title: Genetic variation in the adenosine regulatory cycle is associated with posttraumatic epilepsy development.
abstract: OBJECTIVE
  Determine if genetic variation in enzymes/transporters influencing extracellular adenosine homeostasis, including adenosine kinase (ADK), [ecto-5'-nucleotidase (NT5E), cluster of differentiation 73 (CD73)], and equilibrative nucleoside transporter type-1 (ENT-1), is significantly associated with epileptogenesis and posttraumatic epilepsy (PTE) risk, as indicated by time to first seizure analyses.
  
  
  METHODS
  Nine ADK, three CD73, and two ENT-1 tagging single nucleotide polymorphisms (SNPs) were genotyped in 162 white adults with moderate/severe traumatic brain injury (TBI) and no history of premorbid seizures. Kaplan-Meier models were used to screen for genetic differences in time to first seizure occurring >1 week post-TBI. SNPs remaining significant after correction for multiple comparisons were examined using Cox proportional hazards analyses, adjusting for subdural hematoma, injury severity score, and isolated TBI status. SNPs significant in multivariate models were then entered simultaneously into an adjusted Cox model.
  
  
  RESULTS
  Comparing Kaplan-Meier curves, rs11001109 (ADK) rare allele homozygosity and rs9444348 (NT5E) heterozygosity were significantly associated with shorter time to first seizure and an increased seizure rate 3 years post-TBI. Multivariate Cox proportional hazard models showed that these genotypes remained significantly associated with increased PTE hazard up to 3 years post-TBI after controlling for variables of interest (rs11001109: hazard ratio (HR) 4.47, 95% confidence interval (CI) 1.27-15.77, p = 0.020; rs9444348: HR 2.95, 95% CI 1.19-7.31, p = 0.019) .
  
  
  CONCLUSIONS
  Genetic variation in ADK and NT5E may help explain variability in time to first seizure and PTE risk, independent of previously identified risk factors, after TBI. Once validated, identifying genetic variation in adenosine regulatory pathways relating to epileptogenesis and PTE may facilitate exploration of therapeutic targets and pharmacotherapy development.
authors.affiliation: Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Diamond
authors.affiliation: Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Ritter
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Jackson
authors.affiliation: Department of Health Promotion and Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.|Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
authors.forename: Yvette P
authors.initials: YP
authors.lastname: Conley
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.|Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Kochanek
authors.affiliation: RS Dow Neurobiology Labs, Legacy Research Institute, Portland, Oregon, U.S.A.
authors.forename: Detlev
authors.initials: D
authors.lastname: Boison
authors.affiliation: Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.|Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.|Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
authors.forename: Amy K
authors.initials: AK
authors.lastname: Wagner
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics*; D000248:Adenosine Kinase / Q000235:genetics*; D000328:Adult; D001930:Brain Injuries / Q000150:complications; D004834:Epilepsy, Post-Traumatic / Q000209:etiology / Q000235:genetics*; D033721:Equilibrative Nucleoside Transporter 1 / Q000235:genetics*; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models
chemical_list: D033721:Equilibrative Nucleoside Transporter 1; D058851:GPI-Linked Proteins; C438649:SLC29A1 protein, human; D000248:Adenosine Kinase; D015720:5'-Nucleotidase; C548241:NT5E protein, human
keywords: Adenosine; Epileptogenesis; Genetics; Posttraumatic epilepsy; Rehabilomics; Traumatic brain injury