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

Abstract

Background Mortality predictions following traumatic brain injury (TBI) 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 (SNPs) rs6265r (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 16–79. Mortality was examined acutely (0–7 days post-injury) and post-acutely (8–365 days post-injury). 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. Post-acutely, 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.

Posttraumatic Brain Injury Cognitive Performance Is Moderated by Variation Within ANKK1 and DRD2 Genes

“…However, it is also possible the mechanism of rs6279's impact on cognition post-TBI may be diminished at 12 months. The temporal dynamics of these DRD2 associations is consistent with other studies from our group that demonstrate transient genetic outcome associations across recovery post-TBI 64,65 . Domain specific analysis supports slightly different roles for each SNP in overall cognitive recovery.…”

Acute CSF interleukin-6 trajectories after TBI: Associations with neuroinflammation, polytrauma, and outcome

“…Many studies have shown that genetic variation is associated with outcomes and conditions following TBI (Hoh et al, 2010;Weaver et al, 2012;Wagner et al, 2012;Garringer et al, 2013;Diamond et al, 2014;Failla et al, 2014). Of note, an IL-6 polymorphism (À174 G/C) has been reported as associated with mortality after severe TBI (Dalla Libera et al, 2011) and the development of Alzheimer's disease in non-TBI populations (Qi et al, 2012).…”

Brain-Derived Neurotrophic Factor (BDNF) in Traumatic Brain Injury–Related Mortality

“…Age 26–28 and experimental TBI 29 can shift regional balances in BDNF receptor ratios from pro-survival to pro-apoptotic. In fact, our previous work demonstrated age and injury specific associations with the BDNF gene and mortality post-TBI 10 . We examined two single nucleotide polymorphisms (SNP) within BDNF , rs6265, with reduced activity-dependent secretion of BDNF 30 , and rs7124442, which impairs neuronal BDNF mRNA trafficking 31 .…”

“…Consistent with previous work 10 , mortality was evaluated over two time-epochs, 0-7d post-injury ( acute ) and 8d-365d post-injury ( post-acute ), and then across the entire recovery span of 0-365. For 0-7d, survivorship was right censored at 7d post-injury.…”