SCN1A Polymorphisms Research Articles

Association of SCN1A Polymorphisms rs3812718 and rs2298771 with Epilepsy.

Background/Objectives: Epilepsy is a brain disease with both environmental and genetic inputs. Ion channel dysfunction seems to be of great significance for abnormal neuronal behavior during epileptic seizures. Within neurons, the voltage-gated sodium channels are crucial proteins contributing to the initiation and propagation of action potentials. The voltage-gated sodium channel α subunit 1 (SCN1A) gene encodes for the α subunit of a voltage-gated ion channel. The aim of the study was to investigate the relation of two common SCN1A variants, i.e., rs3812718 and rs2298771, with distinct epileptic phenotypes in a South-Eastern European population. Methods: DNA was extracted from 214 unrelated participants with focal onset, focal to bilateral tonic-clonic, or generalized onset epileptic seizures and genotyped using real-time PCR (LightSNiP assays) followed by melting curve analysis. Statistical analysis of the results was performed using IBM SPSS Statistics software (version 29.0 for Windows). Results: Genotype frequency distribution analysis indicated an association for the A-allele-containing genotypes of both rs3812718 and rs2298771 polymorphisms of SCN1A with generalized onset seizures and focal to bilateral tonic-clonic seizures versus focal onset seizures. Conclusions: Consequently, the study provides evidence that supports a potential association of the investigated SCN1A polymorphisms with distinct seizure subtype susceptibility in South-Eastern Europeans.

Association between Genetic Polymorphism of SCN1A, GABRA1 and ABCB1 and Drug Responsiveness in Vietnamese Epileptic Children.

Background and Objectives: Drug resistant epilepsy (DRE) is a major hurdle in epilepsy, which hinders clinical care, patients' management and treatment outcomes. DRE may partially result from genetic variants that alter proteins responsible for drug targets and drug transporters in the brain. We aimed to examine the relationship between SCN1A, GABRA1 and ABCB1 polymorphism and drug response in epilepsy children in Vietnam. Materials and Methods: In total, 213 children diagnosed with epilepsy were recruited in this study (101 were drug responsive and 112 were drug resistant). Sanger sequencing had been performed in order to detect six single nucleotide polymorphisms (SNPs) belonging to SCN1A (rs2298771, rs3812718, rs10188577), GABRA1 (rs2279020) and ABCB1 (rs1128503, rs1045642) in study group. The link between SNPs and drug response status was examined by the Chi-squared test or the Fisher's exact test. Results: Among six investigated SNPs, two SNPs showed significant difference between the responsive and the resistant group. Among those, heterozygous genotype of SCN1A rs2298771 (AG) were at higher frequency in the resistant patients compared with responsive patients, playing as risk factor of refractory epilepsy. Conversely, the heterozygous genotype of SCN1A rs3812718 (CT) was significantly lower in the resistant compared with the responsive group. No significant association was found between the remaining four SNPs and drug response. Conclusions: Our study demonstrated a significant association between the SCN1A genetic polymorphism which increased risk of drug-resistant epilepsy in Vietnamese epileptic children. This important finding further supports the underlying molecular mechanisms of SCN1A genetic variants in the pathogenesis of drug-resistant epilepsy in children.

Association between SCN1A polymorphism and risk of epilepsy in children: A systematic review and meta-analysis.

Epilepsy is a common neurological disorder in children. Numerous studies have demonstrated the association between SCN1A polymorphisms and risk of epilepsy in adults, but their role in epilepsy in children has just gained traction and results have remained inconsistent. In this work, we performed a systematic review and meta-analysis to assess the association between SCN1A polymorphisms and risk for epilepsy in children. A systematic literature search was performed in PubMed, Scopus, Web of Science, China National Knowledge Internet, Wanfang and VIP databases to identify eligible studies up to June 2023. Quantitative data synthesis was then performed under five genetic models: dominant, recessive, homozygous, heterozygous, and allele. Five studies involving 1380 subjects were included in the meta-analysis. Among many SCN1A polymorphisms reported, only rs2298771 was repeatedly studied in these reports. Pooled analysis demonstrated that there was no significant association between the polymorphism and risk of epilepsy in children (P>0.05). In conclusion, SCN1A rs2298771 polymorphism was not significantly associated with the risk of epilepsy in children.

