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Previous Volume 348:1442-1448 April 10, 2003 Number 15 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Editorial by Pedley, T. A. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

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.

Source Information

From the Departments of Molecular Pathogenesis (A. Siddiqui, N.W.W.) and Clinical and Experimental Epilepsy (A. Siddiqui, S.M.S.), Institute of Neurology, and the Department of Biology (A. Smith, D.B.G.), University College London, London; Genostics, London (M.E.W.); the Pharmacogenetics Laboratory, Epidauros Biotechnology, Bernried, Germany (R.K., U.B.); and the National Neurological Institute, Singapore (M.E.W., D.B.G., N.W.W.).

Address reprint requests to Dr. Sisodiya at the Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London WC1N 3BG, United Kingdom, or at s.sisodiya{at}ion.ucl.ac.uk.

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