A nonsynonymous variation in MRP2/ABCC2 is associated with neurological adverse drug reactions of carbamazepine in patients with epilepsy

Abstract

Multidrug resistance protein 2 (MRP2, ABCC2) is involved in the transport of antiepileptic drugs and is upregulated in the brain tissues of patients with epilepsy. Therefore, genetic variations in the MRP2 gene may affect individual drug responses to the antiepileptic agent carbamazepine. Associations between MRP2 polymorphisms and the adverse drug reactions (ADRs) of carbamazepine were analyzed using an integrated population genetics and molecular functional approach. In the initial case-control study, five tag single nucleotide polymorphisms in the MRP2 gene were analyzed in 146 patients with epilepsy. Patients were divided into two groups: those who experienced ADRs of the central nervous system and those who did not. An independent replication study was performed using DNA samples from 279 patients. A nonsynonymous polymorphism, c.1249G>A (p.V417I, rs2273697), showed a strong association with the neurological ADR caused by carbamazepine (P=0.005). Logistic regression analysis with multiple clinical variables indicated that the presence of A allele at the MRP2 c.1249G>A locus was an independent determinant of central nervous system ADR caused by carbamazepine. Moreover, the positive association of c.1249A was reproduced in the replication study (P=0.042, joint P value of the replication=0.001). The functional study using ATPase assay and FACScan flow cytometer indicated that carbamazepine was a substrate of MRP2 and that the 417I variation selectively reduced carbamazepine transport across the cell membrane. These results strongly suggest that the A-allele of the MRP2 single nucleotide polymorphism c.1247G>A is associated with adverse neurological drug reactions to carbamazepine.