SCN1A Polymorphisms and Haplotypes Are Associated With Valproic Acid Treatment Outcomes in Chinese Children With Epilepsy

BackgroundSodium channel genes, especially SCN1A, were reported to play an important role in the treatment outcomes of antiseizure medications. The aim of this study was to explore the association of SCN1A polymorphisms with efficacy and adverse drug reactions (ADRs) related to valproic acid (VPA) among Chinese children with epilepsy. MethodsA total of 126 children with epilepsy treated with VPA for at least 12 months were enrolled in this study. Three single nucleotide polymorphisms (SNPs) of SCN1A including rs2298771, rs10167228, and rs3812718 were genotyped using Sequenom MassArray system. Bioinformatics tools were used to explore the potential targets and pathways of SCN1A in VPA-related ADRs. ResultsThe three SNPs in this study were found to be closely associated with treatment outcomes for VPA. Carriers of SCN1A rs3812718 TT genotype tended to be seizure-free with VPA treatment (P = 0.007). AA genotype of rs10167228 and TT genotype of rs2298771 might be protective factors for weight gain induced by VPA, whereas TA genotype of rs10167228 and CT genotype of rs2298771 increased the risk. TAT haplotype carriers were found to respond better to VPA treatment (P = 0.017), whereas CTC haplotype might be a risk factor for VPA-induced weight gain (P = 0.035). Bioinformatics analysis suggested that SCN1A might play a role in VPA-induced weight gain by regulating gated channel activity and GABAergic synapse pathway. ConclusionThis study revealed that SCN1A rs2298771, rs10167228, and rs3812718 polymorphisms and haplotypes might affect the treatment outcomes of VPA in Chinese children with epilepsy.

Association of SCN1A Gene Polymorphism with Phenytoin Response in Patients with Epilepsy: Relevance of Stratification by the History of Febrile Seizure

AIM: The SCN1A gene encodes the NaV1.1 sodium channel in the central nervous system that serves as the target for phenytoin. Our study aimed to investigate the association of SCN1A polymorphism (SNP rs3812718) with phenytoin response. MATERIALS AND METHODS: A total of 120 epileptic patients who had received phenytoin for at least 1 year were enrolled in the study and genotyped using the TaqMan assay. They were classified into phenytoin-responsive (n = 62) and phenytoin unresponsive groups (n = 58). Patients were also stratified according to the history of febrile seizure (24 in the febrile seizure subgroup; 96 patients in the no history of febrile seizure subgroup) and epilepsy etiology (47 in idiopathic; 73 in the symptomatic + cryptogenic subgroup). RESULTS: The frequency of AA (19% vs. 11.3%) and AG genotypes (43.1% vs. 40.3%) was found to be more frequent in phenytoin unresponsive. GG genotypes dominated in the phenytoin responsive group (37.9% vs. 48.4%) but were not statistically significant (p > 0.05). We identified two variables associated with phenytoin response: the etiology of epilepsy (p = 0.012) and history of febrile seizure (0.014). A significant positive association between the rs3812718 genotype and phenytoin response was found when patients were stratified by a history of febrile seizures. In patients without a history of febrile seizures, the AA genotype had a higher risk of phenytoin unresponsiveness than the GG genotype (p = 0.048; OR 3.73, 95% CI: 1.01–13.78). CONCLUSION: There was no significant association between the rs3812718 polymorphism and phenytoin responsiveness in patients with epilepsy. In the patients without a history of febrile seizure subgroup, AA increased the risk of phenytoin unresponsiveness compared to the GG genotype.

SCN1A polymorphisms influence the antiepileptic drugs responsiveness in Jordanian epileptic patients.

