Abstracts

Controversy has surrounded the reported association of the single nucleotide polymorphism (SNP) rs1045642 (C3435T) in [italic]ABCB1[/italic] (multidrug resistance gene, [italic]MDR1[/italic]) with refractory epilepsy. We further examined this question by (a) Attempting to replicate the original association and (b) Using a combination of tagging SNPs and direct sequence based methods to examine whether other variants in the gene are associated with drug resistant epilepsy in an Irish epilepsy cohort. 440 patients with an established diagnosis of epilepsy were enrolled. Phenotypic information was recorded in a secure linked anonymised database. We examined C3435T to replicate the original association. We also genotyped 5 additional tagging SNPs and 3 putatively functional variants. Of 440 patients, 242 were drug responsive and 198 were drug resistant. Direct comparison of the genotypes of both groups revealed no significant association of any particular SNP with refractory epilepsy. Haplotype analysis failed to yield significant association of either group with a particular genotype.[underline][/underline] An association of the CC genotype at C3435T has been reported in patients with drug resistant epilepsy(1). An exact replication study has failed to confirm that association.(2).However, the association was replicated by a similar but not identical definition of pharmacoresistance(3). It is possible that the C3435T polymorphism is not itself causal but associating through LD with the causal variant. Hence,analysis of SNPs in strong LD with C3435T has been suggested(4). We attempted an exact replication using map and sequence based methods but failed to find a significant association with drug resistant epilepsy. We examined C3435T as well as all other common variants in [italic]MDR1[/italic] and failed to identify a significant association with drug resistant epilepsy.This supports the view that the original association(1), maybe a false-positive finding. However, the ambiguous nature of the phenotype definition does not rule out a role variation in [italic]MDR1[/italic] with pharmacoresistance in a specific group of antiepileptic drugs. (1) Siddiqui et al. Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene [italic]ABCB1[/italic]. N Engl J Med 2003;348:1442-8.(2) Tan et al. Failure to confirm association of a polymorphism in [italic]ABCB1[/italic] with multidrug-resistant epilepsy. Neurology 2004;63:1090-92.(3)Zimprich et al. Association of an [italic]ABCB1[/italic] gene haplotype with pharmacoresistance in temporal lobe epilepsy.Neurology 2004;63:1087-89.(4)Soranzo et al. Identifying candidate causal variants responsible for altered activity of the [italic]ABCB1[/italic] multidrug resistance gene. Genome Res 2004;14:1333-44. (Supported by International League Against Epilepsy and Programme of Human Genomics.)