Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1.

By A. Siddiqui, R. Kerb, M. Weale, U. Brinkmann, Alice Smith, David B. Goldstein, N. Wood, Sanjay M. Sisodiya. New England Journal of Medicine, 2003

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BACKGROUND One third of patients with epilepsy have drug-resistant epilepsy, which is associated with an increased risk of death and debilitating psychosocial consequences. Because this form is resistant to multiple antiepileptic drugs, the mode of resistance must be nonspecific, involving drug-efflux transporters such as ATP-binding cassette sub-family B member 1 (ABCB1, also known as MDR1 and P-glycoprotein 170). We hypothesized that the CC genotype at the ABCB1 C3435T polymorphism, which is associated with increased expression of the protein, influences the response to antiepileptic-drug treatment. METHODS ABCB1 3435 was genotyped in 315 patients with epilepsy, classified as drug-resistant in 200 and drug-responsive in 115, and 200 control subjects without epilepsy. Recently devised methods were used to control for population stratification, and linkage disequilibrium was calculated across the gene. RESULTS As compared with patients with drug-responsive epilepsy, patients with drug-resistant epilepsy were more likely to have the CC genotype at ABCB1 3435 than the TT genotype (odds ratio, 2.66; 95 percent confidence interval, 1.32 to 5.38; P=0.006). There was no genetic stratification between the two groups of patients. The polymorphism fell within an extensive block of linkage disequilibrium spanning much or all of the gene, implying that the polymorphism may not itself be causal but rather may be linked with the causal variant. CONCLUSIONS These pharmacogenomic results identify a genetic factor associated with resistance to antiepileptic drugs.

Subfields: Oncology, Pharmacology, Psychiatry and Mental health

View Paper: https://www.semanticscholar.org/paper/36210154fd76e672a5796b1485be828c3aadfe98

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Citations in the corpus

Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: A position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies (2008, background): “underlying disorder, or to genetic abnormalities (Kutt & McDowell, 1968; Mattson et al., 1985; Siddiqui et al., 2003).”
P-glycoprotein: from genomics to mechanism (2003, background): “Siddiqui et al. (2003) reported an association of the CC genotype with poor response of patients to antiepileptic drugs.”
Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options (2020, background): “Deriving justification from work in cancer, animal models, and tissue studies in human epileptogenic brain tissue, the first association of ABCB1was a single SNP study in 2003 (Siddiqui et al., 2003) of a cohort considered small by today’s standards.”
The blood-brain barrier in health and chronic neurodegenerative disorders. (2008, positive): “A positive association between the polymorphism in the MDR1 gene encoding P-gp (or ABCB1) and multidrug-resistant epilepsy has been reported in a subset of epilepsy patients (Siddiqui et al., 2003).”
Polymorphisms in Human MDR1 (P‐glycoprotein): Recent Advances and Clinical Relevance (2004, background): “The frequency of the exon 26 3435C allele was noted to be significantly greater in subjects with drug-resistant seizure disorders.(111) Human immunodeficiency virus (HIV) therapy has also been studied in relation to MDR1 polymorphisms.”