Frequencies Of Polymorphisms In ABCB1 And Association Of These Polymorphisms With Antiepileptic Drug Response In People With Epilepsy

Epilepsy is one of the most common neurological disorders. Although 60% of people with epilepsy can achieve seizure free,20-30% continue to have seizures despite antiepileptice drug (AED) treatment. There is accumulating evidence to suggest that the poor response to AEDs is associated with pharmacoresistance genes, of which the most important is ABCB1. This project consists of three sections:with genetic-epidemiology methods, a broad set of gene-wide tagging SNPs of ABCB1 were selected; the main aim is to find the frequencies of the polymorphisms in ABCB1, and the association of these polymorphisms with multidrug-resistant epilepsy, as well as the correlation of these polymorphisms with dosage, blood concentration and concentrations to the dose ratios of oxcarbazepine.Objective:To determine the frequencies of polymorphisms at C3435T and tagging SNPs in ABCB1 and to explore the association of these polymorphisms with pharmacoresistance.Materials and methods:We recruited patients with epilepsy who were treated with optimal AEDs. Demographic and clinical information were collected for all patients. Depending on their response to AEDs, patients were divided into two groups, drug-resistant and drug-responsible group. Drug resistance was defined as four or more seizures/year despite three or more AEDs at maximally tolerated doses, while drug response was defined as seizure free for the previous year. We conducted a retrospective case-control study design. Tagging SNPs were selected through Tagger program, with the Chinese Beijing SNP genotype data downloaded from HapMap. MALDI-TOF MS was employed to genotype the 14 SNPs and haplotypes were reconstructed by SHEsis programs, which implements an expectation-maximization algorithm. With retrospective case-control study method, we analyzed the frequencyies of these polymorphims and association of them with multidrug-resistant epilepsy.Results:Two hundred and eighteen people with epilepsy were recruited, of which 132 were drug-resistant,86 drug responsive,123 male,95 female.13 gene-wide tagging SNPs were selected by Tagger program. For rs10234411, the frequency of TT genotype and T allele was significantly higher in pharmacoresistant patients than that in responsive patients,while AA genotype and A allele lower in drug-resistant patients (p=0.013, p=0.045,respectively); For rs1002204, drug-resistant patients were more likely to have the TT genotype (p=0.038) and T allele(p=0.033). Compared with other haplotypes, T-T haplotype (rs1002204-rs10234411) significantly increased the risk of drug resistance(OR=1.774,95%CI:1.172-2.686,p=0.006). No difference was found in the genotype frequencies of other SNPs between drug-resistant and drug-responsive patients(p>0.05).With multiple logistic regression analysis, rs10234411 TT genotype was an independent risk factor for pharmacoresistance. Independent of other risks such as "age", "sex", "generalized seizure", "partial seizure", "age of seizure onset", "febrile convulsion", " time between seizure onset and treatment" and "seizures before drug treatment", TT genotype associated with a 4.414-fold increased risk for pharmacoresistance than non-TT genotype(OR=4.414,95% CI: 1.483-13.141,p=0.008). Besides, partial seizure(partial vs non-partial seizure: OR=7.807,95%CI:3.075-19.822,p=0.000)and "more than 6 seizures before drug treatment"(more than 6 seizures vs less than 6 seizures:OR=4.437,95% CI: 2.282-8.625,p=0.000) independently increased the risk of drug resistance. Conclusions:The TT genotype in ABCB1 rs10234411 significantly associated with poor AEDs response and rs1002204 TT genotype probably correlated with drug resistance. No association was found between the other ABCB1 polymorphisms and pharmacoresistance.Objective:To investigate the influence on clinical outcomes of different genotypes at ABCB1 C3435T and tagging SNPs.Materials and methods:We included patients with newly diagnosed epilepsy, patients who had failed treatment with previous monotherapy and patients who had entered a period of remisson from seizures but had relapsed after withdrawl of treatment. MALDI-TOF MS was employed to genotype the 14 SNPs. Clinical outcomes were followed-up and measured by time to first seizure and time to 1-year remission. By Log-rank test and Cox proportional hazards multiple model, treatment outcomes were evaluated and compared among different genotypes and the relative risk were adjusted for the clinical factors affecting the outcome of AED therapy. Results:The cohort comprised 240 patients with epilepsy(136 men,104 women). Through Log-rank test, our findings were as follows:For the time to first seizure, the cumulative percentage of patients who experienced a first seizure in rs1002204 TT genotype was the highest, while it is slowest in the GG genotype (p=0.034). By the end of follow-up, the cumulative percentages of patients who experienced a first seizure in rs1002204 TT, GT and GG genotype were 86.4%,66.5% and 63.9% respectively. Besides, the cumulative percentage of patients who experienced a first seizure in rs10234411 TT genotype was the highest, while it is slowest in the AA genotype (p=0.045). By the end of follow-up, the cumulative percentages of patients who experienced a first seizure in rs10234411 TT, AT and AA genotype were 83.7%,66.2% and 63.9% respectively.For the time to 1-year remission, the cumulative percentage of patients who achieved 1-year remission in rs1002204 TT genotype was the lowest, while it is highest in the GG genotype (p=0.046). By the end of follow-up, the cumulative percentages of patients who achieved 1-year remission in rs1002204 TT, GT and GG genotype were 16.2%,24.6% and 32.4% respectively.Through Cox proportional hazards multiple model analysis, our findings were as follows:For the time to first seizure, Cox model suggested that independent of other factors such as "follow period", "age", "sex", "age of seizure onset", "generalized seizure ", "partial seizure", " time between seizure onset and treatment" and "total seizures before drug treatment", the rs 1002204 TT genotype associated with a 1.958-fold increased relative risk for first seizure occurrence than GG genotype (RR=1.958,95%CI:1.243-3.085, p=0.004) and with a 1.638-fold increased relative risk for first seizure occurrence than GT genotype (RR=1.643,95%CI:1.068-2.510, p=0.024).For the time to 1-year remission, Cox model failed to indicated independent association between C3435T and tagging SNPs genotype and time to 1-year remission.Conclusions:ABCB1 rs1002204 and rs10234411 polymorphisms associated with drug response in epilepsy. Rs1002204 TT genotype tended to achieve poor treatment outcome, while the GG genotype tended to be more responsive; rs10234411 TT genotype probably had a tendency to become drug-resistant and AA genotype probably to be responsible to AEDs.Objective:To compare OXC dosage, concentration and concentrations to the dose ratios (C/D ratios) among different genotype groups.Materials and methods:Patients were included if they received a monotherapy with OXC. MALDI-TOF MS was employed to genotype the 14 SNPs. Monohydroxycarbazepine (MHD) blood concentration was detected with high-performance liquid chromatography. OXC dosage, blood concentration and C/D ratios were compared among different genotype groups.Results:Forty-seven patients(27 men,20 women) underwent the concentration detection. OXC dosage/kg and blood concentration/kg in rs1002204 TT genotype group was significantly higher than that in GG genotype group and GT genotype group. Patients with higher OXC dosage/kg and blood concentration/kg were more likely to have rs10234411 TT genotype compared with AA genotype and AT genotype. However, no difference was indicated concerning the OXC C/D rations among the three genotypes of rs1002204 and rs10234411 (p>0.05).Conclusions:The genotypes in ABCB1 rs1002204 and rs10234411 associated with the OXC dosage and blood concentration. In order to control seizure, patients with TT genotype in rs1002204 and rs10234411 may need higher dosage and blood concentration of OXC than patients with the other two genotypes. The TT genotype might prevent OXC from reaching sufficiently high brain concentrations without influencing the deposition of OXC in blood.