The aim of this study was to evaluate whether the voltage-gated sodium channel alpha subunit 1 (SCN1A) gene polymorphisms influence the responsiveness of Jordanian epileptic patients to antiepileptic drugs (AEDs). A total of 72 AEDs-treated epileptics were polymerase chain reaction (PCR)-genotyped for six single nucleotide polymorphisms (SNPs), including SCN1A rs2298771, rs3812718, rs3812719, rs2217199, rs2195144 and rs1972445. Genotype and allele distributions in drug-responsive and drug-resistant patients were compared. The six SNPs haplotypes were examined, and the linkage disequilibrium (LD) was assessed. The genotypes of drug-resistant and drug-responsive groups were in Hardy-Weinberg equilibrium. Three genetic polymorphisms of the SCN1A gene seemed to influence the resistance to AEDs, on the level of alleles and genotypes. Data revealed that rs2298771 G allele, rs3812719 C allele, and rs2195144 T allele increased the risk of developing AEDs-resistance (OR=2.9; 95%CI= 1.4-5.9, p=0.003; OR=2.4; 95%CI=1.2-4.7, p=0.01; OR=2.3; 95%CI=1.2-4.7, p=0.01), respectively. Haplo type analysis of SCN1A polymorphisms revealed high-degree LD associated with resistance to AEDs. A synergetic effect appears with highly significant association in GCCATG haplotype of rs2298771, rs3812718, rs3812719, rs2217199, rs2195144, and rs1972445 respectively (OR=2.8; 95%CI=1.5-6.2, p=0.002). Data suggests that SCN1A polymorphisms could influence the resistance to AEDs in Jordanian epileptics at three SNPs (rs2298771; rs3812719; rs2195144). Additionally, haplotype analysis indicated a substantial degree of LD between the six SCN1A polymorphisms. Further investigation with larger sample size is needed to confirm the results of the current study.

ABCG2, SCN1A and CYP3A5 genes polymorphism and drug-resistant epilepsy in children: A case-control study

Drug Resistant -Epilepsy is still a major challenge in pharmacotherapy of epilepsy. Pharmacogenetic pathways are one of the most important elements that can help clinicians determine medication response and provide more efficient drug therapy, especially in cases of drug resistance. Genetic alterations in drug target and transporter proteins, in part, could explain the development of drug-resistant epilepsy. We sought to assess the association of CYP3A5 (rs776746), SCN1A (rs2298771) and ABCG2 (rs2231137) candidate polymorphisms with drug-resistant epilepsy among Iranian children with epilepsy. In a hospital-based case-control study, 93 participants, including 45 men and 48 women aged 1.5 to 14 years old were recruited. Genotyping of CYP3A5 (rs776746), SCN1A (rs2298771) and ABCG2 (rs2231137) polymorphisms using the high-resolution melting (HRM) method were measured in 46 children with drug-resistant epilepsy and 47 healthy control subjects. The binary logistic regression model was used to estimate the odds ratio (OR) for each polymorphism per effect allele increase. The mean (standard deviation [SD]) age of the drug-resistant patients was 10.7 (9.0) years versus 7.3 (3.6) in the control group. In the case group, most of the patients with epilepsy were diagnosed with generalized seizure (about 87%) and negative epileptic history status (63%). Furthermore, idiopathic epilepsy was dominant in the case group (69%). There was a clinically meaningful increase in the chance of drug-resistant epilepsy in participants with candidate polymorphism in ABCG2 gene (per allele T increase, adjusted odds ratio [OR] 2.41, confidence interval [CI] 0.99 to 5.87, P=0.05). No significant association was found between CYP3A5 (per allele C increase, OR 0.92, CI 0.33 to 2.60, P= 0.88) and SCN1A (per allele *1 increase, OR 0.65, 95% CI 0.34 to 1.23, P= 0.19) with drug-resistant epilepsy. We found evidence for the relationship between the ABCG2 gene polymorphism and a higher chance of drug-resistant epilepsy in children. This finding may have important implications for understanding the role of ABCG2 gene polymorphism in children with drug-resistant epilepsy.

Effects of SCN1A and SCN2A polymorphisms on responsiveness to valproic acid monotherapy in epileptic children: A protocol for systematic review and meta-analysis.

