Aim This case-control study aimed to determine a possible association of single nucleotide polymorphism rs211037 of the gamma-aminobutyric acid receptor subunit gamma-2 (GABRG2) gene with the susceptibility to idiopathic generalized epilepsy (IGE) in the Macedonian population. Methods It enrolled 96 patients with clinically verified IGE and 51 healthy individuals without personal and family history of epilepsy or other neurological disorders as controls. A determination of the GABRG2 rs211037 polymorphism was performed using the TaqMan-based genotyping assay. Results A significant dominant association of the CC genotype (odds ratio - OR=2.100, 95% CI=1.018-4.332; p=0.043) and allelic association of C allele (OR=1.902, CI=1.040-3.477; p=0.035) with susceptibility to IGE was found. Carriers of CC genotype had approximately a 2-fold higher probability of developing IGE than the carriers of CT and TT genotypes. Carriers of the C allele had a 1.9-folds higher probability for IGE than the carriers of the T allele. Conclusion The polymorphism rs211037 of the GABRG2 gene increases the risk of the development of idiopathic generalized epilepsy in the Macedonian population.
Sigel E, Steinmann M. Structure, function, and modulation of GABAA receptors. J Biol Chem. 2012. p. 40224–31.
2.
Mody I, Pearce R. Diversity of inhibitory neurotransmission through GABA A receptors. Trends Neurosci. 2004. p. 569–75.
3.
Farrant M, Nusser Z. Variations on an inhibitory theme: phasic and tonic activation of GABA A receptors. Nat Rev Neurosci. 2005. p. 215–29.
4.
The International League Against Epilepsy Consortium on Complex Epilepsies. Genome-wide megaanalysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies. Nat Commun. 2018. p. 5269.
5.
Baulac S, Huberfeld G, Gourfinkel-An I, Mitropoulou G, Beranger A, Prud’homme J, et al. First genetic evidence of GABAA receptor dysfunction in epilepsy: a mutation in the γ2-subunit gene. Nat Genet. 2001. p. 46–8.
6.
Shen D, Hernandez C, Shen W, Hu N, Poduri A, Datta A, et al. De novo GABRG2 mutations associated with epileptic encephalopathies. Brain. 2017. p. 49–67.
7.
Komulainen-Ebrahim J, Schreiber J, Kangas S, Pylkäs K, Suo-Palosaari M, Rahikkala E, et al. Novel variants and phenotypes widen the phenotypic spectrum of GABRG2-related disorders. Seizure. 2019. p. 99–104.
8.
Wang D, Kriegstein A. Defining the role of GABA in cortical development. J Physiol. 2009. p. 1873–9.
9.
Balan S, Sathyan S, Radha S, Joseph V, Radhakrishnan K, Banerjee M. GABRG2, rs211037 is associated with epilepsy susceptibility, but not with antiepileptic drug resistance and febrile seizures. Pharmacogenet Genomics. 2013. p. 605–10.
10.
Kumari R, Lakhan R, Kalita J, Misra U, Mittal B. Association of alpha subunit of GABAA receptor subtype gene polymorphisms with epilepsy susceptibility and drug resistance in north Indian population. Seizure. 2010. p. 237–41.
11.
Haerian B, Baum L, Kwan P, Cherny S, Shin J, Kim S, et al. Contribution of GABRG2 polymorphisms to risk of epilepsy and febrile seizure: a multicenter cohort study and meta-analysis. Mol Neurobiol. 2016. p. 5457–67.
12.
Haerian B, Baum L. GABRG2 rs211037 polymorphism and epilepsy: a systematic review and meta-Analysis. Seizure. 2013. p. 53–8.
13.
Gitaí L, Almeida D, Born D, Gameleira J, F, Andrade D, et al. Lack of association between rs211037 of the GABRG2 gene and juvenile myoclonic epilepsy in Brazilian population. Neurol India. 2012. p. 585–6.
14.
Chou I, Lee C, Tsai C, Tsai Y, Wan L, Hsu Y, et al. Association of GABRG2 polymorphisms with idiopathic generalized epilepsy. Pediatr Neurol. 2007. p. 40–4.
15.
Butilă A, Sin A, Szabo E, Tilinca M, Zazgyva A. GABRG2 C588T gene polymorphisms might be a predictive genetic marker of febrile seizures and generalized recurrent seizures: a case-control study in a Romanian pediatric population. Arch Med Sci. 2018. p. 157–66.
16.
Scheffer I, Berkovic S, Capovilla G, Connolly M, French J, Guilhoto L, et al. Epilepsia. ILAE Commission for Classification and Terminology; 2017. p. 512–21.
17.
El Ella A, Tawfik S, M, Fotoh A, Soliman W, Oam. The genetic variant “C588T” of GA-BARG2 is linked to childhood idiopathic generalized epilepsy and resistance to antiepileptic drugs. Seizure. 2018. p. 39–43.
18.
Kinirons P, Cavalleri G, Shahwan A, Wood N, Goldstein D, Sisodiya S, et al. Examining the role of common genetic variation in the γ2 subunit of the GABAA receptor in epilepsy using tagging SNPs. Epilepsy Res. 2006. p. 229–38.
19.
Bhat M, Guru S, Mir R, Waza A, Zuberi M, Sumi M, et al. Association of GABAA receptor gene with epilepsy syndromes. J Mol Neurosci. 2018. p. 141–53.
20.
Kananura C, Haug K, Sander T, Runge U, Gu W, Hallmann K, et al. Splice-site mutation in GABRG2 associated with childhood absence epilepsy and febrile convulsions. Arch Neurol. 2002. p. 1137–41.
21.
Kim Y, Kim M, Nam T, Jang S, Park K, Kim E, et al. Mutation screening of the γ-aminobutyric acid type-A receptor subunit γ2 gene in Korean patients with childhood absence epilepsy. J Clin Neurol. 2012. p. 271–5.
22.
Ma S, Abou-Khalil B, Blair M, Sutcliffe J, Haines J, Hedera P. Mutations in GABRA1, GABRA5, GABRG2 and GABRD receptor genes are not a major factor in the pathogenesis of familial focal epilepsy preceded by febrile seizures. Neurosci Lett. 2006. p. 74–8.
23.
Milanovska. Mutations in GABRG2 receptor gene are not a major factor in the pathogenesis of mesial temporal lobe epilepsy in Indian population. Ann Indian Acad Neurol. 2016. p. 236–41.
24.
Wang S, Zhang X, Zhoul, Wu Q, Han Y. Analysis of GABRG2 C588T polymorphism in genetic epilepsy and evaluation of GABRG2 in drug treatment. Clin Transl Sci. 2021.
25.
Leu C, Stevelink R, Smith A, Goleva S, Kanai M, Ferguson L, et al. Epi25 Consortium; Lal D. Polygenic burden in focal and generalized epilepsies. Brain. 2019. p. 3473–81.
26.
Greenfield L. Molecular mechanisms of antiseizure drug activity at GABAA receptors. Seizure. 2013. p. 589–600.
27.
Perucca P, Perucca E. Identifying mutations in epilepsy genes: impact on treatment selection. Epilepsy Res. 2019. p. 18–30.
28.
Kang J, Macdonald R. Molecular pathogenic basis for GABRG2 mutations associated with a spectrum of epilepsy syndromes, from generalized absence epilepsy to dravet syndrome. JAMA Neurol. 2016. p. 1009–16.
The statements, opinions and data contained in the journal are solely those of the individual authors and contributors and not of the publisher and the editor(s). We stay neutral with regard to jurisdictional claims in published maps and institutional affiliations.