Dataset Information

Differential role of sodium channels SCN1A and SCN2A gene polymorphisms with epilepsy and multiple drug resistance in the north Indian population.

ABSTRACT:

Aims

To evaluate sodium channel genes as candidates for epilepsy susceptibility and their role in therapeutic efficacy, we screened coding single-nucleotide polymorphism of SCN1A p. Thr 1067 Ala or c.3184 A-->G (rs2298771) and SCN2A p.Arg19Lys or c.56 G-->A (rs17183814) in north Indian epilepsy patients.

Methods

The genotyping was performed in 160 control subjects and 336 patients with epilepsy, of whom 117 were drug resistant and 219 were drug responsive. Therapeutic drug monitoring for phenytoin, carbamazepine, phenobarbital and valproate was also performed in 20% of the patients to confirm compliance.

Results

AG genotype of SCN1A 3184 A-->G polymorphism was significantly higher and associated in epilepsy patients [P= 0.005; odds ratio (OR) 1.76, 95% confidence interval (CI) 1.19, 2.61], whereas A variant of SCN2A c.56 G-->A was associated with multiple drug resistance in north Indian patients with epilepsy (P= 0.03; OR 1.62, 95% CI 1.03, 2.56).

Conclusions

Overall, results indicate a differential role of genetic polymorphisms of sodium channels SCN1A and SCN2A in epilepsy susceptibility and drug response.

SUBMITTER: Lakhan R

PROVIDER: S-EPMC2767285 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Differential role of sodium channels SCN1A and SCN2A gene polymorphisms with epilepsy and multiple drug resistance in the north Indian population.

Lakhan Ram R Kumari Ritu R Misra Usha K UK Kalita Jayanti J Pradhan Sunil S Mittal Balraj B

British journal of clinical pharmacology 20090801 2

<h4>Aims</h4>To evaluate sodium channel genes as candidates for epilepsy susceptibility and their role in therapeutic efficacy, we screened coding single-nucleotide polymorphism of SCN1A p. Thr 1067 Ala or c.3184 A-->G (rs2298771) and SCN2A p.Arg19Lys or c.56 G-->A (rs17183814) in north Indian epilepsy patients.<h4>Methods</h4>The genotyping was performed in 160 control subjects and 336 patients with epilepsy, of whom 117 were drug resistant and 219 were drug responsive. Therapeutic drug monitor ...[more]

PMID: 19694741

Similar Datasets

Project description:Background: SCN1A and SCN2A genes have been reported to be associated with the efficacy of single and combined antiepileptic therapy, but the results remain contradictory. Previous meta-analyses on this topic mainly focused on the SCN1A rs3812718 polymorphism. However, meta-analyses focused on SCN1A rs2298771, SCN1A rs10188577, SCN2A rs17183814, or SCN2A rs2304016 polymorphisms are scarce or non-existent. Objective: We aimed to conduct a meta-analysis to determine the effects of SCN1A rs2298771, SCN1A rs10188577, SCN2A rs17183814, and SCN2A rs2304016 polymorphisms on resistance to antiepileptic drugs (AEDs). Methods: We searched the PubMed, Embase, Cochrane Library, WANFANG, and CNKI databases up to June 2020 to collect studies on the association of SCN1A and SCN2A polymorphisms with reactivity to AEDs. We calculated the pooled odds ratios (ORs) under the allelic, homozygous, heterozygous, dominant, and recessive genetic models to identify the association between the four single-nucleotide polymorphisms (SNPs) and resistance to AEDs. Results: Our meta-analysis included 19 eligible studies. The results showed that the SCN1A rs2298771 polymorphism was related to AED resistance in the allelic, homozygous, and recessive genetic models (G vs. A: OR = 1.20, 95% CI: 1.012-1.424; GG vs. AA: OR = 1.567, 95% CI: 1.147-2.142; GG vs. AA + AG: OR = 1.408, 95% CI: 1.053-1.882). The homozygous model remained significant after Bonferroni correction (P < 0.0125). Further subgroup analyses demonstrated the significance of the correlation in the dominant model in Caucasians (South Asians) after Bonferroni correction (GG + GA vs. AA: OR = 1.620, 95% CI: 1.165-2.252). However, no association between SCN1A rs2298771 polymorphism and resistance to AEDs was found in Asians or Caucasians (non-South Asians). For SCN1A rs10188577, SCN2A rs17183814, and SCN2A rs2304016 polymorphisms, the correlations with responsiveness to AEDs were not significant in the overall population nor in any subgroup after conducting the Bonferroni correction. The results for SCN1A rs2298771, SCN1A rs10188577, and SCN2A rs2304016 polymorphisms were stable and reliable according to sensitivity analysis and Begg and Egger tests. However, the results for SCN2A rs17183814 polymorphism have to be treated cautiously owing to the significant publication bias revealed by Begg and Egger tests. Conclusions: The present meta-analysis indicated that SCN1A rs2298771 polymorphism significantly affects resistance to AEDs in the overall population and Caucasians (South Asians). There were no significant correlations between SCN1A rs10188577, SCN2A rs17183814, and SCN2A rs2304016 polymorphisms and resistance to AEDs.