Background: The gene mutation of coding sodium channel is one of the most important mechanisms in the pathogenesis of epilepsy. There exists a large inter-individual variation in the efficacy of valproic acid (VPA) against epilepsy. What are the genetic polymorphism influences of sodium channels on VPA response is still under discussion. In this study, a meta-analysis was used to further explore the effects of SCN1A and SCN2A gene polymorphism on VPA response in children with epilepsy.Methods: The PubMed, EMBASE, Web of Science, Chinese National Knowledge Infrastructure, Chinese Science and Technique Journals Database, China Biology Medicine disc, and Wan Fang Database were searched up to April 2021 for appropriate studies regarding the association between SCN1A and SCN2A gene polymorphism on VPA response in children suffering from epilepsy. The meta-analysis was conducted by Review Manager 5.3 software.Results: The results of this meta-analysis will be submitted to a peer-reviewed journal for publication.Conclusion: This meta-analysis will summarize the effects of SCN1A and SCN2A gene polymorphisms on VPA response in children with epilepsy.OSF Registration Number:DOI 10.17605/OSF.IO/N2786.

Associations between CYP3A4, CYP3A5 and SCN1A polymorphisms and carbamazepine metabolism in epilepsy: A meta-analysis

Background and objectiveCYP3A4 (rs2242480), CYP3A5 (rs776746) and SCN1A (rs3812718 and rs2298771) gene polymorphisms were previously indicated to be associated with carbamazepine (CBZ) metabolism and resistance in epilepsy. However, previous studies regarding the effects of these polymorphisms still remain controversial. Therefore, we performed a meta-analysis to evaluate whether the four polymorphisms are associated with CBZ metabolism and resistance. MethodsThe PubMed, EMBASE, Cochrane library, Chinese National Knowledge Infrastructure, Chinese Science and Technique Journals Database, China Biology Medicine disc and Wan Fang Database were searched up to January 2021 for appropriate studies regarding the association of rs2242480, rs776746, rs3812718 and rs2234922 polymorphisms with CBZ metabolism and resistance. The meta-analysis was conducted by Review Manager 5.3 software. ResultsEighteen studies involving 2546 related epilepsy patients were included. We found that the G allele of CYP3A4 rs2242480 markedly decreased the plasma CBZ concentration in epilepsy. For CYP3A5 rs776746 polymorphism, the GG genotype (homozygote codominant model: GG vs. AA) and GG + GA genotype (dominant model: GG + GA vs. AA and recessive model: GG vs. GA + AA) were respectively found to be significantly associated with increased CBZ plasma concentration. Additionally, it was also found that the SCN1A rs3812718 A allele was significantly associated with decreased CBZ plasma concentration and increased CBZ resistance. However, no association was observed between SCN1A rs2298771 polymorphism and CBZ metabolism and resistance. ConclusionThe CYP3A4 rs2242480, CYP3A5 rs776746 and SCN1A rs3812718 polymorphisms may play important roles in CBZ metabolism and resistance, while SCN1A rs2298771 polymorphism is not associated with CBZ in epilepsy. These findings would improve the individualized therapy of epileptic patients in clinics.

