Impact of ABCC2 genotype on antiepileptic drug response in Caucasian patients with childhood epilepsy.

Abstract

BACKGROUND:

Antiepileptic treatment response has been suggested to be modulated by genetic polymorphisms of drug efflux transporters, in particular ABCB1. Recently, we found a significant association of ABCC2 -24C>T with nonresponse, primarily in the context of generalized epilepsy. Moreover, ABCC2 1249G>A was reported to alter transmembranal carbamazepine transport. Therefore, we aimed to confirm the association of ABCC2 variants with pharmacotherapy-resistance in Caucasians mainly affected by partial epilepsy.

PATIENTS AND METHODS:

A total of 208 patients (114 male; age: 11.3±5.9 years) were genotyped for three putatively functionally relevant polymorphisms of ABCC2 (-24C>T, 1249G>A, 3972C>T). Genotype and haplotype frequencies were compared between responders and nonresponders to first-line antiepileptic treatment.

RESULTS:

Carriers of the ABCC2 1249G>A variant (417V>I) were more frequent among responders [odds ratio (OR)=2.68 (1.25-5.78); P=0.010]. This association remained significant after adjusting for age, sex and seizure type, [OR=2.88 (1.23-6.73); P=0.015]. The impact of 1249G>A was more pronounced among 64 patients receiving carbamazepine or oxcarbazepine (P=0.005), but nonsignificant in patients receiving other anticonvulsants. ABCC2 -24C>T and 3972C>T showed lack of association to therapy response. Haplotype analyses revealed that haplotype H2 containing solely the 1249A variant allele was more frequent in the responder group [OR=2.98 (1.38-6.44); P=0.004].

DISCUSSION:

These data argue for a greater probability of antiepileptic drug response among carriers of the ABCC2 1249A variant that is associated with reduced carbamazepine transport. Although we could not confirm an impact of ABCC2 -24C>T, these results suggest that ABCC2 genotype may also modulate the response to anticonvulsants besides the extensively studied ABCB1 (P-glycoprotein).

• Authors: Mike Ufer, Celina von Stülpnagel, Hiltrud Muhle, Sierk Haenisch, Cornelia Remmler, Amani Majed, Herbert Plischke, Ulrich Stephani, Gerhard Kluger, Ingolf Cascorbi
• Journal: Pharmacogenetics and genomics (Pharmacogenet Genomics) Vol. 21 Issue 10 Pg. 624-30 (Oct 2011) ISSN: 1744-6880 [Electronic] United States
• PMID: 21799461 (Publication Type: Journal Article)

Chemical References

• ABCC2 protein, human
• Anticonvulsants
• Biomarkers, Pharmacological
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins
• Carbamazepine
• Valproic Acid
• Oxcarbazepine

Topics

• Adolescent
• Alleles
• Anticonvulsants (therapeutic use)
• Biomarkers, Pharmacological
• Carbamazepine (analogs & derivatives, therapeutic use)
• Child
• Drug Resistance (genetics)
• Epilepsies, Partial (drug therapy)
• Female
• Genetic Association Studies
• Genotype
• Haplotypes
• Humans
• Male
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins (genetics)
• Oxcarbazepine
• Polymorphism, Single Nucleotide
• Valproic Acid (therapeutic use)
• White People (genetics)