Genetic Variation in the TP53 Gene and Patient Outcomes Following Severe Traumatic Brain Injury.
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ABSTRACT:
SUBMITTER: Mellett K
PROVIDER: S-EPMC7492776 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Diagnostic and prognostic biomarkers of traumatic brain injury (TBI) are actively being pursued; potential candidates include glial fibrillary acid protein (GFAP), S100 calcium-binding protein B (S100B), and ubiquitin C-terminal hydrolase L1 (UCHL1), two of which the United States Food and Drug Administration (FDA) recently approved for marketing of blood tests for adult concussion. The relationship between biomarker-encoding genes and TBI outcomes remains unknown. This pilot study explores variation in 18 single nucleotide polymorphisms (SNPs) in biomarker-encoding genes as predictors of neurological outcome in a population of adults with severe TBI. Participants (n = 305) were assessed using the Glasgow Outcome Scale (GOS) at 3, 6, 12, and 24 months post-injury. Multivariate logistical regression was used to calculate the odds ratio (OR) and determine the odds of having a lower score on the GOS ( = 1-2 vs. 3-5) based on variant allele presence, while controlling for confounders. Possession of the variant allele of one S100B SNP (rs1051169) was associated with higher scores on the GOS at 3 months (OR = 0.39; p = 0.04), 6 months (OR = 0.34; p = 0.02), 12 months (OR = 0.32; p = 0.02), and 24 months (OR = 0.30; p = 0.02) post-severe TBI. The relationship among these polymorphisms, protein levels, and biomarker utility, merits examination. These findings represent a novel contribution to the evidence that can inform future studies aimed at enhancing interpretation of biomarker data, identifying novel biomarkers, and ultimately harnessing this information to improve clinical outcomes and personalize care.
| S-EPMC6238603 | biostudies-literature
Project description:INTRODUCTION:Traumatic brain injury (TBI) frequently results in impaired cognition, a function that can be modulated by monoaminergic signaling. Genetic variation among monoaminergic genes may affect post-TBI cognitive performance. The vesicular monoamine transporter-2 (VMAT2) gene may be a novel source of genetic variation important for cognitive outcomes post-TBI given VMAT2's role in monoaminergic neurotransmission. OBJECTIVE:To evaluate associations between VMAT2 variability and cognitive outcomes post-TBI. METHODS:We evaluated 136 white adults with severe TBI for variation in VMAT2 using a tagging single nucleotide polymorphism (tSNP) approach (rs363223, rs363226, rs363251, and rs363341). We show genetic variation interacts with assessed cognitive impairment (cognitive composite [Comp-Cog] T-scores) to influence functional cognition (functional independence measure cognitive [FIM-Cog] subscale] 6 and 12 months postinjury. RESULTS:Multivariate analyses at 6 months postinjury showed rs363226 genotype was associated with Comp-Cog (P = .040) and interacted with Comp-Cog to influence functional cognition (P < .001). G-homozygotes had the largest cognitive impairment, and their cognitive impairment had the greatest adverse effect on functional cognition. DISCUSSION:We provide the first evidence that genetic variation within VMAT2 is associated with cognitive outcomes after TBI. Further work is needed to validate this finding and elucidate mechanisms by which genetic variation affects monoaminergic signaling, mediating differences in cognitive outcomes.
| S-EPMC4967045 | biostudies-literature
Project description:Traumatic brain injury (TBI) causes physical and cognitive-behavioral impairments that reduce participation in employment, leisure, and social relationships. Demographic and injury-related factors account for a small proportion of variance in participation post-injury. Personal factors such as resilience may also impact outcomes. This study aimed to examine the association of resilience alongside demographic, injury-related, cognitive, emotional, and family factors with participation following TBI. It was hypothesized that resilience would make an independent contribution to participation outcomes after TBI. Participants included 245 individuals with mild-severe TBI [Mage = 44.41, SDage = 16.09; post traumatic amnesia (PTA) duration M 24.95 days, SD 45.99] who completed the Participation Assessment with Recombined Tools-Objective (PART-O), TBI Quality of Life Resilience scale, Family Assessment Device General Functioning Scale, Rey Auditory Verbal Learning Test, National Adult Reading Test, and Hospital Anxiety and Depression Scale an average 4.63 years post-injury (SD 3.02, R 0.5-13). Multiple regression analyses were used to examine predictors of PART-O scores as the participation measure. Variables in the model accounted for a significant 38% of the variability in participation outcomes, F(13, 211) = 9.93, p < 0.05, R2 = 0.38, adjusted R2 = 0.34. Resilience was a significant predictor of higher participation, along with shorter PTA duration, more years since injury, higher education and IQ, and younger age. Mediation analyses revealed depression mediated the relationship between resilience and participation. As greater resilience may protect against depression and enhance participation this may be a focus of intervention.
