Single nucleotide polymorphisms in the multidrug resistance 1 gene in Korean epileptics

Kim, Young Ok; Kim, Myeong Kyu; Woo, Young Jong; Lee, Min Cheol; Kim, Jin Hee; Park, Ki Won; Kim, Eun Young; Roh, Young Il; Kim, Chan Jong

doi:10.1016/j.seizure.2005.11.001

Cited by 65 publications

(48 citation statements)

References 24 publications

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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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Section: Introductionmentioning

confidence: 99%

Evidence for epistatic interactions in antiepileptic drug resistance

et al. 2010

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“…A further smaller study using a similar outcome definition as used by Siddiqui et al 81 and Tan et al, 82 could not demonstrate an association of outcome with 3435C4T, 2977 G4T, 1236C4T or three SNP haplotype in 108 drugresponsive and 99 drug-resistant Korean patients with epilepsy. 85 In contrast, another study 86 genotyped 10 polymorphisms in 108 drug-resistant and 223 drug-responsive ethnically similar patients. The definition of drug resistance was at least 10 seizures over the preceding year with trials of two to three appropriate anti-epileptic drugs, whereas drug responsiveness was defined as complete freedom from seizures for at least 2 years in patients on any antiepileptic medication.…”

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confidence: 99%

ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research

et al. 2006

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The product of the ABCB1 gene, P-glycoprotein (PGP), is a transmembrane active efflux pump for a variety of drugs. It is a putative mechanism of multidrug resistance in a range of diseases. It is postulated that ABCB1 polymorphisms contribute to variability in PGP function, and that therefore multidrug resistance is, at least in part, genetically determined. However, studies of ABCB1 genotype or haplotype and PGP expression, activity or drug response have produced inconsistent results. This critical review of ABCB1 genotype and PGP function, including mRNA expression, PGP-substrate drug pharmacokinetics and drug response, highlights methodological limitations of existing studies, including inadequate power, potential confounding by co-morbidity and co-medication, multiple testing, poor definition of disease phenotype and outcomes, and analysis of multiple drugs that might not be PGP substrates. We have produced recommendations for future research that will aid clarification of the association between ABCB1 genotypes and factors related to PGP activity.

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“…It has previously been reported that most of the analytical methods were specific for the parent drug, although some discrepancies in the results were obtained between high-performance liquid chromatography and fluorescence polarization immunoassays (FPIA). This overestimation might reflect cross-reactivity with CsA metabolites, even when monoclonal antibodies are used in the immunoassays [8,11,28] . In the present study, the co-administration of diltiazem affected the correlation between MDR1 genetic polymorphisms and CsA blood concentrations, likely reflecting the reaction of FPIA with CsA and its metabolites.…”

Section: Discussionmentioning

confidence: 99%

“…A total of 50 single nucleotide polymorphisms (SNPs) have been identified in MDR1, including C1236T, G2677T/A and C3435T in exons 12, 21 and 26, respectively, and these functionally important mutations can form different haplotypes. Both SNPs and haplotypes have been demonstrated as highly polymorphic among individuals and different ethnic groups [6][7][8] . The genetic polymorphisms of MDR1 have been implicated as one of the factors resulting in CsA pharmacokinetic variation.…”

Section: Introductionmentioning

confidence: 99%

Diltiazem augments the influence of MDR1 genotype status on cyclosporine concentration in Chinese patients with renal transplantation

Wang

et al. 2015

Acta Pharmacol Sin

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Aim: Co-administration of diltiazem can reduce the dosage of cyclosporine (CsA) in patients with renal transplantation. In this study, we investigated how diltiazem altered the relationship between MDR1 genetic polymorphisms and CsA concentration in Chinese patients with renal transplantation. Methods: A total of 126 renal transplant patients were enrolled. All the patients received CsA (2-4 mg·kg -1 ·d -1 ), and diltiazem (90 mg/d) was co-administered to 76 patients. MDR1-C1236T, G2677T/A, and C3435T polymorphisms were genotyped. The whole blood concentration was measured using the FPIA method, and the adjusted trough concentrations were compared among the groups with different genotypes. Results: In all patients, MDR1-C1236T did not influence the adjusted CsA trough concentration. With regard to MDR1-3435, the adjusted CsA trough concentration was significantly higher in TT carriers than in CC and CT carriers when diltiazam was co-administered (58.83±13.95 versus 46.14±7.55 and 45.18±12.35 ng/mL per mg/kg, P=0.011), and the differences were not observed in patients without diltiazam co-administered. With regard to MDR1-2677, the adjusted CsA trough concentration was significantly higher in TT carriers than in GG and GT carriers when diltiazam was co-administered (61.31±12.93 versus 52.25±7.83 and 39.70±7.26 ng/mL per mg/kg, P=0.0001). The differences were also observed in patients without diltiazam co-administered (43.27±5.95 versus 35.22±7.55 and 29.54±5.35 ng/mL per mg/kg, P=0.001). The adjusted CsA trough blood concentration was significantly higher in haplotype T-T-T and haplotype T-T-C carriers than in non-carriers, regardless of diltiazem co-administered. Conclusion: MDR1 variants influence the adjusted CsA trough concentration in Chinese patients with renal transplant, and the influence more prominent when diltiazem is co-administered.

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Single nucleotide polymorphisms in the multidrug resistance 1 gene in Korean epileptics

Abstract: In Korean epileptics, there was no significant relationship between three known SNPs in MDR1 and drug resistance. And there was no association of MDR1 haplotype based on above three sites with pharmacoresistance.

Cited by 65 publications

References 24 publications

Evidence for epistatic interactions in antiepileptic drug resistance

Evidence for epistatic interactions in antiepileptic drug resistance

ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research

Diltiazem augments the influence of MDR1 genotype status on cyclosporine concentration in Chinese patients with renal transplantation

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