Single nucleotide polymorphisms of TNF-Α gene in febrile seizures Ameneh Zare-Shahabadi a,e , Mahmoud Reza Ashrafi b , Amin Shahrokhi b,c , Samaneh Soltani d , Samaneh Zoghi d , Farin Soleimani c , Roshanak Vameghi c , Reza Shervin Badv b , Nima Rezaei a,d,e, ⁎ a Molecular Immunology Research Center and Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran b Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran c Pediatric Neurorehabilitation Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran d Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran e Universal Scientific Education and Research Network (USERN), Tehran, Iran abstract article info Article history: Received 7 January 2015 Received in revised form 20 June 2015 Accepted 22 June 2015 Available online xxxx Keywords: Febrile seizures TNF-α Cytokine Etiology Pro-inflammatory Single nucleotide polymorphisms Febrile seizures (FS) is the most common seizure disorder during childhood. This study was performed in 78 pa- tients with FS and 137 control subjects to assess polymorphisms of the TNF-α gene at positions -308 and -238, using the polymerase chain reaction and the sequence specific primers method. The highest positive allelic asso- ciation that made the patients susceptible to FS was seen for TNF-α -238/G (p b 0.0001). The GG genotype at TNF-α -238 was significantly higher in the patients with FS, compared to the controls (p = 0.0001). Also, GA genotype at the same position was significantly lower in patients than in controls (P = 0.0001). The GG haplotype had a significant positive association at TNF-α (308, 238) while GA haplotype showed a negative associa- tion (P b 0.001). Our data support the idea that TNF-α single-nucleotide polymorphisms play a role in the path- ogenesis of FS. © 2015 Elsevier B.V. All rights reserved. 1. Introduction Fever is a multiphasic response of elevation of the core body temper- ature that results from an immune challenge which regulates by central thermoregulatory mechanisms localized in the preoptic area of the hypo- thalamus [1,2]. Induction of fever is mediated by the release of pyrogenic cytokines such as tumor necrosis factor (TNF), interleukin-1 (IL), IL-6 into the bloodstream in response to exogenous pyrogens [3]. TNF-α is a potent immune-mediated and proinflammatory cytokine which is implied in the pathogenesis of a large number of human diseases [4]. TNF-α plays a contrary role, which may be related to genetic polymorphisms in the gene regulating its production and effect [5]. This molecule inducts the production of IL-1 and IL-6 which leads to elevated temperature [4]. The polymorphism at -308 position directly affects TNF-α expression. There are two allelic forms of TNF-α, TNF-α1 and 2; one in which guanine defines the common allele and the other in which guanine is substituted by adenosine from the rare allele at position -308 [6]. The presence of TNF-α allele has been found to correlate with enhanced spontaneous or stimulated TNF-α production in both in vitro and in vivo [7]. In mice, increased levels of TNF-α induces inhibition of seizure [8]. Febrile seizures (FS) are the most common convulsive event in chil- dren with a relevance of 2–5%. The International League Against Epilepsy (ILAE) has defined FS as “elevated or rapidly rising fever of short duration associated with an uncomplicated seizure that does not predispose to epilepsy and is not accompanied by neurologic abnormalities, previous neonatal seizures or a previous unprovoked seizure, and not meeting criteria for other acute symptomatic seizures in children between 6 months and 5 years of age” [9]. Simple FS defined as generalized tonic– colonic seizures lasting less than 15 min, only once in 24 h with a brief postictal period, whereas complex FS, lasting more than 15 min, has focal features and multiple recurrences within 24 h and association with postictal neurological abnormalities, for example Todd paresis [10,11]. While the etiology of FS is still unclear, a positive family history of FS is known to be the most important risk factor, and the more relatives affected, the greater the risk is [12,13]. Twin and family studies suggest that genetic factors may have an important effect on the predisposition of FS. This underlying genetic predisposition, along with the association of fever with the seizures, implies the possibility of involvement of some gene or genes for the regulation of pro-inflammatory and anti- inflammatory cytokines IL-1, IL-6 and TNF [13–15]. Vezzani et al. indicated that TNF-α and IL-1B contents were increased in the whole brain tissue after electrical stimulation of the amygdale in rats [16]. Khoshdel et al. found a significant relation Journal of the Neurological Sciences xxx (2015) xxx–xxx ⁎ Corresponding author at: Children's Medical Center Hospital, DrQarib St., Keshavarz Blvd, Tehran 14194, Iran. E-mail address: rezaei_nima@tums.ac.ir (N. Rezaei). JNS-13868; No of Pages 4 http://dx.doi.org/10.1016/j.jns.2015.06.039 0022-510X/© 2015 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns Please cite this article as: A. Zare-Shahabadi, et al., Single nucleotide polymorphisms of TNF-Α gene in febrile seizures, J Neurol Sci (2015), http:// dx.doi.org/10.1016/j.jns.2015.06.039