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

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posted on 09.04.2021, 16:29 by Stefan Wolking, Claudia Moreau, Anne T Nies, Elke Schaeffeler, Mark McCormack, Pauls Auce, Andreja Avbersek, Felicitas Becker, Martin Krenn, Rikke S Møller, Marina Nikanorova, Yvonne G Weber, Sarah Weckhuysen, Gianpiero CavalleriGianpiero Cavalleri, Norman DelantyNorman Delanty, Chantal Depondt, Michael R Johnson, Bobby PC Koeleman, Wolfram S Kunz, Anthony G Marson, Josemir W Sander, Graeme J Sills, Pasquale Striano, Federico Zara, Fritz Zimprich, Matthias Schwab, Roland Krause, Sanjay M Sisodiya, Patrick Cossette, Simon L Girard, Holger Lerche, EpiPGX Consortium

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.

Funding

FP7 grant 279062 “EpiPGX” from the European Commission

Genome Canada and Genome Quebec

German Research Foundation (DFG) (WO 2385/1‐1) (WE4896/4-1) (FOR-2715) (KR 5093/2-1) (LE 1030/16-1)

Clinician Scientist program of the University of Tübingen (418‐0‐0)

BOF‐University of Antwerp (FFB180053) and FWO (1861419N)

Robert Bosch Stiftung Stuttgart, Germany

Horizon 2020‐PHC‐2015 grant U‐PGx 668353

German Society for Epileptology (DGfE), by UCB Pharma

“no epilep”

Canadian Institutes of Health Research

NIHR Biomedical Research Centres funding scheme

UK Department of Health's NIHR Research Centres funding scheme

Dr Marvin Weil Epilepsy Research Fund

UK Epilepsy Society

Eberhard Karls Universitat Tubingen, Grant/Award Number: 418-0-0 and AKF357-0-0

Bundesministerium fur Forschung und Technologie, Grant/Award Number OIGM1907A

UCB

Fonds Wetenschappelijk Onderzoek Grant/Award Number 1861419N

History

Comments

The original article is available at https://onlinelibrary.wiley.com

Published Citation

Wolking S, Moreau C, Nies AT, Schaeffeler E, McCormack M, Auce P, Avbersek A, Becker F, Krenn M, Møller RS, Nikanorova M, Weber YG, Weckhuysen S, Cavalleri GL, Delanty N, Depondt C, Johnson MR, Koeleman BPC, Kunz WS, Marson AG, Sander JW, Sills GJ, Striano P, Zara F, Zimprich F, Schwab M, Krause R, Sisodiya SM, Cossette P, Girard SL, Lerche H; EpiPGX Consortium. Testing association of rare genetic variants with resistance to three common antiseizure medications. Epilepsia. 2020;61(4):657-666.

Publication Date

6 March 2020

PubMed ID

32141622

Department/Unit

  • Beaumont Hospital
  • FutureNeuro Centre
  • School of Pharmacy and Biomolecular Sciences

Research Area

  • Neurological and Psychiatric Disorders

Publisher

Wiley

Version

  • Published Version (Version of Record)