Testing association of rare genetic variants with resistance to three common antiseizure medications

Wolking, S. et al. (2020) Testing association of rare genetic variants with resistance to three common antiseizure medications. Epilepsia, 61(4), pp. 657-666. (doi: 10.1111/epi.16467) (PMID:32141622)

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Objective: Drug resistance is a major concern in the treatment of individuals with epilepsy. No genetic markers for resistance to individual antiseizure medication (ASM) have yet been identified. We aimed to identify the role of rare genetic variants in drug resistance for three common ASMs: levetiracetam (LEV), lamotrigine (LTG), and valproic acid (VPA). Methods: A cohort of 1622 individuals of European descent with epilepsy was deeply phenotyped and underwent whole exome sequencing (WES), comprising 575 taking LEV, 826 LTG, and 782 VPA. We performed gene‐ and gene set–based collapsing analyses comparing responders and nonresponders to the three drugs to determine the burden of different categories of rare genetic variants. Results: We observed a marginally significant enrichment of rare missense, truncating, and splice region variants in individuals who were resistant to VPA compared to VPA responders for genes involved in VPA pharmacokinetics. We also found a borderline significant enrichment of truncating and splice region variants in the synaptic vesicle glycoprotein (SV2 ) gene family in nonresponders compared to responders to LEV. We did not see any significant enrichment using a gene‐based approach. Significance: In our pharmacogenetic study, we identified a slightly increased burden of damaging variants in gene groups related to drug kinetics or targeting in individuals presenting with drug resistance to VPA or LEV. Such variants could thus determine a genetic contribution to drug resistance.

Item Type:Articles
Additional Information:The EpiPGX Consortium was funded by FP7 grant 279062 “EpiPGX” from the European Commission. CENet was funded by joint funding from Genome Canada and Genome Quebec. SW received funding from the German Research Foundation (DFG) (WO 2385/1-1), and the Clinician Scientist program of the University of Tübingen (418-0- 0). SaW was supported by the BOF-University of Antwerp (FFB180053) and FWO (1861419N). This study was supported in part by the Robert Bosch Stiftung Stuttgart, Germany, and in part by the Horizon 2020-PHC-2015 grant U-PGx 668353. Recruitment of patients in Tübingen was partly funded by the German Society for Epileptology (DGfE), by UCB Pharma, and by the foundation “no epilep” (to HL and YGW). SLG is funded by the Canadian Institutes of Health Research. Part of this work was undertaken at University College London Hospitals, which received a proportion of funding from the NIHR Biomedical Research Centres funding scheme. We are grateful to Epilepsy Society, UK, for their support of this work. JWS is based at UCLH/UCL Biomedical Research Centre, which receives a proportion of funding from the UK Department of Health's NIHR Research Centres funding scheme. He receives support from the Dr Marvin Weil Epilepsy Research Fund and UK Epilepsy Society.
Glasgow Author(s) Enlighten ID:Sills, Dr Graeme
Authors: Wolking, S., Moureau, C., Niels, A. T., Schaeffeler, E., McCormack, M., Auce, P., Avbersek, A., Becker, F., Krenn, M., Møller, R. S., Nikanorova, M., Weber, Y. G., Weckhuysen, S., EpiPGX Consortium, , Cavalleri, G. L., Delanty, N., Depondt, C., Johnson, M. R., Koeleman, B. P.C., Kunz, W. S., Marson, A. G., Sander, J. W., Sills, G. J., Striano, P., Zara, F., Zimprich, F., Schwab, M., Krause, R., Sisodiya, S. M., Cossette, P., Girard, S. L., and Lerche, H.
College/School:College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Epilepsia
ISSN (Online):1528-1167
Published Online:06 March 2020
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Epilepsia 61(4):657-666
Publisher Policy:Reproduced under a Creative Commons License

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