Testing association of rare genetic variants with resistance to three common antiseizure medications
Testing association of rare genetic variants with resistance to three common antiseizure medications
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DOI：
10.1111/epi.16467
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发表时间：
2020-04-01
期刊：
影响因子：
5.6
通讯作者：
Lerche, Holger
中科院分区：
文献类型：
--
作者：
Wolking, Stefan;Moreau, Claudia;Lerche, Holger
目的：耐药性是治疗癫痫患者的一个主要问题。目前还没有确定抗癫痫药物（ASM）耐药性的遗传标记。我们旨在确定三种常见asm的罕见遗传变异在耐药中的作用：左乙拉西坦（LEV）、拉莫三嗪（LTG）和丙戊酸（VPA）。方法采用全外显子组测序（WES）对1622例欧洲裔癫痫患者进行深度表型分析，其中575例服用LEV， 826例服用LTG， 782例服用VPA。我们进行了基于基因和基因集的崩溃分析，比较了对三种药物的反应和无反应，以确定不同类别的罕见遗传变异的负担。结果我们观察到，与VPA药代动力学相关基因相比，VPA耐药个体中罕见错义、截断和剪接区变异的富集程度略微显著。我们还发现，与LEV应答者相比，无应答者突触囊泡糖蛋白（SV2）基因家族的截断区和剪接区变异具有显著的边缘富集。使用基于基因的方法，我们没有看到任何显著的富集。在我们的药理学研究中，我们发现在对VPA或LEV具有耐药性的个体中，与药物动力学或靶向相关的基因群中破坏性变异的负担略有增加。因此，这些变异可以确定基因对耐药性的贡献。
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.