Analysis of SCN1A polymorphism as Genetic Risk Factor for Neurological Disorders

Epileptic seizures lead to changes in the importance of the blood laboratory tests which represent changes in various systems of organs in the body. A present study assessed the association between the rs3812718 polymorphism in SCN1A gene and susceptibility with epilepsy. In total, 48 subjects (28 patients and 20 controls) were included in the study. Subjects’ age and sex were matched. The patients' demographic profiles, including the gender (female: 26 and male; 34), mean of ages (21±8.6), the controls gender (female: 6 and male; 19) and age mean (39±13.3). Single nucleotide polymorphisms (SNPs) was used to investigate the distribution of SCN1A rs3812718 genotypes (G > A) in patients with Epilepsy. Direct sequencing is use to identify the (G>A) polymorphisms of the SCN1A gene on chromosome 2q24. Genotypes and allelic frequencies for the SCN1A in both groups were compared. In addition, the results show two other SNPs for the first time in Iraqi patients rs2217199 T>C and rs3812719 G>T and the study determines some biochemical tests (potassium) were performed by Reflotron and (glucose, sodium, chloride and calcium) by a Spectrophotometer in the sera of subjects. In this population, the alleles frequency of rs2217199/ C, rs3812719/ T, rs3812718/A, the susceptibility of epileptic with gene polymorphisms was correlated (OR = 5.84, p = 0.0001; OR = 4.41, p = 0.001; OR = 5.33, p = 0.001; respectively). The haplotype (CTA) was also significantly related with Epileptic patients (OR = 7.08; p = 0.001). Also, the study showed an increase in glucose levels at p-value= 0.008, normal value in serum K, Cl, Ca and Na levels in Epileptic patient with seizure compare with control. The study in an Iraqi population suggests that SCN1A polymorphisms genetic risk factor for Epileptic patients. Simple blood testing, particularly for some encephalopathies, can be a crucial help for recognizing the etiology.

Effects of SCN1A and SCN2A polymorphisms on responsiveness to valproic acid monotherapy in epileptic children

PurposeThis study was conducted to explore the influence of genetic variations on responsiveness to valproic acid (VPA) monotherapy among Chinese children with epilepsy. MethodsOne hundred and forty epileptic children taking VPA as monotherapy were enrolled, and at least one-year follow-up was obtained to assess the therapeutic outcome. Twenty-seven single nucleotide polymorphisms (SNPs) within twelve candidate genes correlated with the metabolic enzymes, transporters and targets of VPA were genotyped. The effects of selected polymorphisms on VPA efficacy were identified by binary logistic regression analysis adjusting for potential confounders. ResultsSCN2A rs2304016 (A > G) AG genotype was more common among the VPA-resistant patients in comparison with the VPA-responsive patients (OR = 3.18, 95 % CI = 1.10−9.14, P = 0.032), and in subgroup of focal seizure, lower frequency of VPA resistance was found in epileptic children with SCN1A rs2298771 AG genotype than those with AA genotype (OR = 0.11, 95 % CI = 0.01−0.91, P = 0.040). ConclusionsOur study indicated that SCN2A rs2304016 and SCN1A rs2298771 polymorphisms might be associated with the response to VPA monotherapy in Chinese epileptic children. Further and larger researches are required to validate these results.

Association of SCN1A, SCN2A, and UGT2B7 Polymorphisms with Responsiveness to Valproic Acid in the Treatment of Epilepsy.

Purpose The efficacy of valproic acid (VPA) varies widely in clinical treatment of epileptic patients. Our study is aimed at exploring a potential association between polymorphisms of SCN1A, SCN2A, and UGT2B7 genetic factors and VPA responses. Methods In this observational study, a total of 114 epileptic patients only treated with VPA for at least 1 year were included to explore the genetic polymorphisms of drug responses (mean follow-up time: 3.68 ± 1.78 years). Thirty-one single-nucleotide polymorphisms (SNPs) in three candidate genes that related with drug-metabolizing enzymes and receptors were genotyped. Results Of the 31 SNPs, eight were significantly associated with VPA responses, including rs1381105, rs2162600, rs10197716, rs2119068, rs2119067, rs353116, rs353112 and rs6740895. The interaction between rs10197716 and rs2119068 was the most significantly correlated with VPA responses compared with other combinations (the highest VPA-responsive rate 0.92 versus the lowest VPA-responsive rate 0.33, p = 0.007). Conclusion The study indicated that eight SNPs and SNP-SNP interaction may be associated with VPA responses in Chinese Han epileptic patients. The SNPs were rs1381105 (SCN1A), rs2162600 (SCN1A), rs10197716 (SCN2A), rs2119068 (SCN2A), rs2119067 (SCN2A), rs353116 (SCN2A), rs353112 (SCN2A) and rs6740895 (SCN2A), respectively. The interaction between the three pairs of rs10197716-rs2119068, rs10197716-rs11889342 and rs7598931-rs12233719 was the most significant for VPA. This implied that these SNPs may play an important role in the pharmacogenomics mechanism of valproic acid.

