Abstract
OBJECTIVE: Several antiepileptic drugs (AEDs) are known to target the GABAA receptor through positive allosteric modulation of the receptors, thereby enhancing GABAA receptor-mediated inhibition. The large diversity of GABAA 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 METHODS: We 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. RESULTS: A 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 GABAA 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. CONCLUSION: We could substantiate that among the GABAA receptor subunit gene cluster polymorphisms, the GABRG2, rs211037 predisposes susceptibility to epilepsy, irrespective of its phenotype, but not to AED resistance.
Original language | English (US) |
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Pages (from-to) | 605-610 |
Number of pages | 6 |
Journal | Pharmacogenetics and Genomics |
Volume | 23 |
Issue number | 11 |
DOIs | |
State | Published - Nov 2013 |
Externally published | Yes |
Keywords
- Antiepileptic drug resistance
- Epilepsy
- GABRG2
- Hippocampal sclerosis
- Juvenile myoclonic epilepsy
- Temporal lobe epilepsy
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Genetics
- Genetics(clinical)