Stefan Wolking1,2, Claudia Moreau3, Anne T Nies4,5, Elke Schaeffeler4,5, Mark McCormack6, Pauls Auce7, Andreja Avbersek8,9, Felicitas Becker1, Martin Krenn10, Rikke S Møller11,12, Marina Nikanorova12, Yvonne G Weber1,13, Sarah Weckhuysen14,15,16, Gianpiero L Cavalleri6,17, Norman Delanty6,18,19, Chantal Depondt20, Michael R Johnson17, Bobby P C Koeleman21, Wolfram S Kunz22, Anthony G Marson23, Josemir W Sander8,9,24, Graeme J Sills23, Pasquale Striano25,26, Federico Zara26, Fritz Zimprich10, Matthias Schwab4,5,27, Roland Krause28, Sanjay M Sisodiya8,9, Patrick Cossette2, Simon L Girard3, Holger Lerche1. 1. Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. 2. Department of Neurosciences, Research Center of the University of Montreal Hospital Center (CRCHUM), University of Montreal, Montreal, Canada. 3. Department of Applied Sciences, University of Quebec in Chicoutimi, Saguenay, Canada. 4. Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany. 5. University of Tübingen, Tübingen, Germany. 6. Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland. 7. Walton Centre NHS Foundation Trust, Liverpool, UK. 8. Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK. 9. Chalfont Centre for Epilepsy, London, UK. 10. Department of Neurology, Medical University of Vienna, Vienna, Austria. 11. Danish Epilepsy Centre - Filadelfia, Dianalund, Denmark. 12. Department of Regional Health Research, University of Southern Denmark, Odense, Denmark. 13. Department of Epileptology and Neurology, University of Aachen, Aachen, Germany. 14. Neurogenetics Group, VIB-UAntwerp, Center for Molecular Neurology, Antwerp, Belgium. 15. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. 16. Department of Neurology, Antwerp University Hospital, Antwerp, Belgium. 17. Division of Brain Sciences, Imperial College Faculty of Medicine, London, UK. 18. Division of Neurology, Beaumont Hospital, Dublin, Ireland. 19. The FutureNeuro Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland. 20. Department of Neurology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. 21. Department of Genetics, University Medical Center Utrecht, Utrecht, Netherlands. 22. Institute of Experimental Epileptology and Cognition Research and Department of Epileptology, University of Bonn, Bonn, Germany. 23. Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. 24. Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, Netherlands. 25. IRCCS "G. Gaslini" Institute, Genova, Italy. 26. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy. 27. Department of Clinical Pharmacology, Pharmacy and Biochemistry, University Tübingen, Tübingen, Germany. 28. Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
Abstract
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.
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.
Authors: Stefan Wolking; Claudia Moreau; Mark McCormack; Roland Krause; Martin Krenn; Samuel Berkovic; Gianpiero L Cavalleri; Norman Delanty; Chantal Depondt; Michael R Johnson; Bobby P C Koeleman; Wolfram S Kunz; Holger Lerche; Anthony G Marson; Terence J O'Brien; Slave Petrovski; Josemir W Sander; Graeme J Sills; Pasquale Striano; Federico Zara; Fritz Zimprich; Sanjay M Sisodiya; Simon L Girard; Patrick Cossette Journal: Ann Clin Transl Neurol Date: 2021-05-21 Impact factor: 4.511
Authors: Stefan Wolking; Ciarán Campbell; Caragh Stapleton; Mark McCormack; Norman Delanty; Chantal Depondt; Michael R Johnson; Bobby P C Koeleman; Roland Krause; Wolfram S Kunz; Anthony G Marson; Josemir W Sander; Graeme J Sills; Pasquale Striano; Federico Zara; Sanjay M Sisodiya; Gianpiero L Cavalleri; Holger Lerche Journal: Front Pharmacol Date: 2021-06-09 Impact factor: 5.810