title: The controversial association of ABCB1 polymorphisms in refractory epilepsy: an analysis of multiple SNPs in an Irish population.
abstract: Controversy has surrounded the reported association of the single nucleotide polymorphism (SNP) C3435T of the ATP-binding cassette subfamily B member 1 (ABCB1, MDR1) gene, with refractory epilepsy. Here we examine this question by: (1) attempting to replicate the original association, (2) assessing the association of other variants in high linkage disequilibrium (LD) with C3435T, and (3) evaluating and comparing our findings with other published studies. We defined drug-responsiveness as seizure freedom or a 50% or more reduction in seizure frequency in the preceding year. Drug resistance was defined as a less than 50% reduction in seizure frequency in the preceding year. We used a combination of map-based (tagging SNPs) and direct sequence-based methods allowing a comprehensive assessment of variation across the associated interval. Genotypic data on 8 SNPs was collected on 440 patients, of whom 242 were drug-responsive and 198 were drug-resistant. We were unable to observe the original association of drug-resistant epilepsy with C3435T, nor any association with other functional variants at SNP or haplotype level in the ABCB1 gene. Evaluation of other attempted replication studies suggest that if the original C3435T association is indeed real, it would appear highly sensitive to the phenotype used. Alternatively, the discrepant results of this and other association attempts may be indicative of the original report of the CC genotype at C3435T in ABCB1 being a false positive finding. Variability in phenotypic descriptions in genetic association studies may partly explain the inconsistency of attempted replications.
authors.affiliation: Department of Clinical Neurological Sciences, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
authors.forename: Amre
authors.initials: A
authors.lastname: Shahwan
authors.forename: Kevin
authors.initials: K
authors.lastname: Murphy
authors.forename: Colin
authors.initials: C
authors.lastname: Doherty
authors.forename: Gianpiero L
authors.initials: GL
authors.lastname: Cavalleri
authors.forename: Clare
authors.initials: C
authors.lastname: Muckian
authors.forename: Pat
authors.initials: P
authors.lastname: Dicker
authors.forename: Mary
authors.initials: M
authors.lastname: McCarthy
authors.forename: Peter
authors.initials: P
authors.lastname: Kinirons
authors.forename: David
authors.initials: D
authors.lastname: Goldstein
authors.forename: Norman
authors.initials: N
authors.lastname: Delanty
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000328:Adult; D000927:Anticonvulsants / Q000627:therapeutic use; D004351:Drug Resistance / Q000235:genetics*; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics*; D005091:Exons; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007438:Introns; D007494:Ireland; D015810:Linkage Disequilibrium; D027361:Organic Anion Transporters / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D027361:Organic Anion Transporters