SCN1A and SCN2A polymorphisms are associated with response to valproic acid in Chinese epilepsy patients.

There is a large inter-individual variation in the efficacy of valproic acid (VPA) against epilepsy. The genetic polymorphism influence of sodium channels on VPA response remains a matter of debate. The aim of the study was to explore the effect of SCN1A and SCN2A gene polymorphisms on VPA response in the treatment of epilepsy among Chinese patients. A total of 354 epileptic patients with VPA treatment were genotyped for five single nucleotide polymorphisms (SNP), including SCN1A rs10188577 T>C, rs2298771 T>C, rs3812718 G>A, and SCN2A rs2304016 A>G, rs17183814 G>A. A binary logistic regression analysis was performed to evaluate the association of genotype with VPA antiepileptic effects, adjusting the influence of confounding factors. Genotype distributions of all selected SNPs were consistent with the Hardy-Weinberg equilibrium in epilepsy patients. SCN1A rs3812718 and SCN2A rs2304016 were found to be significantly associated with VPA response, both in monotherapy and in VPA-based polytherapy. Patients with the rs3812718 A allele were more frequently seen in the VPA-responsive group (P < 0.05), and the rs2304016 G allele was related to an increased risk of resistance to VPA therapy (P < 0.05). Our study revealed that SCN1A rs3812718 and SCN2A rs2304016 polymorphisms might be markers of VPA response in Chinese epilepsy patients. ChiCTR-1800016477.

Association between SCN1A polymorphism rs3812718 and valproic acid resistance in epilepsy children: a case-control study and meta-analysis.

Resistance to valproic acid (VPA), a first-line antiepileptic drug (AED), is occurring at an alarming rate, particularly in children. Signal nucleotide polymorphisms are considered crucial in this process. Therefore, we investigated whether the SCN1A polymorphism rs3812718 could be associated with VPA resistance. A total of 231 children with epilepsy who were solely administered VPA were enrolled. DNA was extracted from the peripheral blood samples and was genotyped by the Mass Array method. Furthermore, a meta-analysis was conducted between the drug responsive and resistant patients who were exposed to voltage-gated sodium channels. Results revealed that the TT genotype was associated with a higher risk of developing drug resistance (OR = 2.636, 95% CI 1.08–6.433, P = 0.033). After adjusting for the risk factors, a significant difference was still observed between the responsive and resistant groups (OR = 2.861, 95% CI 1.141–7.174, P = 0.025). Moreover, the recessive model was associated with a decreased drug resistance (OR = 0.402, 95% CI 0.167–0.968, P = 0.042) after correcting the risk factors. Meta-analysis of nine studies revealed similar results. In conclusion, our results proved that the rs3812718 TT genotype was associated with a high risk of developing drug resistance, and the recessive model could decrease the risk of VPA resistance.

The possible effect of SCN1A and SCN2A genetic variants on carbamazepine response among Khyber Pakhtunkhwa epileptic patients, Pakistan.

