دورية أكاديمية
Testing association of rare genetic variants with resistance to three common antiseizure medications
| العنوان: | Testing association of rare genetic variants with resistance to three common antiseizure medications |
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| المؤلفون: | 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 |
| المساهمون: | Wellcome Trust, Imperial College Healthcare NHS Trust- BRC Funding, Commission of the European Communities, Medical Research Council (MRC) |
| المصدر: | 666 ; 657 |
| بيانات النشر: | Wiley |
| سنة النشر: | 2020 |
| المجموعة: | Imperial College London: Spiral |
| مصطلحات موضوعية: | Science & Technology, Life Sciences & Biomedicine, Clinical Neurology, Neurosciences & Neurology, burden analysis, lamotrigine, levetiracetam, pharmacogenomics, rare variants, valproic acid, ANTIEPILEPTIC DRUGS, ILAE COMMISSION, EPILEPSY, SV2A, HYPOTHESIS, PHARMACORESISTANCE, EXPRESSION, MICROSOMES, EpiPGX Consortium, Neurology & Neurosurgery, 1103 Clinical Sciences, 1109 Neurosciences |
| جغرافية الموضوع: | United States |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 0013-9580 |
| العلاقة: | Epilepsia; http://hdl.handle.net/10044/1/77998Test; 066056/Z/01/Z; RDA03; RD610; 279062; P35076; 602102; MR/S02638X/1 |
| DOI: | 10.1111/epi.16467 |
| الإتاحة: | https://doi.org/10.1111/epi.16467Test http://hdl.handle.net/10044/1/77998Test |
| حقوق: | © 2020 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
| رقم الانضمام: | edsbas.E6AFAA2B |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 00139580 |
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| DOI: | 10.1111/epi.16467 |