GABRG2, rs211037 is associated with epilepsy susceptibility, but not with antiepileptic drug resistance and febrile seizures
GABRG2, rs211037 is associated with epilepsy susceptibility, but not with antiepileptic drug resistance and febrile seizures
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DOI：
10.1097/fpc.0000000000000000
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发表时间：
2013-11-01
影响因子：
2.6
通讯作者：
Banerjee, Moinak
中科院分区：
文献类型：
--
作者：
Balan, Shabeesh;Sathyan, Sanish;Banerjee, Moinak
已知几种抗癫痫药物（AED）通过受体的正变构调节靶向GABA（A）受体，从而增强GABA（A）受体介导的抑制。GABA（A）受体在中枢神经系统中具有很大的多样性，其中一些与癫痫易感性和AED抵抗性有关，我们的目的是检测这些差异。rs 2279020（GABRA 1）、rs3219151（GABRA 6）、rs 2229944（GABRB 2）和rs 211037（GABRG 2），具有癫痫易感性和AED耐药性。这是在种族匹配的南印度血统的三个队列中评估的：内侧颞叶癫痫伴海马硬化（抗AED癫痫综合征的原型），青少年肌阵挛性癫痫（AED反应性癫痫综合征的原型）和非癫痫对照。（P=0.0006，比值比=1.6，95%置信区间=1.22-2.08）和基因型（P=0.001）GABRG 2同义变异rs 211037（Asn 196 Asn）被观察到与癫痫无关的表型，即MTLE-HS或青少年肌阵挛性癫痫。然而，在有热性惊厥病史的癫痫患者中，这种相关性并没有保留。GABA（A）受体亚单位基因与AED耐药无关。计算机模拟分析表明，rs 211037在转录调控和剪接调控中起重要作用。结论在GABA（A）受体亚基基因簇多态性中，GABRG 2，rs 211037与癫痫易感性有关，而与AED耐药无关。(C)2013年威科医疗|利平科特·威廉姆斯和威尔金斯。
ObjectiveSeveral antiepileptic drugs (AEDs) are known to target the GABA(A) receptor through positive allosteric modulation of the receptors, thereby enhancing GABA(A) receptor-mediated inhibition. The large diversity of GABA(A) receptors has been reported in the central nervous system; some of these have been implicated in epilepsy susceptibility and AED resistance, which we aimed to examine.Materials and methodsWe investigated the association of single-nucleotide polymorphisms in GABA(A) receptor subunit subtype genes namely; rs2279020 (GABRA1), rs3219151 (GABRA6), rs2229944 (GABRB2), and rs211037 (GABRG2) with predisposition to epilepsy and AED resistance. This was assessed in three cohorts of ethnically matched South Indian ancestry: mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) (prototype of AED-resistant epilepsy syndrome), juvenile myoclonic epilepsy (prototype of AED-responsive epilepsy syndrome), and nonepilepsy controls.ResultsA significant allelic (P=0.0006, odds ratio=1.6, 95% confidence interval=1.22-2.08) and genotypic (P=0.001) association of a synonymous variant in GABRG2, rs211037 (Asn196Asn) was observed with epilepsy irrespective of its phenotype, that is, MTLE-HS or juvenile myoclonic epilepsy. However, this association was not retained in epilepsy patients with a history of febrile seizures. The GABA(A) receptor subunit subtype genes were not found to have any association with AED resistance. In-silico analysis indicated that rs211037 plays a significant role in the transcriptional regulation and splicing regulation.ConclusionWe could substantiate that among the GABA(A) receptor subunit gene cluster polymorphisms, the GABRG2, rs211037 predisposes susceptibility to epilepsy, irrespective of its phenotype, but not to AED resistance. (C) 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.