BCL-2 Genotypes and Outcomes After Traumatic Brain Injury
Background: Mortality and morbidity of patients following traumatic brain injury (TBI) remains extremely high. TBI sets into motion a cascade of apoptotic events that includes bcl-2, which inhibits apoptosis. Patients with higher levels of bcl-2 protein after TBI appear to have smaller areas of ischemia and better functional outcomes as measured by Glasgow Outcome Scores (GOS).
Purpose: The purpose of this study was to examine the relationship between BCL-2 genotypes in patients with severe TBI and global functional outcomes, cognitive-behavioral outcomes, mortality, and biological/clinical data.
Methods: This pilot study was an ancillary study that examined biological/clinical markers in TBI patients and global functional and cognitive-behavioral outcomes after severe TBI (n=230). Nuclear DNA was extracted from CSF or blood. Based on HapMap, the DNA was analyzed for the genotypes of 17 high priority tagging single nucleotide polymorphisms (tSNPs) with a minor allele frequency ?0.3 via TaqMan® allele discrimination. Biological/clinical data (bcl-2 protein levels, neurometabolites (lactate, pyruvate, and lactate pyruvate (LP) ratio) and cerebral blood flow (CBF) were analyzed following the first five to six (protein only) days post injury. Mortality and global functional outcomes [GOS & Disability Rating Scale (DRS)], analyzed at 3, 6, 12, and 24 months. The cognitive behavioral outcomes [Neurobehavioral Rating Scale Revised (NRS-R), Trails A, and Trails B] were analyzed at 3, 6, and 12 months post injury. Statistical analysis for BCL-2s relationship with neuropsychological outcomes and biological/ clinical data overtime utilized was mixed modeling, (mortality utilized generalized mixed modeling).
Results: There were 3 tSNPs of particular interest: Rs1801018: homozygous variant (GG) significant associated with decreased mortality (p=0.0055; OR=5.01), higher GOS (p=0.0004), lower DRS (p=0.0002), lower Global CBF (p=0.0031), [presence of the variant allele (G)] lower LP ratios (p=0.024); all better outcomes. Rs17756073: presence of variant allele (G) was associated with higher NRS-R (p=0.0331) and longer Trails B times (p=0.0516); both poorer outcomes. Rs7236090: homozygous wild type (CC) was associated with lower bcl-2 protein concentrations when analyzed without outliers (p=0.0056); the literature associates this with poor outcomes.
Conclusion: BCL-2 genotypes had a significant relationship with global functional outcomes, cognitive behavioral outcomes, bcl-2 protein concentrations, neurometabolites, and CBF.
Advisor:Dianxu Ren; Sheila A. Alexander; Yvette P. Conley; Amy K. Wagner
School:University of Pittsburgh
School Location:USA - Pennsylvania
Source Type:Master's Thesis
Date of Publication:12/19/2008