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

ObjectivePosttraumatic 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 cerebral spinal fluid (CSF) and serum, and CSF/serum IL-1 ratios would predict PTE development post-TBI. MethodsWe 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. ResultsMultivariate 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). SignificanceThis 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. A PowerPoint slide summarizing this article is available for download in the Supporting Information section . This article was previously published: IL-1 associations with posttraumatic epilepsy development: A genetics and biomarker cohort study Vol. 55, Issue 7, 1109-1119, Article first published online: 22 APR 2014