Role of ABCB1 C3435T variant in response to antiepileptic drugs in epilepsy: a review

Over-expression of P-glycoprotein (P-gp), the encoded product of the ATP-binding cassette (ABC), sub-family B, member 1 (ABCB1/MDR1) gene, plays an important role in mediating multidrug resistance to antiepileptic drugs (AEDs) in about 30% of patients with epilepsy. Genetic variation may in part explain inter-individual differences in phenotype-genotype relationships in the pharmacological response of epilepsy patients to AEDs. The synonymous C3435T polymorphism is one of the most common allelic variants in the ABCB1/MDR1 gene, proposed in the causation of refractory epilepsy. Many studies have shown the relationship between C3435T polymorphism and refractoriness to AEDs in epilepsy. However, there is controversy between the findings of various studies, that is, whether ABCB1/MDR1 C3435T gene polymorphism is associated with response to AEDs in epilepsy patients. This review provides a background and discusses the results of investigations on possible confounding factors affecting the interpretation and implementation of association studies in this area

Polymorphic variants of SCN1A and EPHX1 influence plasma carbamazepine concentration, metabolism and pharmacoresistance in a population of Kosovar Albanian epileptic patients

Aim The present study aimed to evaluate the effects of gene variants in key genes influencing pharmacokinetic and pharmacodynamic of carbamazepine (CBZ) on the response in patients with epilepsy. Materials & Methods Five SNPs in two candidate genes influencing CBZ transport and metabolism, namely ABCB1 or EPHX1, and CBZ response SCN1A (sodium channel) were genotyped in 145 epileptic patients treated with CBZ as monotherapy and 100 age and sex matched healthy controls. Plasma concentrations of CBZ, carbamazepine-10,11-epoxide (CBZE) and carbamazepine-10,11-trans dihydrodiol (CBZD) were determined by HPLC-UV-DAD and adjusted for CBZ dosage/kg of body weight. Results The presence of the SCN1A IVS5-91G>A variant allele is associated with increased epilepsy susceptibility. Furthermore, carriers of the SCN1A IVS5-91G>A variant or of EPHX1 c.337T>C variant presented significantly lower levels of plasma CBZ compared to carriers of the common alleles (0.71±0.28 vs 1.11±0.69 μg/mL per mg/Kg for SCN1A IVS5-91 AA vs GG and 0.76±0.16 vs 0.94±0.49 μg/mL per mg/Kg for EPHX1 c.337 CC vs TT; PG showed a reduced microsomal epoxide hydrolase activity as reflected by a significantly decreased ratio of CBZD to CBZ (0.13±0.08 to 0.26±0.17, pT SNP and SCN1A 3148A>G variants were not associated with significant changes in CBZ pharmacokinetic. Patients resistant to CBZ treatment showed increased dosage of CBZ (657±285 vs 489±231 mg/day; P<0.001) but also increased plasma levels of CBZ (9.84±4.37 vs 7.41±3.43 μg/mL; P<0.001) compared to patients responsive to CBZ treatment. CBZ resistance was not related to any of the SNPs investigated. Conclusions The SCN1A IVS5-91G>A SNP is associated with susceptibility to epilepsy. SNPs in EPHX1 gene are influencing CBZ metabolism and disposition. CBZ plasma levels are not an indicator of resistance to the therapy

Association of GABRG2 rs211037 polymorphism with susceptibility to epilepsy in Asians: a multicentre cohort study and meta-analysis

