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 cerebrospinal 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.
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.forename: Anne C
authors.initials: AC
authors.lastname: Ritter
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Failla
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Boles
authors.forename: Yvette P
authors.initials: YP
authors.lastname: Conley
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Kochanek
authors.forename: Amy K
authors.initials: AK
authors.lastname: Wagner
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D015331:Cohort Studies; D004834:Epilepsy, Post-Traumatic / Q000097:blood / Q000134:cerebrospinal fluid / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D053583:Interleukin-1beta / Q000097:blood / Q000134:cerebrospinal fluid / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D055815:Young Adult
chemical_list: D015415:Biomarkers; D005819:Genetic Markers; D053583:Interleukin-1beta
keywords: Genetic variation; IL-1β; Inflammation; Posttraumatic epilepsy; Traumatic brain injury
references.citation: Genet Med. 2008 Feb;10(2):83-8
references.pmid: 18281914
references.citation: N Engl J Med. 1998 Jan 1;338(1):20-4
references.pmid: 9414327
references.citation: J Neurotrauma. 2014 Apr 15;31(8):699-712
references.pmid: 24354775
references.citation: Arch Phys Med Rehabil. 2003 Mar;84(3):365-73
references.pmid: 12638104
references.citation: Epilepsia. 2012 Jul;53(7):1215-24
references.pmid: 22708826
references.citation: J Neurotrauma. 2005 Aug;22(8):885-95
references.pmid: 16083355
references.citation: Exp Mol Pathol. 2002 Oct;73(2):139-41
references.pmid: 12231216
references.citation: J Trauma. 2009 Nov;67(5):950-3
references.pmid: 19901653
references.citation: Nat Neurosci. 2005 Jun;8(6):752-8
references.pmid: 15895084
references.citation: Epilepsy Res. 2006 Oct;71(2-3):107-16
references.pmid: 16806825
references.citation: Brain Res. 2006 Jan 27;1070(1):31-4
references.pmid: 16406269
references.citation: Exp Neurol. 2009 Apr;216(2):258-71
references.pmid: 19162013
references.citation: Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11534-9
references.pmid: 11016948
references.citation: Epilepsia. 2008;49 Suppl 2:24-32
references.pmid: 18226169
references.citation: J Neurotrauma. 2009 Sep;26(9):1471-7
references.pmid: 19508123
references.citation: N Engl J Med. 1990 Aug 23;323(8):497-502
references.pmid: 2115976
references.citation: J Cereb Blood Flow Metab. 2011 Feb;31(2):658-70
references.pmid: 20717122
references.citation: J Neurotrauma. 1999 Mar;16(3):225-32
references.pmid: 10195470
references.citation: Eur J Neurosci. 1990 Jan;2(1):69-76
references.pmid: 12106104
references.citation: Nucleic Acids Res. 1988 Feb 11;16(3):1215
references.pmid: 3344216
references.citation: J Immunol. 1996 Feb 15;156(4):1531-9
references.pmid: 8568257
references.citation: J Neurochem. 2009 Oct;111(1):111-8
references.pmid: 19656257
references.citation: J Neurotrauma. 2007;24 Suppl 1:S37-44
references.pmid: 17511544
references.citation: Neurosurgery. 2011 Jan;68(1):12-9; discussion 19
references.pmid: 21150751
references.citation: PLoS One. 2013;8(1):e53376
references.pmid: 23301065
references.citation: Hum Mol Genet. 2006 Feb 15;15(4):519-29
references.pmid: 16399797
references.citation: J Trauma. 1974 Mar;14(3):187-96
references.pmid: 4814394
references.citation: J Neurotrauma. 1997 Oct;14(10):715-27
references.pmid: 9383090
references.citation: Brain Inj. 2013;27(5):578-86
references.pmid: 23472705
references.citation: Cancer Epidemiol Biomarkers Prev. 2006 Sep;15(9):1674-87
references.pmid: 16985030
references.citation: Brain Inj. 2007 May;21(5):499-504
references.pmid: 17522989
references.citation: J Immunol. 1993 Apr 1;150(7):2659-67
references.pmid: 8454848
references.citation: Ann Neurol. 1996 Jan;39(1):123-7
references.pmid: 8572657
references.citation: Epilepsy Res. 2013 Feb;103(2-3):180-94
references.pmid: 22840783
references.citation: Br J Pharmacol. 2009 Apr;156(7):1115-23
references.pmid: 19298391
references.citation: Blood. 1997 Oct 15;90(8):2911-5
references.pmid: 9376570
references.citation: Epilepsy Res. 2010 Aug;90(3):259-72
references.pmid: 20609566
references.citation: Epilepsia. 2006 Jul;47(7):1160-8
references.pmid: 16886979
references.citation: Exp Neurol. 1994 Dec;130(2):173-7
references.pmid: 7867748
references.citation: Epilepsia. 2005 Apr;46(4):470-2
references.pmid: 15816939
references.citation: Eur J Clin Invest. 1992 Jun;22(6):396-402
references.pmid: 1353022
references.citation: Pathobiology. 1999;67(5-6):236-40
references.pmid: 10725792
references.citation: Injury. 2006 Dec;37(12):1083-91
references.pmid: 17092503
references.citation: J Neurosci. 1995 Jul;15(7 Pt 2):5316-23
references.pmid: 7623154
references.citation: Cell Immunol. 1991 Jan;132(1):84-93
references.pmid: 1648453
references.citation: J Biol Chem. 2009 Oct 9;284(41):27857-27865
references.pmid: 19690169
references.citation: Brain. 2013 Jan;136(Pt 1):28-42
references.pmid: 23365092
references.citation: Epilepsia. 2013 Apr;54(4):589-95
references.pmid: 23398413
references.citation: J Neuroinflammation. 2012 Oct 12;9:236
references.pmid: 23061919
references.citation: Neurorehabil Neural Repair. 2013 Nov-Dec;27(9):878-88
references.pmid: 23812605
references.citation: Arthritis Rheum. 2004 Jun;50(6):1976-83
references.pmid: 15188375
references.citation: Epilepsia. 2003;44(s10):18-20
references.pmid: 14511390
references.citation: Nat Rev Immunol. 2005 Aug;5(8):629-40
references.pmid: 16034365