Association of Multidrug Resistance in Epilepsy with a Polymorphism in the Drug-Transporter Gene<i>ABCB1</i>

Siddiqui, Asra Tus Saleha; Kerb, Reinhold; Weale, Michael E.; Brinkmann, Ulrich; Smith, Alice C.; Goldstein, David B.; Wood, Nicholas W.; Sisodiya, Sanjay M.

doi:10.1056/nejmoa021986

Cited by 620 publications

(487 citation statements)

References 26 publications

(27 reference statements)

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“…This question must be viewed in relation to the magnitude of genetic effects under study. Given a substantial magnitude of effect and a highly significant P value, only a few dozen markers probably need to be genotyped to rule out gross stratification as an explanation for the positive association 11,22 (Table 3). In contrast, if the results point to more modest influences on disease, such as the risk due to variation in CTLA4 on autoimmune thyroid disease and type 1 diabetes 23 , it may be necessary to genotype a larger number of markers to rule out modest amounts of stratification.…”

Section: Figurementioning

confidence: 99%

Assessing the impact of population stratification on genetic association studies

et al. 2004

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Population stratification refers to differences in allele frequencies between cases and controls due to systematic differences in ancestry rather than association of genes with disease. It has been proposed that false positive associations due to stratification can be controlled by genotyping a few dozen unlinked genetic markers. To assess stratification empirically, we analyzed data from 11 case-control and casecohort association studies. We did not detect statistically significant evidence for stratification but did observe that assessments based on a few dozen markers lack power to rule out moderate levels of stratification that could cause false positive associations in studies designed to detect modest genetic risk factors. After increasing the number of markers and samples in a case-cohort study (the design most immune to stratification), we found that stratification was in fact present. Our results suggest that modest amounts of stratification can exist even in well designed studies.

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Section: Figurementioning

confidence: 99%

Assessing the impact of population stratification on genetic association studies

et al. 2004

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“…Refractory epilepsy is a common neurologic disease that accounts for approximately one-third of epileptic patients with resistance to single or multiple drugs used for antiepileptic treatment [1,2] . Clinical studies have shown that if the first antiepileptic drug (AED) prescribed was ineffective, switching to another AED or to a combination of AEDs yielded similar negative results.…”

Section: Introductionmentioning

confidence: 99%

Multidrug resistance-associated protein 1 decreases the concentrations of antiepileptic drugs in cortical extracellular fluid in amygdale kindling rats

et al. 2013

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Aim: To investigate whether multidrug resistance-associated protein 1 (MRP1) was responsible for drug resistence in refractory epilepsy in amygdale kindling rats. Methods: Rat amygdale kindling was used as a model of refractory epilepsy. The expression of MRP1 mRNA and protein in the brains was examined using RT-PCR and Western blot. MRP1-positive cells in the cortex and hippocampus were studied with immunohistochemical staining. The rats were intraperitoneally injected with phenytoin (50 mg/kg) or carbamazepine (20 mg/kg), and their concentrations in the cortical extracellular fluid were measured using microdialysis and HPLC. Probenecid, a MRP1 inhibitor (40 mmol/L, 50 μL) was administered through an inflow tube into the cortex 30 min before injection of the antiepileptic drugs. Results: The expression of MRP1 mRNA and protein was significantly up-regulated in the cortex and hippocampus in amygdale kindling rats compared with the control group. Furthermore, the number of MRP1-positive cells in the cortex and hippocampus was also significantly increased in amygdale kindling rats. Microdialysis studies showed that the concentrations of phenytoin and carbamazepine in the cortical extracellular fluid were significantly decreased in amygdale kindling rats. Pre-administration of probenecid could restore the concentrations back to their control levels. Conclusion: Up-regulation of MRP1 is responsible for the resistance of brain cells to antiepileptic drugs in the amygdale kindling rats.

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“…[6][7][8] However, most candidate gene association studies on AED resistance have focused on an individual genetic variant with the potential main effect, and none of these studies could find evidence for a strong, single-gene effect on AED resistance. [9][10][11][12] This is partially because of the limitations of parametric statistical methods for detecting gene effects that are solely or partially dependent on interactions with other genes. 13,14 In this study, with the working hypothesis that AED resistance is a polygenic disorder in which several genetic variants with a modest effect interact with each other, we tried to find pharmacogenetic evidence of epistatic interactions underlying AED resistance using a new statistical method.…”

Section: Introductionmentioning

confidence: 99%

Evidence for epistatic interactions in antiepileptic drug resistance

et al. 2010

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To investigate the epistatic interactions involved in antiepileptic drug (AED) resistance, 26 coding single-nucleotide polymorphisms (SNPs) were selected from 16 candidate genes. A total of 200 patients with drug-resistant localization-related epilepsy and 200 patients with drug-responsive localization-related epilepsy were genotyped individually for the SNPs. Rather than using the traditional parametric statistical method, a new statistical method, multifactor dimensionality reduction (MDR), was used to determine whether gene-gene interactions increase the risk of AED resistance. The MDR method indicated that a combination of four SNPs (rs12658835 and rs35166395 from GABRA1, rs2228622 from EAAT3 and rs2304725 from GAT3) was the best model for predicting susceptibility to AED resistance with a statistically significant testing accuracy of 0.625 (Po0.001) and cross-validation consistency of 10/10. This best model had an odds ratio of 3.68 with a significant 95% confidence interval of 2.32-5.85 (Po0.0001). Our results may provide meaningful information on the mechanism underlying AED resistance and, to the best of our knowledge, this is the first report of evidence for gene-gene interactions underlying AED resistance.

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Association of Multidrug Resistance in Epilepsy with a Polymorphism in the Drug-Transporter GeneABCB1

Cited by 620 publications

References 26 publications

Assessing the impact of population stratification on genetic association studies

Assessing the impact of population stratification on genetic association studies

Multidrug resistance-associated protein 1 decreases the concentrations of antiepileptic drugs in cortical extracellular fluid in amygdale kindling rats

Evidence for epistatic interactions in antiepileptic drug resistance

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