| S-EPMC6054998 | biostudies-other
Project description:Severe traumatic brain injury (sTBI) is a major contributor to long-term disability and a leading cause of death worldwide. Medical management of the sTBI patient, beginning with prehospital triage, is aimed at preventing secondary brain injury. This review discusses prehospital and emergency department management of sTBI, as well as aspects of TBI management in the intensive care unit where advances have been made in the past decade. Areas of emphasis include intracranial pressure management, neuromonitoring, management of paroxysmal sympathetic hyperactivity, neuroprotective strategies, prognostication, and communication with families about goals of care. Where appropriate, differences between the third and fourth editions of the Brain Trauma Foundation guidelines for the management of severe traumatic brain injury are highlighted.
| S-EPMC5700862 | biostudies-other
Project description:Patient outcomes are variable following severe traumatic brain injury (TBI); however, the biological underpinnings explaining this variability are unclear. Mitochondrial dysfunction after TBI is well documented, particularly in animal studies. The aim of this study was to investigate the role of mitochondrial polymorphisms on mitochondrial function and patient outcomes out to 1 year after a severe TBI in a human adult population. The Human MitoChip V2.0 was used to evaluate mitochondrial variants in an initial set of n=136 subjects. SNPs found to be significantly associated with patient outcomes [Glasgow Outcome Scale (GOS), Neurobehavioral Rating Scale (NRS), Disability Rating Scale (DRS), in-hospital mortality, and hospital length of stay] or neurochemical level (lactate:pyruvate ratio from cerebrospinal fluid) were further evaluated in an expanded sample of n=336 subjects. A10398G was associated with DRS at 6 and 12 months (p=0.02) and a significant time by SNP interaction for DRS was found (p=0.0013). The A10398 allele was associated with greater disability over time. There was a T195C by sex interaction for GOS (p=0.03) with the T195 allele associated with poorer outcomes in females. This is consistent with our findings that the T195 allele was associated with mitochondrial dysfunction (p=0.01), but only in females. This is the first study associating mitochondrial DNA variation with both mitochondrial function and neurobehavioral outcomes after TBI in humans. Our findings indicate that mitochondrial DNA variation may impact patient outcomes after a TBI potentially by influencing mitochondrial function, and that sex of the patient may be important in evaluating these associations in future studies.
| S-EPMC3880110 | biostudies-literature
Project description:BackgroundAcute respiratory distress syndrome (ARDS) is common after traumatic brain injury (TBI) and is associated with worse neurologic outcomes and longer hospitalization. However, the incidence and associated causes of ARDS in isolated TBI have not been well studied.MethodsWe performed a subgroup analysis of 210 consecutive patients with isolated severe TBI enrolled in a prospective observational cohort at a Level 1 trauma center between 2005 and 2014. Subjects required endotracheal intubation and had isolated severe TBI defined by a head Abbreviated Injury Scale (AIS) score of 3 or greater and AIS score lower than 3 in all other categories. ARDS within the first 8 days of admission was rigorously adjudicated using Berlin criteria. Regression analyses were used to test the association between predictors of interest and ARDS.ResultsThe incidence of ARDS in the first 8 days after severe isolated TBI was 30%. Patients who developed ARDS were administered more crystalloids (4.3 L vs. 3.5 L, p = 0.005) and blood products in the first 12 hours of admission. Patients with ARDS had significantly worse clinical outcomes measured at 28 days, including longer median intensive care unit and hospital stays (4 days vs. 13 days, p < 0.001, and 7.5 days vs. 14.5 days, p < 0.001, respectively). In unadjusted logistic regression analyses, the odds of developing ARDS were significantly associated with head AIS score (odds ratio [OR], 1.8; p = 0.018), male sex (OR, 2.9; p = 0.012), and early transfusion of platelets (OR, 2.8; p = 0.003). These associations were similar in a multivariate logistic regression model.ConclusionIn the era of balanced hemostatic resuscitation practices, severity of head injury, male sex, early crystalloids, and early transfusion of platelets are associated with a higher risk of ARDS after severe isolated TBI. Early transfusion of platelets after severe TBI may be a modifiable risk factor for ARDS, and these findings invite further investigation into causal mechanisms driving this observed association.Level of evidencePrognostic/epidemiologic study, level III.
