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

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