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

Abstract

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

Association Between IL1B and SCN1A Polymorphism and Febrile Seizures in Children in Siberia

“…(7,13,14) Our investigation of rs1143634 polymorphism of IL1B gene, demonstrating a high risk of FS development in carriers of high-producing allele C, is consistent with the data in the literature, according to which the CT genotype of rs1143634 leads to a higher IL1B, cerebrospinal, fluid/serum ratio and is associated with increased risk of developing posttraumatic epilepsy. (15) Moreover, the data shown by Diamond and coauthors, suggests that TT homozygotes are relatively protected from posttraumatic epilepsy, (15) which in our study corresponds to the low risk of FS development.…”

“…An interesting opinion was discussed by M.Hong that heterozygous associations for genetic variation for genes coding membrane receptors can occur and may result in multiple actions that affect the phenotype of interest (e.g., differential effects of membrane trafficking for receptor protein heterodimers vs. homodimers). (15) In general, FS are a common multifactorial disease, and only the interaction of genetic and environmental factors can induce FS development. (23) Despite the fact that the issues of treatment and prevention of FS have been discussed for several decades, many aspects of genetics and preventive measures of FS recurrences and their transformation into afebrile epileptical seizures remain debatable.…”

Epileptogenesis

“…Cite this article as Cold Spring Harb Perspect Med 2015;5:a022822 genetic and environmental influences in a given individual Wagner et al 2010;Darrah et al 2013;Ndode-Ekane and Pitkänen 2013;Diamond et al 2014;Henshall et al 2014;Kobow and Blümcke 2014). All of these aspects pose challenges for the analysis or prediction of epileptogenesis in human populations.…”

Seizures and Epilepsies due to Channelopathies and Neurotransmitter Receptor Dysfunction: A Parallel between Genetic and Immune Aspects

“…The expression and concentration profile of IL-1β, a proinflammatory cytokine, was recently studied in patients with post-traumatic epilepsy [Diamond et al, 2014]. IL-1β is produced in the CNS by activated microglia and astrocytes, and in the blood mostly by macrophages; it was previously demonstrated to be increasingly expressed and chronically released after traumatic brain injury, and hence, to contribute to the appearance of subsequent post-traumatic epilepsy in certain patients [Ferrari et al, 1996;Lu et al, 2005;Diamond et al, 2014].…”

“…IL-1β is produced in the CNS by activated microglia and astrocytes, and in the blood mostly by macrophages; it was previously demonstrated to be increasingly expressed and chronically released after traumatic brain injury, and hence, to contribute to the appearance of subsequent post-traumatic epilepsy in certain patients [Ferrari et al, 1996;Lu et al, 2005;Diamond et al, 2014]. A specific SNP in IL-1B , the gene that encodes IL-1β, had itself been involved in certain forms of nontraumatic temporal lobe epilepsy in other studies [Kauffman et al, 2008].…”