Association Analysis of Interleukin-1β, Interleukin-6, and HMGB1 Variants with Postictal Serum Cytokine Levels in Children with Febrile Seizure and Generalized Epilepsy with Febrile Seizure Plus

Abstract

Background and PurposeFebrile seizure (FS) is a unique type of seizure that only occurs during childhood. Genelized epilepsy with febrile seizure plus (GEFS+) is a familial epilepsy syndrome associated with FS and afebrile seizure (AFS). Both seizure types are related to fever, but whether genetic susceptibility to inflammation is implicated in them is still unclear. To analyze the associations between postictal serum cytokine levels and genetic variants in the cytokine genes interleukin (IL)-1β, IL-6, and high mobility group box-1 (HMGB1) in FS and GEFS+.MethodsGenotyping was performed in 208 subjects (57 patients with FS, 43 patients with GEFS+, and 108 controls) with the SNaPshot assay for IL-1β-31 (rs1143627), IL-1β-511 (rs16944), IL-6-572 (rs1800796), and HMGB1 3814 (rs2249825). Serum IL-1β, IL-6, and HMGB1 levels were analyzed within 2 hours after seizure attacks using the ELISA in only 68 patients (38 FS, 10 GEFS+, and 20 controls). The allele distribution, genotype distribution, and correlations with serum cytokine levels were analyzed.ResultsNear-complete linkage disequilibrium exists between IL-1β-31 and IL-1β-511 variants. CT genotypes of these variants were associated with significantly higher postictal serum IL-1β levels than were CC+TT genotypes in FS (both p<0.05). CT genotypes of IL-1β-31 and IL-1β-511 variants were more strongly associated with FS than were CC+TT genotypes (odds ratio=1.691 and 1.731, respectively). For GEFS+, serum IL-1β levels after AFS for CT genotypes of IL-1β-31 and IL-1β-511 were also higher than for CC+TT genotypes. No significant associations were found for IL-6 and HMGB1.ConclusionsGenetic variants located in IL-1β-31 and IL-1β-511 promotor regions are correlated with higher postictal IL-1β levels in FS. These results suggest that IL-1 gene cluster variants in IL-1β-31 and IL-1β-511 are a host genetic factor for provoking FS in Korean children.

Polymorphism of IL-1β rs16944(T/C) Associated with Serum Levels of IL-1β and Subsequent Stimulation of Extracellular Matrix Degradation Affects Intervertebral Disk Degeneration Susceptibility

“…The polymorphism of IL-1β rs16944(T/C) is correlated with various clinical conditions, such as lumbar disc disease, rheumatoid arthritis, breast cancer, keratoconus and febrile seizure. 15 , 16 , 18 , 22 , 23 In this study, our results showed that the polymorphism of IL-1β rs16944(T/C) was associated with IDD with adjustment for smoking, occupation, physical activity, load weight at work and rs1143623(G/C), and the risk for IDD was significantly increased in TT and TC genotype compared with CC genotype. At the same time, serum concentrations of IL-1β, MMP-3 and ADAMTS-4 demonstrated the tendency of IL-1β rs16944 TT genotype > TC genotype > CC genotype, and serum concentrations MMP-1 and MMP-9 were higher in TT genotype than in TC and CC genotype.…”

“…The polymorphism of IL-1β rs16944(T/C) is correlated with various clinical conditions, such as lumbar disc disease, rheumatoid arthritis, breast cancer, keratoconus and febrile seizure. 15,16,18,22,23 In this study, our results showed that the polymorphism of IL-1β rs16944(T/C) was associated with IDD with adjustment for smoking, occupation, degradation. In this study, the sample size was calculated according to the method for "Tests for Two Proportions (Odds Ratios)": 1-β=0.80, α=0.05, sample allocation ratio=1.0.…”

Stress Hyperglycemia as Predictive Factor of Recurrence in Children with Febrile Seizures

“…Although the mechanisms of febrile seizure are still under debate, the immune activity may overlap with the counter regulating hormonal activity and proinflammatory status described in stress hyperglycemia [1,4,5,72,73]. In febrile seizures, the role of inflammatory cytokines in the pathogenic cascade of febrile seizures has been supported by several studies [55][56][57][58]. Figure A2.…”

“…During acute severe illness, the role of proinflammatory cytokines in inducing stress hyperglycemia is complex. The role of inflammatory cytokines in the pathogenic cascade of febrile seizures is supported by several studies and could provide the common pathways with stress hyperglycemia [55][56][57][58]. Proinflammatory cytokines like Insulin resistance is mainly characterized by reduced insulin-mediated glucose uptake secondary to defects in postreceptor insulin signaling and altered glucose transporter.…”

How to Find Candidate Drug-targets for Antiepileptogenic Therapy?

“…Excessive activation of inflammation response in the brain might be one of the most extensively studied pathways underling epileptogenesis, which has been commonly identified in various animal models of epilepsy and in humans [ 60 ]. The main inflammatory pathways for epilepsy include the damage-associated molecular pattern of high-mobility group box 1(HMGB1)-Toll-like receptor 4(TLR4)/advanced glycation end products(RAGE)-nuclear factor-kappa B (NF-κB)-interleukin(IL)-1 beta axis [ 61 ], and the arachidonic acid (AA)-cyclooxygenases (COX)-prostaglandin (PGs) cascade [ 62 ]. Neuroinflammation can be initiated by numbers of PEEs for epilepsy, such as infectious diseases and non-infectious brain injuries [ 63 ].…”