Abstract | OBJECTIVE: METHODS: A total of 221 pediatric or adolescent Caucasian patients with epilepsy (105 females; age: 14.5+/-6.54 years) were genotyped for nine putatively functionally relevant ABCB1, ABCC2, CYP2C8, CYP2C9, and CYP2C19 polymorphisms. In addition, 70 adult patients (35 females, age: 41.9+/-11.5 years) with drug-refractory epilepsy who had earlier undergone neurosurgical therapy were genotyped and partly (n = 22) investigated for hippocampal ABCB1 and ABCC2 mRNA expression. Finally, 242 healthy volunteers (167 females, age: 27.0+/-6.77 years) from the same region were included as controls. RESULTS: The young cohort consisted of 103 (46.6%) responders and 118 (53.4%) non-responders to the first-line anticonvulsant. Carriers of the putatively low-expression ABCC2 -24T variant were significantly overrepresented among non-responders [odds ratio (OR) 2.15 (1.16-3.99); P = 0.016)]. This overrepresentation was confirmed by comparing young responders with adult drug-refractory patients [OR 3.36 (1.71-6.59); P<0.001]. Conversely, ABCB1 genotype distribution did not significantly differ between young responders and non-responders or adult drug-refractory patients. Excluding patients with febrile convulsions, heterozygous CYP2C8*4 [OR 0.35 (0.13-0.95); P = 0.038] and CYP2C9*3 [OR 0.34 (0.14-0.81); P = 0.015] variant allele carriers were underrepresented among non-responders. ABCC2 -24C>T genotype did not affect hippocampal ABCC2 expression, but was associated with increased ABCB1 expression (P = 0.034). CONCLUSION: These data suggest a higher risk of antiepileptic drug failure in ABCC2 -24T allele carriers possibly because of compensatory upregulation of ABCB1.
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Authors | Mike Ufer, Igor Mosyagin, Hiltrud Muhle, Thies Jacobsen, Sierk Haenisch, Robert Häsler, Frank Faltraco, Cornelia Remmler, Sarah von Spiczak, Heyo K Kroemer, Uwe Runge, Rainer Boor, Ulrich Stephani, Ingolf Cascorbi |
Journal | Pharmacogenetics and genomics
(Pharmacogenet Genomics)
Vol. 19
Issue 5
Pg. 353-62
(May 2009)
ISSN: 1744-6872 [Print] United States |
PMID | 19415824
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- ABCB1 protein, human
- ABCC2 protein, human
- ATP Binding Cassette Transporter, Subfamily B
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- Anticonvulsants
- Multidrug Resistance-Associated Protein 2
- Multidrug Resistance-Associated Proteins
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Topics |
- ATP Binding Cassette Transporter, Subfamily B
- ATP Binding Cassette Transporter, Subfamily B, Member 1
(genetics)
- Adolescent
- Adult
- Age Factors
- Anticonvulsants
(therapeutic use)
- Case-Control Studies
- Child
- Cohort Studies
- Drug Resistance
(genetics)
- Epilepsy
(drug therapy, genetics)
- Epistasis, Genetic
(physiology)
- Female
- Gene Frequency
- Genetic Predisposition to Disease
- Humans
- Male
- Middle Aged
- Multidrug Resistance-Associated Protein 2
- Multidrug Resistance-Associated Proteins
(genetics)
- Polymorphism, Single Nucleotide
(physiology)
- Treatment Failure
- Young Adult
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