The association between toll-like receptor 4 (TLR4) genotyping and the risk of epilepsy in children

Abstract

Background Epilepsy is one of the most widely recognized neurological disorders; unfortunately, twenty to thirty percent of patients do not get cured from epilepsy, despite many trials of antiepileptic drug (AED) therapy. Immunotherapy may be a viable treatment strategy in a subset of epileptic patients. The association between Toll-like receptor polymorphisms and epilepsy clarifies the role of the immune system in epilepsy and its response to the drug. Thus, this study will focus on the relation between TLR4 rs1927914, rs11536858, rs1927911SNPs, and epilepsy in an Egyptian case-control study to assess their link to antiepileptic drug response. Results According to TLR4 rs1927914, there is a significant association between the SNP and the development of epilepsy, as CC genotype is 15.3 times more at risk for developing epilepsy than TT genotype, and CT is 11.1 times more at risk for developing epilepsy than TT. Also, patients with CC genotypes are 6.3 times more at risk for developing primary epilepsy than TT genotype. According to rs11536858, there is a significant association between cases and control groups, as AA genotypes are found to be more at risk for developing epilepsy than GG genotypes. Also, there is a statistically significant association between clonazepam resistance and rs11536858, as p value < 0.001* with the highest frequency of TT genotypes at 4.3%. According to rs1927911, there are no significant results between the cases and the control groups or between drug-responsive and drug resistance. Conclusion Possible involvement of the Toll-like receptor clarifies the importance of innate immunity in initiating seizures and making neuronal hyperexcitability. In this work, multiple significant associations between TLR SNPs and epilepsy, epileptic phenotype, and drug-resistant epilepsy have been found. More studies with bigger sample sizes and different techniques with different SNPs are recommended to find the proper immunotherapy for epilepsy instead of the treatment by antiepileptic drugs.

The association between MDR1 C3435T genetic polymorphism and the risk of multidrug-resistant epilepsy in Egyptian children

“…Alternatively, Siddiqui et al found an increase in 3435CC genotype frequency in DRE patients who were taking valproic acid [5]. The relationship between Toll-like receptor (TLR4) SNPs and resistance to various AEDs such as Na valproate, carbamazepine, clonazepam, phenytoin, and topiramate was examined by Abdelsalam et al, except for rs11536858 with clonazepam, no association was identified between the SNPs tested and drug resistance [1].…”

“…Epilepsy is one of the most severe neurological chronic diseases, its types and response to drugs affected by multiple genetic polymorphisms in innate immunity receptors [1]. Despite its excellent prognosis, 20-30% of epileptic children were not cured of seizures, even with the various trials of antiepileptic drug (AED) therapy [2][3][4].…”

Alterations in DNA 5-hydroxymethylation Patterns in the Hippocampus of an Experimental Model of Refractory Epilepsy

“…Brain derived neurotrophic factor ( Bdnf ) has antiseizure effects, however, infusion of BDNF can also lead to seizures [24, 45, 65, 92, 107]. Toll-like receptor 4 ( Tlr4 ) activation increases inflammation which can lead to seizures [1, 20, 37, 55, 122]. Glutamate decarboxylase 2 ( Gad2 ) converts glutamate into GABA, and loss of expression and activity of GAD2 is associated with seizure activity [18, 51, 132].…”

The role of Toll‐like receptors in neuropsychiatric disorders: Immunopathology, treatment, and management

“…For rs1927911, there was no meaningful difference between drugresponsive and drug resistance or case/control groups. 374 The evidence is not limited to TLRs, and includes adaptor proteins as well. Villegas et al 375 showed a link between TRAF1/C5 Locus polymorphisms with seizures and clinical features in mexican cases with neurocysticercosis.…”