PurposeSCN1A (3184 A>G) and SCN2A (56G>A) gene encodes α subunit of the neuronal voltage-gated sodium channel, which is a target for carbamazepine (CBZ). Recent studies have demonstrated that polymorphism of SCN1A (3184 A>G) and SCN2A (56G>A) was associated with use of CBZ. However, it has not been determined whether the polymorphism affects CBZ or other antiepileptic drug responsiveness. The aim of the study was to establish whether the SCN1A (3184 A>G) and SCN2A (56G>A) polymorphisms of the SCN1A and SCN2A genes affect responsiveness to CBZ.MethodsSCN1A (3184 A>G) and SCN2A (56G>A) gene polymorphisms were genotyped in 93 Khyber Pakhtunkhwa epileptic patients treated with CBZ. The association between CBZ responsiveness and the polymorphism was estimated by adjusting for clinical factors affecting the outcome of therapy. The number of seizure episodes was documented at baseline, and the therapy of each of the 93 patients was followed up. The plasma level of CBZ was determined using reverse-phase high-performance liquid chromatography. SCN1A and SCN2A genes were genotyped using RFLP. Data were analyzed using Graph Pad Prism 6.ResultsMean age of the patients was 18.6±9.3 at the 3rd month and 18.7±9.5 at the 6th month. The baseline dose of CBZ was 468±19.8 mg/d and titrated at the rate of 48±1.4 and 4.0±0.2 mg/d. The difference in plasma level of CBZ was significant (P=0.004) between 3rd and 6th month among different genotypes of SCN1A gene in nonresponder and responder patients. At the 3rd month of the therapy, the poor responders were more likely (P=0.003 and P=0.01) to have variants (3184AG and 3184GG) of SCN1A gene. Similarly, poor responsders were more likely (P=0.0007 and P=0.001) to have variant genotypes (56GA, 56AA) of SCN2A gene at the 3rd month of the therapy.ConclusionThis study demonstrated a significant association between the SCN1A (3184 AG and GG) and SCN2A (56GA and AA) genotype with CBZ-nonresponsive epilepsy.

Association between two SCN1A polymorphisms and resistance to sodium channel blocking AEDs: a meta-analysis.

Sodium channel blocking antiepileptic drugs (SCB-AEDs) are common effective medications available for epilepsy. However, not all patients respond to this regimen and drug resistance is frequently encountered. Rs2298771(c.3184A > G/p.Thr1067Ala) and rs3812718(IVS5N +5G > A) polymorphisms are two of the most common polymorphisms in the SCN1A gene, which is closely related to resistance to SCB-AEDs. Therefore, we have conducted a meta-analysis to investigate the contribution of the two polymorphisms to resistance of SCB-AEDs. The PubMed, Embase, MEDLINE, and Cochrane Library databases were searched up to September 2017, for studies on the association of SCN1A polymorphisms with resistance to SCB-AEDs. A fixed-effects or random-effects model was used to calculate the pooled odds ratios based on the results from the heterogeneity tests. A total of eight studies were eligible for the pooled analysis, of which eight studies included SCN1A rs3812718 polymorphism and four studies included SCN1A rs2298771 polymorphism. The results showed that SCN1A rs2298771 polymorphism was significantly associated with resistance to SCB-AEDs. (A vs. G: OR = 0.76, 95% CI 0.61-0.95, P = 0.02; AA vs. AG + GG: OR = 0.71, 95% CI 0.54-0.94, P = 0.022). However, no association was observed between SCN1A rs3812718 polymorphism and resistance to SCB-AEDs. Our results indicate that the A-allele of SCN1A rs2298771 polymorphism, especially AA genotype, may play an important role in responsiveness to SCB-AEDs, while SCN1A rs3812718 polymorphism is not associated with SCB-AEDs.

SCN1A and ABCB1 Polymorphisms in Epilepsy

: Genetic variability in drug metabolism affects its treatment with anti epilepsy drugs (AEDs). Allelic variations in genes include SCN1A and ABCB1. Encoding the AEDs’ target and drug transport proteins may affect the efficacy and tolerability of antiepileptic drugs. A study was designed to evaluate the frequency of the ABCB1- and the SCN1A-selected SNPs in the genotype and haplotype combination within the Iranian population who were affected by idiopathic refractory epilepsy (IRE). About 81 healthy normal samples and 34 probands, clinically diagnosed as one type of IRE, were selected. The genotype of the two SNPs in the SCN1A gene (rs2298771, rs7601520) and one SNP in ABCB1 (rs1045642) were determined in two groups by ARMS-PCR and PCR-RFLP, and confirmed by direct sequencing. The data analysis shows no statistically significant differences, and thus, the predicted haplotype frequencies (including the three SNPs) did not show any significant differences between the patients and the control groups.

