title: 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.
  
  
  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].
  
  
  CONCLUSIONS
  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.affiliation: Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Mike
authors.initials: M
authors.lastname: Ufer
authors.forename: Celina
authors.initials: C
authors.lastname: von Stülpnagel
authors.forename: Hiltrud
authors.initials: H
authors.lastname: Muhle
authors.forename: Sierk
authors.initials: S
authors.lastname: Haenisch
authors.forename: Cornelia
authors.initials: C
authors.lastname: Remmler
authors.forename: Amani
authors.initials: A
authors.lastname: Majed
authors.forename: Herbert
authors.initials: H
authors.lastname: Plischke
authors.forename: Ulrich
authors.initials: U
authors.lastname: Stephani
authors.forename: Gerhard
authors.initials: G
authors.lastname: Kluger
authors.forename: Ingolf
authors.initials: I
authors.lastname: Cascorbi
mesh_terms: D000293:Adolescent; D000483:Alleles; D000927:Anticonvulsants / Q000627:therapeutic use*; D054316:Biomarkers, Pharmacological; D002220:Carbamazepine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D002648:Child; D004351:Drug Resistance / Q000235:genetics*; D004828:Epilepsies, Partial / Q000188:drug therapy*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D000078330:Oxcarbazepine; D020641:Polymorphism, Single Nucleotide; D014635:Valproic Acid / Q000627:therapeutic use; D044465:White People / Q000235:genetics
chemical_list: D000927:Anticonvulsants; D054316:Biomarkers, Pharmacological; D002220:Carbamazepine; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000078330:Oxcarbazepine; D014635:Valproic Acid; C000715087:ABCC2 protein, human