title: IL-1β associations with posttraumatic epilepsy development: A genetics and biomarker cohort study.
abstract: OBJECTIVE
  Posttraumatic epilepsy (PTE) is a significant complication following traumatic brain injury (TBI), yet the role of genetic variation in modulating PTE onset is unclear. We hypothesized that TBI-induced inflammation likely contributes to seizure development. We assessed whether genetic variation in the interleukin-1beta (IL-1β) gene, Il-1β levels in cerebral spinal fluid (CSF) and serum, and CSF/serum IL-1β ratios would predict PTE development post-TBI.
  
  
  METHODS
  We investigated PTE development in 256 Caucasian adults with moderate-to-severe TBI. IL-1β tagging and functional single nucleotide polymorphisms (SNPs) were genotyped. Genetic variance and PTE development were assessed. Serum and CSF IL-1β levels were collected from a subset of subjects (n = 59) during the first week postinjury and evaluated for their associations with IL-1β gene variants, and also PTE. Temporally matched CSF/serum IL-1β ratios were also generated to reflect the relative contribution of serum IL-1β to CSF IL-1β.
  
  
  RESULTS
  Multivariate analysis showed that higher CSF/serum IL-1β ratios were associated with increased risk for PTE over time (p = 0.008). Multivariate analysis for rs1143634 revealed an association between the CT genotype and increased PTE risk over time (p = 0.005). The CT genotype group also had lower serum IL-1β levels (p = 0.014) and higher IL-1β CSF/serum ratios (p = 0.093).
  
  
  CONCLUSIONS
  This is the first report implicating IL-1β gene variability in PTE risk and linking (1) IL-1β gene variation with serum IL-1β levels observed after TBI and (2) IL-1β ratios with PTE risk. Given these findings, we propose that genetic and IL-1β ratio associations with PTE may be attributable to biologic variability with blood-brain barrier integrity during TBI recovery. These results provide a rationale for further studies (1) validating the impact of genetic variability on IL-1β production after TBI, (2) assessing genetically mediated signaling mechanisms that contribute to IL-1β CSF/serum associations with PTE, and (3) evaluating targeted IL-1β therapies that reduce PTE. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
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 Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.|Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Failla
authors.affiliation: Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Boles
authors.affiliation: Department of Health Promotion and Development, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
authors.forename: Yvette P
authors.initials: YP
authors.lastname: Conley
authors.affiliation: Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.|Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Kochanek
authors.affiliation: Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.|Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.|Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
authors.forename: Amy K
authors.initials: AK
authors.lastname: Wagner
keywords: Genetic variation; IL-1β; Inflammation; Posttraumatic epilepsy; Traumatic brain injury