Complex Haplotypic Effects of the ABCB1 Gene on Epilepsy Treatment Response

Abstract

Our results showed that the three loci, C1236T, G2677T and C3435T, jointly influenced the treatment response for epileptic patients. They should be regarded together as a complex polymorphic drug-response system. These findings suggest that examination of the haplotypes of the three loci could be useful in predicting drug resistance in epilepsy.

ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research

“…Secondly, the definition of outcome has varied between studies, the exception being the Tan et al study, 82 which still failed to replicate the original finding. 81 In particular, Hung et al 86 utilized extreme definitions of drug resistance and drug responsiveness, and this might explain the positive findings of this study. In addition, in this study, there were significant differences in the proportions of patients with temporal lobe epilepsy and epilepsy syndromes between case and control groups, and the association reported may therefore have been with epilepsy aetiology rather than with outcome.…”

“…In fact, only one study made a true effort to correct for multiple testing. 86 By contrast, another study reported up to 300 P-values without any correction. 88 While the rest of the studies did not undertake multiple testing to quite such an extent, even those studies testing for one SNP performed multiple tests through subgroup analysis.…”

“…A particularly stark example of inappropriate case and control selection is the study of Kaya et al, 99 in which the drug-responsive group consisted almost entirely of patients with acute lymphoblastic leukaemia, whereas almost all of the drug-resistant group were patients with acute myeloid leukaemia. Similarly in epilepsy, the Hung et al 86 study had different proportions of temporal lobe epilepsy patients in the case and control groups, and so what was reported as an association with therapeutic drug response may well have been an association with disease aetiology.…”

“…A further smaller study using a similar outcome definition as used by Siddiqui et al 81 and Tan et al, 82 could not demonstrate an association of outcome with 3435C4T, 2977 G4T, 1236C4T or three SNP haplotype in 108 drugresponsive and 99 drug-resistant Korean patients with epilepsy. 85 In contrast, another study 86 genotyped 10 polymorphisms in 108 drug-resistant and 223 drug-responsive ethnically similar patients. The definition of drug resistance was at least 10 seizures over the preceding year with trials of two to three appropriate anti-epileptic drugs, whereas drug responsiveness was defined as complete freedom from seizures for at least 2 years in patients on any antiepileptic medication.…”

“…These inconsistent results may be due to several factors. First, both replicating ABCB1 genotype and therapeutic drug response GD Leschziner et al studies were based either solely on temporal lobe epilepsy, 83 or were mainly temporal lobe epilepsy patients, 86 and it is conceivable that the association is only true in this subgroup of patients. Secondly, the definition of outcome has varied between studies, the exception being the Tan et al study, 82 which still failed to replicate the original finding.…”