GABRG2, rs211037 is associated with epilepsy susceptibility, but not with antiepileptic drug resistance and febrile seizures.
OBJECTIVE
Several 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.


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 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.


CONCLUSIONS
We 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.
aHuman Molecular Genetics Department, Rajiv Gandhi Center for Biotechnology bR. Madhavan Nayar Center for Comprehensive Epilepsy Care, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Kerala, India cDepartment of Medicine, and Cancer Biology and Genetics, Memorial-Sloan Kettering Cancer Center, New York, New York, USA.
Shabeesh
S
Balan
Sanish
S
Sathyan
Saradalekshmi K
SK
Radha
Vijai
V
Joseph
Kurupath
K
Radhakrishnan
Moinak
M
Banerjee
D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000627:therapeutic use*; D016022:Case-Control Studies; D004351:Drug Resistance / Q000235:genetics*; D004827:Epilepsy / Q000235:genetics*; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D007194:India; D008297:Male; D020190:Myoclonic Epilepsy, Juvenile / Q000188:drug therapy / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011963:Receptors, GABA-A / Q000235:genetics*; D012598:Sclerosis; D003294:Seizures, Febrile / Q000188:drug therapy* / Q000235:genetics*; D055815:Young Adult
D000927:Anticonvulsants; C546240:GABRA1 protein, human; C546171:GABRA6 protein, human; C495710:GABRB2 protein, human; C546279:GABRG2 protein, human; D011963:Receptors, GABA-A