Testing association of rare genetic variants with resistance to three common antiseizure medications
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.
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
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
Fonds Wetenschappelijk Onderzoek Grant/Award Number 1861419N
CommentsThe original article is available at https://onlinelibrary.wiley.com
Published CitationWolking 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 Date6 March 2020
- Beaumont Hospital
- FutureNeuro Centre
- School of Pharmacy and Biomolecular Sciences
- Neurological and Psychiatric Disorders
- Published Version (Version of Record)