J Clin Neurol.  2019 Oct;15(4):555-563. 10.3988/jcn.2019.15.4.555.

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

Affiliations
  • 1Department of Pediatrics, SMG-SNU Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea. jechoi66@snu.ac.kr
  • 2Department of Pediatrics, Dankook University Hospital, Cheonan, Korea.
  • 3Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea.
  • 4Department of Pediatrics, Seoul National University Bundang Hospital, Seoul, Korea.
  • 5Department of Biostatistics, SMG-SNU Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea.
  • 6Department of Microbiology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Science Institute and Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea. jsshin6203@yuhs.ac

Abstract

BACKGROUND AND PURPOSE
Febrile 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+.
METHODS
Genotyping 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.
RESULTS
Near-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.
CONCLUSIONS
Genetic 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.

Keyword

interleukin-1β; interleukin-6; high mobility group box-1; febrile seizure; genelized epilepsy with febrile seizure plus; variant

MeSH Terms

Alleles
Child*
Enzyme-Linked Immunosorbent Assay
Epilepsy
Epilepsy, Generalized*
Fever
Genetic Predisposition to Disease
Genotype
HMGB1 Protein*
Humans
Inflammation
Interleukin-1
Interleukin-6*
Interleukins
Linkage Disequilibrium
Multigene Family
Promoter Regions, Genetic
Seizures
Seizures, Febrile*
HMGB1 Protein
Interleukin-1
Interleukin-6
Interleukins

Figure

  • Fig. 1 Comparison of postictal serum cytokine levels in children with FS and GEFS+ compared to controls. Data are mean and standard-error values; *p<0.05 (A–C). Comparative analysis of postictal serum levels of IL-1β (A), IL-6 (B), and HMGB1 (C) between each group of FS and GEFS+ patients compared to controls. Postictal serum levels of IL-1β (A), IL-6 (B), and HMGB1 (C) were significantly increased in children with FS after an attack compared to controls. In children with GEFS+, postictal serum levels of IL-1β (A), IL-6 (B), and HMGB1 (C) after an afebrile seizure attack showed no statistically significant differences. FS: febrile seizure, GEFS+: genetic epilepsy with febrile seizure plus, HMGB1: high mobility group box-1, IL: interleukin.

  • Fig. 2 Correlation of postictal serum cytokine levels after an FS attack or after an AFS in GEFS+ depending on the genotypes of IL-1β variants (A–D). Association analyses were performed between postictal serum levels of IL-1β and genotypes of IL-1β-31 and IL-1β-511 in children with FS (A and B) and GEFS+ (C and D). Postictal serum levels of IL-1β were significantly higher in CT genotypes of IL-1β-31 (A) and IL-1β-511 (B) than in CC+TT genotypes in children with FS after an FS attack (both p=0.032). In children with GEFS+, postictal serum levels of IL-1β did not show statiscally significant deferences between genotypes of IL-1β-31 (C) and IL-1β-511 (D) after an AFS attack. AFS: afebrile seizure, FS: febrile seizure, GEFS+: genetic epilepsy with febrile seizure plus.

  • Fig. 3 Correlations of postictal serum cytokine levels after an FS attack or after an afebrile seizure in GEFS+ with the genotypes of IL-6 and HMGB1 variants (A–D). Association analyses of postictal serum levels of IL-6 and HMGB1 were performed with genotypes of IL-6-572 and HMGB1 3814 in children with FS (A and B) and GEFS+ (C and D). Postictal serum IL-6 levels were not significantly associated with the genotypes of the IL-6-572 variant both in FS (A) and GEFS+ (C). Postictal serum levels of HMGB1 were also not significantly associated with the genotypes of the HMGB1 3814 variant both in FS (B) and GEFS+ (D). FS: febrile seizure, GEFS+: genetic epilepsy with febrile seizure plus.


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