Abstract | OBJECTIVES: METHODS: 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. RESULTS: 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. CONCLUSION: 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.
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Authors | Won-Joo Kim, Ji Hyun Lee, Jihyun Yi, Yang-Je Cho, Kyoung Heo, Sung Hee Lee, So Won Kim, Myeong-Kyu Kim, Kyung Hwan Kim, Byung In Lee, Min Goo Lee |
Journal | Pharmacogenetics and genomics
(Pharmacogenet Genomics)
Vol. 20
Issue 4
Pg. 249-56
(Apr 2010)
ISSN: 1744-6880 [Electronic] United States |
PMID | 20216337
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- ABCC2 protein, human
- Anticonvulsants
- Multidrug Resistance-Associated Protein 2
- Multidrug Resistance-Associated Proteins
- Recombinant Proteins
- Carbamazepine
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Topics |
- Alleles
- Anticonvulsants
(adverse effects, pharmacokinetics)
- Carbamazepine
(adverse effects, pharmacokinetics)
- Case-Control Studies
- Cell Line
- Central Nervous System
(drug effects)
- Drug-Related Side Effects and Adverse Reactions
(genetics, metabolism)
- Epilepsy
(drug therapy, genetics, metabolism)
- Female
- Gene Frequency
- Humans
- Male
- Multidrug Resistance-Associated Protein 2
- Multidrug Resistance-Associated Proteins
(genetics, metabolism)
- Pharmacogenetics
- Polymorphism, Single Nucleotide
- Recombinant Proteins
(genetics, metabolism)
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