title: 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), 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.
authors: Department of Physical Medicine & Rehabilitation, University of Pittsburgh, School of Medicine, Pittsburgh PA Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA.
authors: Michelle D
authors: MD
authors: Failla
authors: Department of Physical Medicine & Rehabilitation, University of Pittsburgh, School of Medicine, Pittsburgh PA.
authors: Raj G
authors: RG
authors: Kumar
authors: Department of Surgery, University of Pittsburgh, School of Medicine, Pittsburgh PA.
authors: Andrew B
authors: AB
authors: Peitzman
authors: Department of Health Promotion & Development, University of Pittsburgh, School of Nursing, Pittsburgh, PA.
authors: Yvette P
authors: YP
authors: Conley
authors: Department of Human Genetics, University of Pittsburgh, School of Public Health, Pittsburgh, PA.
authors: Robert E
authors: RE
authors: Ferrell
authors: Department of Physical Medicine & Rehabilitation, University of Pittsburgh, School of Medicine, Pittsburgh PA Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA Safar Center for Resuscitation Research, University Pittsburgh, Pittsburgh, PA wagnerak@upmc.edu.
authors: Amy K
authors: AK
authors: Wagner
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D001930:Brain Injuries / Q000235:genetics* / Q000401:mortality*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009026:Mortality; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011446:Prospective Studies; D012372:ROC Curve; D012307:Risk Factors; D055815:Young Adult
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C579455:BDNF protein, human
keywords: BDNF; TrkB; age; brain injury; genetic association study; mortality