Non-response to antiepileptic pharmacotherapy is associated with the ABCC2 -24C>T polymorphism in young and adult patients with epilepsy.
OBJECTIVE
We aimed to evaluate the association of non-response to antiepileptic pharmacotherapy with the frequency of variant alleles in the drug transporter genes ABCB1 and ABCC2 or in the CYP2C locus in young patients with epilepsy and an independent cohort of adults with drug-refractory epilepsy.


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).


CONCLUSIONS
These data suggest a higher risk of antiepileptic drug failure in ABCC2 -24T allele carriers possibly because of compensatory upregulation of ABCB1.
University Hospital Schleswig-Holstein, Germany.
Mike
M
Ufer
Igor
I
Mosyagin
Hiltrud
H
Muhle
Thies
T
Jacobsen
Sierk
S
Haenisch
Robert
R
Häsler
Frank
F
Faltraco
Cornelia
C
Remmler
Sarah
S
von Spiczak
Heyo K
HK
Kroemer
Uwe
U
Runge
Rainer
R
Boor
Ulrich
U
Stephani
Ingolf
I
Cascorbi
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000927:Anticonvulsants / Q000627:therapeutic use*; D016022:Case-Control Studies; D002648:Child; D015331:Cohort Studies; D004351:Drug Resistance / Q000235:genetics*; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics*; D004843:Epistasis, Genetic / Q000502:physiology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000502:physiology*; D017211:Treatment Failure; D055815:Young Adult
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human