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