BCL2 Genotypes: Functional and Neurobehavioral Outcomes after Severe Traumatic Brain Injury

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.