Conference theme: Transforming the Future through SciencePoster session: Physiology: Genetics, Genomics and ProteomicsPURPOSE:The gamma-aminobutyric acid receptor subunit gamma-2 (GABRG2) gene encodes GABR-gamma2 protein, which has been implicated in susceptibility to epilepsy. Several studies have investigated whether the synonymous GABRG2 rs211037 polymorphism is a risk factor for various epilepsy types including febrile seizure (FS), idiopathic generalized epilepsy (IGE) and symptomatic epilepsy (SE), however results have been inconclusive. Therefore, we examined association of this polymorphism in FS, IGE, SE, and cryptogenic epilepsy (CE), through both a multicenter case control study and a meta-analysis. METHODS: The rs211037 was genotyped in Hong Kong Chinese and in Malaysian Chinese, Indian, and Malay participants. Genotypes of 5101 participants, of which 1769 were from Malaysia and 3332 from Hong Kong, were included in this case-control study. KEY FINDINGS:Of the 1179 patients, 66%, 13%, and 21% were Chinese, Indians, and Malays, respectively. Of the Chinese patients, 37% were from Malaysia and 63% were from Hong Kong. Significant association was observed between rs211037 polymorphism and susceptibility to SE (T vs. Cp=0.000003 and TT vs. CC, p=0.00001) or to epilepsy with FS (T vs. C p=0.02 and CT vs. CC, p=0.02) in overall Chinese and to IGE in Chinese from Malaysia (TT vs. CC, p=0.01), but not to CE. Meta-analysis revealed a strong association between rs211037 with FS and SE in Asians for alleles (p=0.02, p=0.002 and p<0.00001, respectively) and for all genotype models. SIGNIFICANCE: Our data suggests that GABRG2 rs211037 polymorphism is a risk factor for susceptibility to SE and FS in Asians, particularly in Chinese

The Anticonvulsant Triheptanoin Shows Anaplerotic Activity in the Pilocarpine Model of Temporal Lobe Epilepsy in Mice

This journal suppl. entitled: Special Issue: 30th International Epilepsy Congress, Montreal, Canada, 23-27 June 2013Late Breaking Abstracts: LBP1090PURPOSE: High frequency action potentials are mediated by voltage-gated sodium channels, composed of one large a subunit and two small β subunits, encoded mainly by SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B genes in the CNS. Since mutations of these can cause certain genetic epilepsy syndromes, we investigated whether polymorphisms in these genes may affect epilepsy risk in general. METHOD: Epilepsy patients and control subjects from Hong Kong and Kuala Lumpur were matched in age, sex and ethnicity. Epilepsy was broadly classified based on ILAE criteria. Blood was withdrawn for DNA extraction. Using Haploview, we tagged the five genes with 43 polymorphisms: 27 in Hong Kong, 28 in Malaysia, and 12 in both locations. Polymorphisms were genotyped by Sequenom Mass Array. RESULTS: The study included 1529 epilepsy patients (mean+/-SD age: 35 +/- 16 years) and 1935 control subjects (34 +/- 16 years) from four ethnic groups or locations: Malay, Indian, and Chinese, all from Malaysia, and Chinese from Hong Kong (the latter comprising 54% of patients and 44% of controls). Of patients, 19% were idiopathic, 42% symptomatic, and 40% cryptogenic. The strongest association with epilepsy was rs3812718, or SCN1A IVS5N+5G>A, odds ratio (OR) = 0.85 for allele G (p = 0.0009) and 0.73 for genotypes GG vs. AA (p = 0.003). The association was consistent across ethnicities. Allele G is known to affect splicing and to speed recovery from inactivation. Since SCN1A is preferentially expressed in inhibitory neurons, G may decrease epilepsy risk. SCN1A rs10188577 displayed OR = 1.20 for allele C (p = 0.003); SCN2A rs12467383 had OR = 1.16 for allele A (p = 0.01), and displayed LD with rs2082366 (r2 = 0.67), whose genotypes tended toward association with SCN2A brain expression (p = 0.10). SCN1A rs2298771 was associated with epilepsy in Indians (OR = 0.56, p = 0.005). SCN2B rs602594 was associated with idiopathic epilepsy (OR = 0.62, p = 0.002). CONCLUSION: Common genetic variants in neuronal sodium channel genes are associated with the risk of epilepsy.link_to_OA_fulltex