A POLYMORPHISM IN THE SCN1A GENE INFLUENCES THE EFFECT OF CARBAMAZEPINE ON CORTICAL EXCITABILITY - A PHARMACOGENETIC TMS-STUDY
Abstract number :
1.316
Submission category :
11. Genetics
Year :
2012
Submission ID :
15805
Source :
www.aesnet.org
Presentation date :
11/30/2012 12:00:00 AM
Published date :
Sep 6, 2012, 12:16 PM
Authors :
K. Menzler, A. Hermsen, K. Balkenhol, C. Duddek, H. Bugiel, P. Reif, K. Klein, A. Haag, S. Knake, H. Hamer, H. Trucks, T. Sander, F. Rosenow
Rationale: The SCN1A gene encodes the sodium channel alpha subunit NAv1.1. A biallelic splice-site variation in this gene (SNP IVS5N+5 G>A, rs3812718) is associated with electrophysiological properties of the channel and the effect of sodium-channel blocking antiepileptic drugs in vivo and in vitro. In the present study, we investigated the effects of the SNP genotype on cortical excitability at baseline and after administration of carbamazepine. Methods: Paired-pulse transcranial magnetic stimulation (TMS) was applied to 49 healthy volunteers with genotype AA and 43 with genotype GG of the SCN1A IVS5N+5 G>A polymorphism at baseline and 5 hours after administration of 400mg of carbamazepine or placebo in a double-blind, randomized, cross-over design. Resting motor threshold (RMT), short interval intracortical inhibition (SICI) and facilitation (SICF) as well as cortical silent period (CSP) were determined. Results: There was a significant influence of SNP genotype on the effect of carbamazepine. Volunteers with genotype GG had a higher increase in CSP duration compared with genotype AA after intake of carbamazepine as compared to placebo (21.53±6.31 ms vs. 0.56±5.93 ms, p=.013). Furthermore, we observed, as other studies have, an increase in RMT, independent of genotype. At baseline, there was no significant difference in any TMS parameter between subjects with genotype AA and GG. Conclusions: We showed a differential effect of carbamazepine on the CSP duration which depended on the SCN1A SNP genotype and reflects changes in GABAergic cortical inhibition. Our results support earlier studies which showed that alternative splicing of the SCN1A gene modulates inhibition of GABAergic cortical interneurons, possibly due to selective expression of NAv1.1 in these interneurons. In accordance with clinical observations, our results provide further evidence that this SNP affects pharmacoresponse to sodium channel blockers. Furthermore, this study shows that TMS can be used to investigate the pharmacogenetics of cortical excitability.
Genetics