by systems biology, to understanding behavioral recovery after pediatric TBI. A mixture of biologic pathways and processes are associated with behavioral recovery, specifically genes associated with cell death, inflammatory response, neurotransmitter signaling, and brain development. These results provide insights into the complex biology of TBI recovery.

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Section: Discussionmentioning

confidence: 99%

Genetic Influences on Behavioral Outcomes After Childhood TBI: A Novel Systems Biology-Informed Approach

et al. 2019

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“…Application of PGx testing is well established and used in other fields of medicine [[1], [2], [3], [4]]. There is a paucity of information on the application of this data for management of trauma patients [5,6,8]. This case report, one of the first in trauma care, is part of our broader study to incorporate PGx data to select the best pharmacotherapy for trauma patients, a group, we submit, is particularly well suited to benefit from use of this tool.…”

Section: Discussionmentioning

confidence: 99%

Application of pharmacogenomics for trauma and critical care patients: A case report

McFadgen

Jensen

Mahajan

2019

Trauma Case Reports

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BackgroundPharmacogenomics is increasingly becoming a valuable tool for improving health outcomes, reducing health care costs and avoiding adverse drug reactions. While application of pharmacogenomics is quite common in oncology and cardiology, routine use of this technology is rare in certain other fields including Trauma and Critical Care Surgery. We are testing feasibility of applying pharmacogenomic testing to improve therapeutic outcomes of trauma and acute care patients at MercyOne Medical Center in Des Moines, IA.MethodsTrauma patients admitted to the hospital with projected stay of >5 days, or with admission extended due to failed multiple trials of medication volunteered to participate in this IRB-approved study. Effectiveness of medical therapy was evaluated using standard pain scores recorded prior to admission of any pain medication to conscious and competent patients. Pharmacogenomic results were obtained from commercial providers within 3–5 days and used to alter medical therapy as needed.ResultsAn 18-year-old African American male, admitted for gunshot wounds to the neck, exhibited an ASIA A spinal cord injury, with no sensation or movement of his extremities, persistent nausea with emesis and a history of depression. He also developed gastritis with hematemesis. In addition to all standard trauma procedures, he received standard doses of tramadol, oxycodone or hydrocodone, ondansetron, citalopram, and intravenous protonix daily. He reported no pain relief. The patient's pharmacogenomic analysis revealed his ultrarapid and rapid genotype for CYP2D6 and CYP2C19 respectively, allowing us to choose dilaudid resulting in immediate improvement of his pain scores. Additionally, using metoclopramide, duloxetine and famotidine led to immediate improvement or complete resolution of symptoms.ConclusionPharmacogenomics testing is a useful tool for selecting appropriate pain management of trauma patients with expected hospital stay ≥5 days. Additionally, standard pharmacogenomic panels allow tailoring medical therapy to common conditions associated with traumatic injury.

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“…For example, intrinsic factors like age and sex, which play a large role in most conditions, must be considered. Also, genetic variation as well as gene*environment interactions and epigenetic considerations may affect an individual's response to treatment as well as risk for TBIrelated complications (Adams et al, 2017).…”

Section: Tbi Rehabilomics: Defining and Characterizing The Humoral Trmentioning

confidence: 99%

TBI Rehabilomics Research: Conceptualizing a humoral triad for designing effective rehabilitation interventions

Wagner

Kumar

2019

Neuropharmacology

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Most areas of medicine use biomarkers in some capacity to aid in understanding how personal biology informs clinical care. This article draws upon the Rehabilomics research model as a translational framework for programs of precision rehabilitation and intervention research focused on linking personal biology to treatment response using biopsychosocial constructs that broadly represent function and that can be applied to many clinical populations with disability. The summary applies the Rehabilomics research framework to the population with traumatic brain injury (TBI) and emphasizes a broad vision for biomarker inclusion, beyond typical brain-derived biomarkers, to capture and/or reflect important neurological and non-neurological pathology associated with TBI as a chronic condition. Humoral signaling molecules are explored as important signaling and regulatory drivers of these chronic conditions and their impact on function. Importantly, secondary injury cascades involved in the humoral triad are influenced by the systemic response to TBI and the development of non-neurological organ dysfunction (NNOD). Biomarkers have been successfully leveraged in other medical fields to inform pre-randomization patient selection for clinical trials, however, this practice largely has not been utilized in TBI research. As such, the applicability of the Rehabilomics research model to contemporary clinical trials and comparative effectiveness research designs for neurological and rehabilitation populations is emphasized. Potential points of intervention to modify inflammation, hormonal, or neurotrophic support through rehabilitation interventions are discussed.

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The pharmacogenomics of Severe Traumatic Brain Injury

Cited by 15 publications

References 95 publications

Genetic Influences on Behavioral Outcomes After Childhood TBI: A Novel Systems Biology-Informed Approach

Genetic Influences on Behavioral Outcomes After Childhood TBI: A Novel Systems Biology-Informed Approach

Application of pharmacogenomics for trauma and critical care patients: A case report

TBI Rehabilomics Research: Conceptualizing a humoral triad for designing effective rehabilitation interventions

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