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Variation in the BDNF Gene Interacts With Age to Predict Mortality in a Prospective, Longitudinal Cohort with Severe TBI

Background. Mortality predictions following traumatic brain injury (TBI), and our understanding of TBI pathology, may be improved by including genetic risk in addition to traditional prognostic variables. One promising target is the gene coding for brain-derived neurotrophic factor (BDNF), a ubiquitous neurotrophin important for neuronal survival and neurogenesis. Objective. We hypothesized the addition of BDNF genetic variation would improve mortality prediction models and that BDNF Met-carriers (rs6265) and C-carriers (rs7124442) would have the highest mortality rates post-TBI. Methods. This study examined BDNF functional single nucleotide polymorphisms rs6265 (val66met) and rs7124442 (T>C) in relation to mortality in a prospective, longitudinal cohort with severe TBI. We examined 315 individuals receiving care for a closed head injury within the University of Pittsburgh Medical Center, aged 16 to 74 years. Mortality was examined acutely (0-7 days postinjury) and postacutely (8-365 days postinjury). A gene risk score (GRS) was developed to examine both BDNF loci. Cox proportional hazards models were used to calculate hazard ratios for survivability post-TBI while controlling for covariates. Results. BDNF GRS was significantly associated with acute mortality, regardless of age. Interestingly, subjects in the hypothesized no-risk allele group had the lowest survival probability. Postacutely, BDNF-GRS interacted with age such that younger participants in the no-risk group had the highest survival probability, while older participants in the hypothesized no-risk group had the lowest probability of survival. Conclusions. These data suggest complex relationships between BDNF and TBI mortality that interact with age to influence survival predictions beyond clinical variables alone. Evidence supporting dynamic, temporal balances of pro-survival/pro-apoptotic target receptors may explain injury and age-related gene associations.