Association between ABCB1 Gene Variation and Response to Anti Epileptic Drugs and Seizure Susceptibility
Abstract number :
4.217
Submission category :
Human Genetics
Year :
2006
Submission ID :
7106
Source :
www.aesnet.org
Presentation date :
12/1/2006 12:00:00 AM
Published date :
Nov 30, 2006, 06:00 AM
Authors :
1Russell J. Buono, 2Michael R. Sperling, 3Dennis J. Dlugos, 1Michael D. Privitera, 4Jacqueline A. French, 5Warren Lo, 6Steven C. Schachter, 7Patrick Cossette, 8</
The ABCB1 gene encodes P-Glycoprotein, a membrane transporter of xenobiotics and natural molecules in many tissues. Of seven studies reporting association tests between variation in ABCB1 and response to anti epileptic drugs (AEDs), three showed positive association, while four did not. Two papers showed association in a case control design, suggesting ABCB1 variation is related to seizure susceptibility. We report the first association study on a cohort of patients and controls from the US and Canada., Genotyping single nucleotide polymorphisms (SNPs) c1236t and c3435t was performed using TaqMan assays. Samples were collected at 7 sites and all subjects (ages 3-70) were recruited according to local institutional review board policies. Blood samples were obtained and most are available as cell lines from the Coriell Institute. Both markers were typed in 297 generalized patients (70 AED resistant), 253 focal patients (88 AED resistant) and 184 controls, all of European ancestry. Hardy-Weinberg equilibrium (HWE) was checked and alleles tested for association using chi square tests. Linkage Disequilibrium (LD) and haplotype effects were calculated using likelihood ratio and CHAPLIN respectively. AED response was defined as one year of seizure freedom since last checkup., All markers were in HWE and the SNPs were in strong LD, p=1 x 10-3. Single marker analyses showed a lack of association for drug response or seizure susceptibility. However, an association was observed between AED response and the CC haplotype in generalized patients (p=0.007). Haplotypes CC and TT were strongly associated with seizure susceptibility comparing all cases to controls p=1 x 10 -7., We conclude that variation in ABCB1 is weakly associated with AED response in our generalized patients and is strongly associated with seizure susceptibility in all patients. The same haplotpye that confers drug resistance also increases risk for seizures suggesting a relationship between susceptibility and AED response., (Supported by NIH R01NS40396 to RJB, The University of Cincinnati Dept of Neurology and The Neuroscience Institute, and The Center for Neurobiology and Behavior at the University of Pennsylvania.)
Genetics