The potential implication of SCN1A and CYP3A5 genetic variants on antiepileptic drug resistance among Egyptian epileptic children

PurposeDespite the advances in the pharmacological treatment of epilepsy, pharmacoresistance still remains challenging. Understanding of the pharmacogenetic causes is critical to predict drug response hence providing a basis for personalized medications. Genetic alteration in activity of drug target and drug metabolizing proteins could explain the development of pharmacoresistant epilepsy. So the aim of this study was to explore whether SCN1A c.3184 A/G (rs2298771) and CYP3A5*3 (rs776746) polymorphisms could serve as genetic based biomarkers to predict pharmacoresistance among Egyptian epileptic children. MethodsGenotyping of SCN1A c.3184 A/G and CYP3A5*3 polymorphisms using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was performed in 65 healthy control subjects and 130 patients with epilepsy, of whom 50 were drug resistant and 80 were drug responsive. ResultsThere was a significant higher frequency of the AG genotype (p=0.001) and G allele (p=0.006) of SCN1A polymorphism in epileptic patients than in controls. Also their frequency was significantly higher in drug resistant patients in comparison with drug responders (p=0.005 and 0.054 respectively). No significant association between CYP3A5*3 polymorphism and drug-resistance was found. ConclusionsOverall, results confirmed the claimed role of SCN1A c.3184 A/G polymorphism in epilepsy and moreover in development of pharmacoresistance among Egyptian epileptic children. CYP3A5*3 variants have no contributing effect on pharmacoresistance among Egyptian epileptic children.

SCN1A and SCN1B gene polymorphisms and their association with plasma concentrations of carbamazepine and carbamazepine 10, 11 epoxide in Iranian epileptic patients.

From a genetic point of view, epilepsy is a polygenic multifactorial syndrome. The SCN1A and B genes belong to a family of genes that provide instructions for making sodium channels. Understanding the relevance of SCN1A and SCN1B gene polymorphisms to plasma concentration of carbamazepine (CBZ) and 'its active metabolite carbamazepine 10, 11 epoxide (CBZE), may shed more light on inter-individual variations in response to CBZ. In this cross-sectional study, genotype distribution and allele frequency of six non-synonymous exonic single nucleotide polymorphisms (SNPs) of the SCN1A and B genes were selected and determined using PCR-RFLP in 70 epileptic patients treated with CBZ for at least 6 months. The patients had no hepatic or renal diseases and received no medications known to have a major interaction with CBZ. Serum concentrations of CBZ and CBZE were measured using High-Performance Liquid Chromatography (HPLC). The AA, AG and GG alleles of SCN1A were found in 23, 37 and 10 patients, respectively. There were no statistically significant differences in the mean (± standard deviation) of plasma concentrations of CBZ (P=0.8) and CBZE (P=0.1) among these 3 groups. Likewise, there was no statistically significant relationship between SCN1A polymorphisms and CBZ concentration/dose ratio (P=0.7). A significant association was found between CBZ plasma level and CBZ concentration/dose with CBZ daily dose. All patients had the same genotype of SCN1B gene(CC). and no statistical analysis was performed. No significant association between SCN1A gene polymorphisms and plasma levels of CBZ and CBZE were found[u1].

SCN1A, ABCC2 and UGT2B7 gene polymorphisms in association with individualized oxcarbazepine therapy.

Associations between the effects of SCN1A, SCN2A, ABCC2 and UGT2B7 genetic polymorphisms and oxcarbazepine (OXC) maintenance doses in Han Chinese epileptic patients were investigated. Genetic polymorphisms were detected in 184 epileptic patients receiving OXC monotherapy by high-resolution melting curve and TaqMan method. Carriers of the SCN1A IVS5-91G>A, UGT2B7 c.802T>C and ABCC2 c.1249G>A variant alleles required significantly higher OXC maintenance doses than noncarriers (p < 0.05). Corresponding relative ln (concentration-dose ratios) values for SCN1A IVS5-91 variants differed by the genotypic order GG > GA > AA. SCN1A, UGT2B7 and ABCC2 genetic polymorphisms are associated with OXC maintenance doses and may be useful for the personalization of OXC therapy in epileptic patients. Further studies are needed. Original submitted 6 June 2014; Revision submitted 5 September 2014.