| S-EPMC5851280 | biostudies-literature
Project description:ObjectiveTo use a patient-centered approach or participatory action research design combined with advanced psychometrics to develop a comprehensive patient-reported outcomes (PRO) measurement system specifically for individuals with traumatic brain injury (TBI). This TBI Quality-of-Life (TBI-QOL) measurement system expands the work of other large PRO measurement initiatives, that is, the Patient-Reported Outcomes Measurement Information System and the Neurology Quality-of-Life measurement initiative.SettingFive TBI Model Systems centers across the United States.ParticipantsAdults with TBI.DesignClassical and modern test development methodologies were used. Qualitative input was obtained from individuals with TBI, TBI clinicians, and caregivers of individuals with TBI through multiple methods, including focus groups, individual interviews, patient consultation, and cognitive debriefing interviews. Item pools were field tested in a large multisite sample (n = 675) and calibrated using item response theory methods.Main outcomes measuresTwenty-two TBI-QOL item banks/scales.ResultsThe TBI-QOL consists of 20 independent calibrated item banks and 2 uncalibrated scales that measure physical, emotional, cognitive, and social aspects of health-related quality of life.ConclusionsThe TBI-QOL measurement system has potential as a common data element in TBI research and to enhance collection of health-related quality-of-life and PRO data in rehabilitation research and clinical settings.
| S-EPMC4697960 | biostudies-literature
Project description:Traumatic brain injury (TBI) triggers a cascade of apoptotic-related events that include BCL2 expression, a pro-survival protein in the apoptosis pathway. The purpose of this study was to use tagging single nucleotide polymorphism (tSNP) genotypes to screen the BCL2 gene to determine if genetic variability in the BCL2 gene influences outcomes in 205 patients with severe TBI. Outcomes (Glasgow Outcome Scale [GOS], Disability Rating Scale [DRS], mortality, and Neurobehavioral Rating Scale-Revised [NRS-R]) were analyzed at 3, 6, 12, and 24 months. Multivariate analysis demonstrates that there were four tSNPs of significant interest: rs17759659, rs1801018, rs7236090, and rs949037. Presence of the variant allele for rs17759659 was associated with poorer outcomes (GOS p = 0.001; DRS p = 0.002), higher mortality (p = 0.02; OR = 4.23; CI 1.31,13.61), and worse NRS-R scores (p = 0.05). Presence of the variant allele for rs1801018 was associated with poorer outcomes (GOS p = 0.02; DRS p = 0.009), and mortality (p = 0.03; OR = 3.86; CI 1.18,12.59). Being homozygous for the wild-type allele for rs7236090 was associated with favorable outcomes on the NRS-R (p = 0.007), while homozygosity for the variant genotype was associated with favorable outcomes on the GOS (p = 0.007) and DRS (p = 0.006). The homozygous variant for rs949037 was associated with favorable outcomes (GOS p = 0.04; DRS p = 0.03), and the homozygous wild-type was associated with increased mortality at 3 months (p = 0.005; OR = 3.67; CI 1.08,12.49). The only finding that stood up to Bonferroni correction was rs17759659 for GOS. These data support the possibility that genetic variability for pro-survival proteins, particularly genetic variation in the BCL2 gene, impacts outcomes after severe TBI.
