Dataset Information

IL-1? associations with posttraumatic epilepsy development: a genetics and biomarker cohort study.

ABSTRACT: 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-1?) gene, IL-1? levels in cerebrospinal fluid (CSF) and serum, and CSF/serum IL-1? ratios would predict PTE development post-TBI.We investigated PTE development in 256 Caucasian adults with moderate-to-severe TBI. IL-1? tagging and functional single nucleotide polymorphisms (SNPs) were genotyped. Genetic variance and PTE development were assessed. Serum and CSF IL-1? levels were collected from a subset of subjects (n = 59) during the first week postinjury and evaluated for their associations with IL-1? gene variants, and also PTE. Temporally matched CSF/serum IL-1? ratios were also generated to reflect the relative contribution of serum IL-1? to CSF IL-1?.Multivariate analysis showed that higher CSF/serum IL-1? 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-1? levels (p = 0.014) and higher IL-1? CSF/serum ratios (p = 0.093).This is the first report implicating IL-1? gene variability in PTE risk and linking (1) IL-1? gene variation with serum IL-1? levels observed after TBI and (2) IL-1? ratios with PTE risk. Given these findings, we propose that genetic and IL-1? 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-1? production after TBI, (2) assessing genetically mediated signaling mechanisms that contribute to IL-1? CSF/serum associations with PTE, and (3) evaluating targeted IL-1? therapies that reduce PTE.

SUBMITTER: Diamond ML

PROVIDER: S-EPMC4107119 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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IL-1β associations with posttraumatic epilepsy development: a genetics and biomarker cohort study.

Diamond Matthew L ML Ritter Anne C AC Failla Michelle D MD Boles Jennifer A JA Conley Yvette P YP Kochanek Patrick M PM Wagner Amy K AK

Epilepsia 20140422 7

<h4>Objective</h4>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.<h4>Methods</h4>We investiga ...[more]

PMID: 24754437

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Project description:BackgroundWhile life-long impacts exist for infants born one or two weeks early little evidence exists for those infants born after their due date. However interventions could be used to expedite birth if the risks of continuing the pregnancy are higher than intervening. It is known that the risk of epilepsy in childhood is higher in infants exposed to perinatal compromise and therefore may be useful as a proxy for intrapartum compromise. The aim of this work is to quantify the likelihood of children developing epilepsy based on their gestational age at birth (37-39 weeks or ?41 weeks).MethodsThe work is based on term infants born in Sweden between 1983 and 1993 (n = 1,030,168), linked to data on disability pension, child mortality and in-patient epilepsy care. The reference group was defined as infants born at 39 or 40 completed weeks of gestation; compared with infants born at early term (37/38 weeks) or late/post term (41 weeks or more). Primary outcome was defined a-priori as a diagnosis of epilepsy before 20 years of age. Secondary outcomes were childhood mortality (before five years of age), and registered for disability pension before 20 years of age. Logistic regression models were used to assess any association of the outcomes with gestational age at birth.FindingsIn the unadjusted results, infants born 7 or more days after their due date had higher risks of epilepsy and disability pension than the reference group, but similar risks of child death. Early term infants showed higher risks of epilepsy, disability pension and child death. After adjustment for confounders, there remained a higher risk of epilepsy for both early term (OR 1·19 (1·11-1·29)) and late/post term infants (OR 1·13 (1·06-1·22)).InterpretationInfants born at 37/38 week or 41 weeks and above, when compared to those born at 39 or 40 weeks gestation, have an increased risk of developing epilepsy. This data could be useful in helping women and care givers make decisions with regard to the timing of induction of labour.

Project description:ObjectiveDetermine 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.MethodsNine 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.ResultsComparing 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) .SignificanceGenetic 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.

Dataset Information

IL-1? associations with posttraumatic epilepsy development: a genetics and biomarker cohort study.

Publications

IL-1β associations with posttraumatic epilepsy development: a genetics and biomarker cohort study.

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