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MDR-1 and MRP2 Gene Polymorphisms in Mexican Epileptic Pediatric Patients with Complex Partial Seizures

David Escalante-Santiago1, Iris Angélica Feria-Romero2, Rosa María Ribas-Aparicio3

  • 1Programa de Biomedicina y Biotecnología Molecular, Escuela Nacional de Ciencias Biológicas del Instituto Politécnico Nacional , Mexico City , Mexico ; Unidad de Investigación Médica en Enfermedades Neurológicas, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social , Mexico City , Mexico.

Frontiers in Neurology
|October 28, 2014
PubMed

Insights

Genetic variations in ABCB1 and ABCC2 genes are linked to antiepileptic drug resistance (ADR) in Mexican epilepsy patients. New nucleotide changes in ABCC2 were found in drug-resistant individuals, suggesting genetic variability.

Area of Science:

  • Pharmacogenomics
  • Epilepsy Genetics
  • Drug Metabolism

Background:

  • Overexpression of Pgp efflux transport protein in epilepsy patients suggests a role in drug resistance.
  • The association between specific gene polymorphisms (MDR1/ABCB1, MRP2/ABCC2) and antiepileptic drug resistance (ADR) remains controversial.
  • Valproic acid concentrations in saliva may differ between drug-resistant and drug-responsive epilepsy patients.

Purpose of the Study:

  • To identify nucleotide changes and mutations in ABCB1 and ABCC2 genes in Mexican patients with epilepsy.
  • To explore genetic variations associated with antiepileptic drug resistance (ADR) versus good drug response (CTR).
  • To investigate potential genetic risk factors for ADR in a rigorously selected patient population.

Main Methods:

  • Genomic DNA was extracted from leukocytes of 22 ADR patients and 7 CTR patients.
  • Eleven exons of both ABCB1 and ABCC2 genes were genotyped.
  • Drug concentrations (valproic acid) were measured in saliva and plasma.

Main Results:

  • Five reported SNPs and five novel nucleotide changes were identified in the ABCB1 gene.
  • Specific ABCB1 SNPs (rs2229109, rs2032582) and ABCC2 SNPs (rs3740066, 66744T>A) were found exclusively in ADR patients.
  • The TA genotype of ABCB1 rs2032582 and the T allele of ABCC2 rs3740066 were identified as the strongest risk factors for ADR.

Conclusions:

  • Mexican epilepsy patients exhibit common ABCC1 polymorphisms, but novel nucleotide changes in ABCC2 are associated with higher risk of drug resistance.
  • The study identified significant genetic variability in ABCB1 and ABCC2 genes among Mexican patients with AED-resistant epilepsy (ADR).
  • Further investigation in larger populations is warranted to confirm the role of these polymorphisms in ADR.
Keywords:
ABCB1ABCC2Mexican patientsdrug-resistantepilepsysingle-nucleotide polymorphisms, anti-epileptic drugs

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