Dataset Information

Association between C3435T polymorphism of MDR1 gene and the incidence of drug-resistant epilepsy in the population of Polish children.

ABSTRACT: Epilepsy is a disease of neurological character. Approximately one third of epileptic patients demonstrate a drug-resistant phenotype, which is associated with the development of drug-resistant epilepsy. The multidrug resistance protein 1 and glycoprotein P, encoded by MDR1, play a significant role in the transmembrane transport of anti-epileptic agents. Single nucleotide polymorphism C3435T (rs1045642) within MDR1 gene may be associated with an increased expression of P-gp which affects the levels of antiepileptic drugs in plasma. The presented studies analysed the association between C3435T polymorphism of MDR1 gene and the incidence of drug-resistant epilepsy in the population of Polish children.C3435T polymorphism of MDR1 gene was analysed by the high resolution melting technique in a group of patients with drug-resistant (n = 106) and drug-responsive epilepsy (n = 67), as well as in non-epileptic children (n = 98) hospitalised at the Department of Neurology, Polish Mother's Memorial Hospital in Lodz. Genotype and allele distributions were evaluated and their compatibility with the Hardy-Weinberg distribution was assessed by means of the ?(2) test. Genotype and allele evaluation, regarding their relationship with a given feature, was supported by an analysis of odds ratio and 95 % confidence interval, calculated according to the logistic regression model.An association was observed between the incidence rate of DRE and the presence of C allele in C3435T polymorphism of MDR1 gene, which may enhance the risk of the disease. The T allele may then play a protective role. No differences were found in the studied groups, regarding either genotype or allele distribution in reference to patient's gender or concomitant diseases.Following the obtained results, C3435T polymorphism of MDR1 gene may be connected with the incidence of drug-resistant epilepsy in the population of Polish children. ISRCTN ISRCTN73824458. Registered 28th September 2014.

SUBMITTER: Stasiolek M

PROVIDER: S-EPMC4938960 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Association between C3435T polymorphism of MDR1 gene and the incidence of drug-resistant epilepsy in the population of Polish children.

Stasiołek Mariusz M Romanowicz Hanna H Połatyńska Katarzyna K Chamielec Maciej M Skalski Dominik D Makowska Marianna M Smolarz Beata B

Behavioral and brain functions : BBF 20160708 1

<h4>Purpose</h4>Epilepsy is a disease of neurological character. Approximately one third of epileptic patients demonstrate a drug-resistant phenotype, which is associated with the development of drug-resistant epilepsy. The multidrug resistance protein 1 and glycoprotein P, encoded by MDR1, play a significant role in the transmembrane transport of anti-epileptic agents. Single nucleotide polymorphism C3435T (rs1045642) within MDR1 gene may be associated with an increased expression of P-gp which ...[more]

PMID: 27391700

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Project description:AIMS: To investigate the frequency of the single nucleotide polymorphism C3435T in exon 26 of the MDR1 gene in Asians and to determine the functional significance of this SNP with the clinical pharmacokinetics of oral cyclosporin (Neoral) in 10 stable heart transplant patients. METHODS: The MDR1 C3435T polymorphism was investigated in 290 healthy Asian subjects (98 Chinese, 99 Malays and 93 Indians). We also compared the MDR1 polymorphism between the Asian population studied here and the published data on Africans and Caucasians. The clinical relevance of this SNP on oral bioavailability of a known P-gp substrate, cyclosporin, was assessed in 10 stable Chinese heart transplant patients. RESULTS: The homozygous TT genotype was observed in 32%, 28% and 43% of Chinese, Malays and Indians. The homozygous CC genotype was found in 25% of Chinese and Malays compared with 18% of Indians. The Indians had a lower frequency of the C allele [0.38 (0.31-0.45)] compared with the Chinese [0.46 (0.39-0.53)] and Malays [0.48 (0.42-0.55)]. Chi-squared test showed that the distribution of allele frequencies between the Malays and Indians differed significantly (P = 0.04). In this Asian population, the overall distribution of genotypes (CC, CT and TT) and allele frequencies were significantly different from those in Africans (P < 0.001). The results were also significant when the Chinese, Malays and Indians were compared separately with the African group (P < 0.001). Compared with the Caucasian data, the overall distribution of genotype and allele frequencies in the Asian population were also significantly different (P < or = 0.05). However, when each Asian ethnic group was compared separately with the Caucasians, only the Indians were found to be significantly different (P < or = 0.004). Genotypic-phenotypic correlations of this SNP were assessed in 10 stable Chinese heart transplant patients. The median AUC(0,4 h) was 11% lower in patients with CC genotype compared with subjects with TT genotype. However, the interpatient variability in AUC(0,4 h) was high in patients, especially in those with CC genotype. CONCLUSIONS: The distribution of the SNP C3435T in exon 26 in the Chinese and Malay population was found to be similar to the Caucasians whereas the Indians were different. The Asian population also differed significantly from the African and Caucasian population in the distribution of the C3435T SNP. The low frequency of the T allele in the Indian population implies lower expression of P-gp and may have important therapeutic and prognostic implications for use of P-gp dependent drugs in individuals of Indian origin.

Project description:ObjectiveEarly onset drug-resistant epilepsy is a neurologic disorder in which 2 antiepileptic drugs fail to maintain the seizure-free status of the patient. Heterogeneous clinical presentations make the diagnosis challenging. We aim to identify the underlying genetic causes of a pediatric cohort with drug-resistant epilepsy and evaluate whether the findings can provide information on patient management.MethodsWe include patients with drug-resistant epilepsy onset before 18 years of age. Singleton clinical chromosomal microarray (CMA) followed by whole exome sequencing (WES) was performed using genomic DNA. In the first-tier analysis of the exome data, we aimed to identify disease-causing mutations in 546 genes known to cause, or to be associated with, epilepsy. For negative cases, we proceeded to exome-wide analysis. Rare coding variants were interrogated for pathogenicity based on the American College of Medical Genetics and Genomics (ACMG) guidelines.ResultsWe recruited 50 patients. We identified 6 pathogenic or likely pathogenic mutations, giving a diagnostic yield of 12%. Mutations were found in 6 different genes: SCN8A, SCN1A, MECP2, CDKL5, DEPDC5, and CHD2. The CDKL5 variant was found to be mosaic. One variant of unknown significance (VUS) in KCNT1 was found in a patient with compatible clinical features. Of note, a reported pathogenic SCN5A mutation known to contribute to Brugada syndrome, was also found in the patient with an SCN1A mutation.SignificanceOur study suggests that singleton WES is an effective diagnostic tool for drug-resistant epilepsy. Genetic diagnosis can help to consolidate the clinical diagnosis, to facilitate phenotypic expansion, and to influence treatment and management options for seizure control in our patients. In our study, a significant portion of the genetic findings are known to be associated with an increased risk of sudden unexpected death in epilepsy (SUDEP). These findings could assist with more appropriate management in patients with epilepsy.

Dataset Information

Association between C3435T polymorphism of MDR1 gene and the incidence of drug-resistant epilepsy in the population of Polish children.

Publications

Association between C3435T polymorphism of MDR1 gene and the incidence of drug-resistant epilepsy in the population of Polish children.

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