| S-EPMC2967822 | biostudies-literature
Project description:OBJECTIVES:To examine the impact of early myocardial workload on in-hospital mortality following isolated severe traumatic brain injury. DESIGN:Retrospective cohort study. SETTING:Data from the National Trauma Databank, a multicenter trauma registry operated by the American College of Surgeons, from 2007 to 2014. PATIENTS:Adult patients with isolated severe traumatic brain injury (defined as admission Glasgow Coma Scale < 8 and head Abbreviated Injury Score ? 4). INTERVENTIONS:Admission rate-pressure product, categorized into five levels based on published low, normal, and submaximal human thresholds: less than 5,000; 5,000-9,999; 10,000-14,999; 15,000-19,999; and greater than 20,000. MEASUREMENTS AND MAIN RESULTS:Data from 26,412 patients were analyzed. Most patients had a normal rate-pressure product (43%), 35% had elevated rate-pressure product, and 22% had depressed rate-pressure product at hospital admission. Compared with the normal rate-pressure product group, in-hospital mortality was 22 percentage points higher in the lowest rate-pressure product group (cumulative mortality, 50.2%; 95% CI, 43.6-56.9%) and 11 percentage points higher in the highest rate-pressure product group (cumulative mortality, 39.2%; 95% CI, 37.4-40.9%). The lowest rate-pressure product group was associated with a 50% increased risk of mortality, compared with the normal rate-pressure product group (adjusted relative risk, 1.50; 95% CI, 1.31-1.76%; p < 0.0001), and the highest rate-pressure product group was associated with a 25% increased risk of mortality, compared with the normal rate-pressure product group (adjusted relative risk, 1.25; 95% CI, 1.18-1.92%; p < 0.0001). This relationship was blunted with increasing age. Among patients with normotension, those with depressed and elevated rate-pressure products experienced increased mortality. CONCLUSIONS:Adults with severe traumatic brain injury experience heterogeneous myocardial workload profiles that have a "U-shaped" relationship with mortality, even in the presence of a normal blood pressure. Our findings are novel and suggest that cardiac performance is important following severe traumatic brain injury.
| S-EPMC5953788 | biostudies-literature
Project description:ObjectivesThe microbiome may be affected by trauma and critical illness. Many studies of the microbiome in critical illness are restricted to a single body site or time point and confounded by preexisting conditions. We report temporal and spatial alterations in the microbiome of previously healthy children with severe traumatic brain injury (TBI).DesignWe collected oral, rectal, and skin swabs within 72 hours of admission and then twice weekly until ICU discharge. Samples were analyzed by 16S rRNA gene amplicon sequencing. Children undergoing elective outpatient surgery served as controls. Alpha and beta diversity comparisons were performed with Phyloseq, and differentially abundant taxa were predicted using Analysis of Composition of Microbiomes.SettingFive quaternary-care PICUs.PatientsPatients less than 18 years with severe TBI requiring placement of an intracranial pressure monitor.InterventionsNone.Measurements and main resultsThree hundred twenty-seven samples were analyzed from 23 children with severe TBI and 35 controls. The community composition of initial oral (F = 3.2756, R2 = 0.0535, p = 0.012) and rectal (F = 3.0702, R2 = 0.0649, p = 0.007) samples differed between TBI and control patients. Rectal samples were depleted of commensal bacteria from Ruminococcaceae, Bacteroidaceae, and Lachnospiraceae families and enriched in Staphylococcaceae after TBI (p < 0.05). In exploratory analyses, antibiotic exposure, presence of an endotracheal tube, and occurrence of an infection were associated with greater differences of the rectal and oral microbiomes between TBI patients and healthy controls, whereas enteral nutrition was associated with smaller differences (p < 0.05).ConclusionsThe microbiome of children with severe TBI is characterized by early depletion of commensal bacteria, loss of site specificity, and an enrichment of potential pathogens. Additional studies are needed to determine the impact of these changes on clinical outcomes.
| S-EPMC9203870 | biostudies-literature