Project description:BackgroundMutations in the neuronal sodium voltage-gated channel, alpha subunit 1 (SCN1A) gene have been associated with epilepsy. We investigated the SCN1A-A3184G polymorphism among Egyptian children and adolescents with non-lesional epilepsy.MethodsA prospective case - control observational study was done in Mansoura University Children's Hospital, Egypt including 326 children with non-lesional epilepsy (163 antiepileptic drugs (AEDs) resistant cases & 163 AEDs responders) and 163 healthy controls. One step real time polymerase chain reaction (PCR) was used for the molecular analysis. Student's t-test, and Monto Carlo, chi-square and Mann-Whitney tests were used for the statistical analysis.ResultsAll study participants were matched as regards the age, sex and body weight (p = 0.07, 0.347 and 0.462, respectively). They had the (AA) and (AG) genotypes but not the (GG) variant. No significant differences were found between cases and controls regarding (AG) and (AA) genotypes and A- and G-alleles (p = 0.09 and 0.3, respectively). We did not find significant differences between AEDs responders and resistant cases regarding the studied genotypes and alleles (p = 0.61 and 0.746, respectively). In the resistant group, we observed significant associations between the (AG) genotype and seizure frequency (p = 0.05), the tonic-clonic seizure (p < 0.001), the younger age of first seizure attack (p = 0.03), abnormal electroencephalogram (EEG) (p < 0.001), the positive family history of epilepsy (p = 0.006), topiramate (p = 0.03) and valproic acid (p < 0.001), while the (AA) genotype was associated with carbamazepine (p = 0.03). While in AEDs responders, there were significant associations between the AG genotype and the abnormal EEG activity, levetiracetam and carbamazepine (p = 0.016, 0.028 and 0.02).ConclusionsThe SCN1A-A3184G genotypes and alleles were not associated with the epilepsy risk among Egyptian children. Significant associations were reported between the AG genotype and some predictors of refractory epilepsy.

Project description:Loss of function mutations of SCN1A, the gene coding for the voltage-gated sodium channel NaV1.1, cause different types of epilepsy, whereas gain of function mutations cause sporadic and familial hemiplegic migraine type 3 (FHM-3). However, it is not clear yet how these opposite effects can induce paroxysmal pathological activities involving neuronal networks' hyperexcitability that are specific of epilepsy (seizures) or migraine (cortical spreading depolarization, CSD). To better understand differential mechanisms leading to the initiation of these pathological activities, we used a two-neuron conductance-based model of interconnected GABAergic and pyramidal glutamatergic neurons, in which we incorporated ionic concentration dynamics in both neurons. We modeled FHM-3 mutations by increasing the persistent sodium current in the interneuron and epileptogenic mutations by decreasing the sodium conductance in the interneuron. Therefore, we studied both FHM-3 and epileptogenic mutations within the same framework, modifying only two parameters. In our model, the key effect of gain of function FHM-3 mutations is ion fluxes modification at each action potential (in particular the larger activation of voltage-gated potassium channels induced by the NaV1.1 gain of function), and the resulting CSD-triggering extracellular potassium accumulation, which is not caused only by modifications of firing frequency. Loss of function epileptogenic mutations, on the other hand, increase GABAergic neurons' susceptibility to depolarization block, without major modifications of firing frequency before it. Our modeling results connect qualitatively to experimental data: potassium accumulation in the case of FHM-3 mutations and facilitated depolarization block of the GABAergic neuron in the case of epileptogenic mutations. Both these effects can lead to pyramidal neuron hyperexcitability, inducing in the migraine condition depolarization block of both the GABAergic and the pyramidal neuron. Overall, our findings suggest different mechanisms of network hyperexcitability for migraine and epileptogenic NaV1.1 mutations, implying that the modifications of firing frequency may not be the only relevant pathological mechanism.

Dataset Information

Differential role of sodium channels SCN1A and SCN2A gene polymorphisms with epilepsy and multiple drug resistance in the north Indian population.

Aims

Methods

Results

Conclusions

Publications

Differential role of sodium channels SCN1A and SCN2A gene polymorphisms with epilepsy and multiple drug resistance in the north Indian population.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets