Elsevier

Clinica Chimica Acta

Volume 412, Issues 13–14, 11 June 2011, Pages 1244-1248
Clinica Chimica Acta

Potential role of GABAA receptor subunit; GABRA6, GABRB2 and GABRR2 gene polymorphisms in epilepsy susceptibility and pharmacotherapy in North Indian population

https://doi.org/10.1016/j.cca.2011.03.018Get rights and content

Abstract

Background

GABAA receptors influence the susceptibility to seizures, and variations in the receptor genes can contribute to antiepileptic drug resistance also.

Methods

We investigated the possible associations of single nucleotide polymorphisms (SNPs) present in GABRA6 c. 1512 T>C, GABRB2 c. 1412 C>T, and GABRR2 c. IVS2C>G genes of GABAA receptors in epilepsy susceptibility and drug resistance in northern Indian patients with epilepsy. After screening a total of 202 healthy controls and 401 epilepsy patients were enrolled in study. The genotyping was done by PCR-RFLP methods.

Results

The GABRA6 c. 1512 T>C, polymorphism was conferring risk for epilepsy susceptibility for TC (P = 0.018), CC (P = 0.0001) genotype and for C allele (P = 0.0002). Another polymorphism GABRB2 c. 1412 C>T was also conferring high risk for epilepsy susceptibility CT (P = 0.012), TT (P = 0.778) genotype and for variant T allele (P = 0.034) but was not associated with drug resistance. No association was found with epilepsy susceptibility or with drug resistance in case of GABRR2 c. IVS2C>G gene polymorphism.

Conclusion

Overall, our findings suggest significant involvement of alpha (GABRA6) and beta (GABRB2) subunits of GABAA receptor in epilepsy susceptibility in north Indian population.

Introduction

The epilepsies are one of the most common but serious brain disorders which are characterized by an enduring predisposition to generate epileptic seizures [1]. The incidence of epilepsy in developed countries is around 50 per 100,000 people per year, and is higher in infants and elderly people [2]. The epilepsy affects an estimated 60 million people worldwide of all ages [3]. Earlier reports suggest that almost half of all epilepsies have some genetic component which could directly or indirectly modulate seizure phenotype [4]. According to Epilepsy Genetic Association Study database (http://www.epilepsygenes.org/ page/show/EGAD), more than 50 association studies have been performed and genetic variants of several genes such as neuronal sodium channels, potassium channels, and GABA receptors have been found to be associated in variety of epilepsy phenotypes [5]. Recent progress in genetic research in epilepsy mainly concerns two important aspects of the disease-complexity; the genetic etiology and drug therapy [6]. At the present time, GABA receptors have gained concern regarding their role in epilepsy susceptibility and therapeutic response of epilepsy patients undergoing AED treatment [7], [8].

γ-aminobuytric acid (GABA), is the primary inhibitory neurotransmitter in the CNS, which operates primarily via chloride-permeable GABAA receptor channels. From a genetic perspective, all mutations documented to date are localized to GABAA receptors rather than GABAB and GABAC receptors. Structurally, GABAA receptors are pentameric chloride ion channels formed from various combinations of proteins encoded by α (α 1–α 6), β (β 1–β 3), γ (γ 1–γ 3); δ, ε, θ, and ρ (ρ1–ρ3) subunit gene families [9]. Numerous experimental and clinical observations suggest that epilepsy may result from an imbalance in excitatory and inhibitory neurotransmitter systems resulting in decreased net inhibition. Conventional antiepileptic drugs (e.g. barbiturates, benzodiazepines) suppress seizures by increasing GABAA receptor activity, or by inhibition of GABA breakdown (vigabatrin) or reuptake (tiagabin) [10]. It is also hypothesized that, target receptor sites are somehow altered in epileptic brain so that they are much less sensitive to anticonvulsive effects of administered antiepileptic drugs [11].

These receptors are also key therapeutic targets for benzodiazepines, barbiturates, neurosteroids and general anesthetics [12]. Genetic variations in genes encoding GABA receptors have been shown to bring about inter-individual variation in susceptibility to various neurological syndromes including schizopherenia, epilepsy and alcohol-withdrawal syndromes. In our earlier study, we documented influence of susceptibility and drug response in epilepsy [13]. We have shown that genetic polymorphism present at alpha subunit of GABAA receptor GABRA1 IVS11 + 15 A>G is significantly associated with epilepsy susceptibility and drug resistance. However, GABRG2 588 C>T polymorphism was not found to be associated either with epilepsy susceptibility or with drug resistance. As different subunits of GABA receptors have differential role in epilepsy, the present study was designed to evaluate the association of GABAA receptor subunit subtypes; GABRA6 c. 1512 T>C (rs3219151), GABRB2 c. 1412 C>T (rs2229944), and GABRR2 c. IVS2 C>G (rs9362632) gene polymorphisms with epilepsy susceptibility and pharmacotherapy in north Indian epilepsy patients.

Section snippets

Study population

Epilepsy patients were enrolled from the outpatient department (OPD) of the Neurology attending the clinics of Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), and Chhatrapati Shahuji Maharaj Medical University (CSMMU), Lucknow, India. The patients were diagnosed and classified by experienced neurologists. The clinical profile of drug responsive and drug resistant epilepsy patients were based on hospital investigations. Exclusion criteria included severe adverse drug

Results

The mean age ± SD of patients with epilepsy was 24.25 ± 11.65. Among all the patients with epilepsy, 73.1% (293/401) were male and 26.9% (108/401) were female. Patients were also categorized on the basis of their drug response status. The mean age of the drug resistant patients was 23.61 ± 11.73 years versus drug responsive patients was 24.52 ± 11.31 years. Mean age of onset for seizures in drug resistant patients was 14.68 ± 10.24 years versus drug responsive patients was 17.09 ± 10.51 years. We were not able

Discussion

Alterations in GABAA receptor subtypes differing in subunit expression and composition in epilepsy are well documented in humans [18] and in animal models [19], [20], [21], [22], [23]. In the present study, we elucidated the association among potentially functional genetic variants of three different subunits of the GABAA receptors; GABRA6 c. 1512 T>C at 3′UTR region, GABRB2 c. 1412 C>T at exon 11, and an intronic GABRR2 c. IVS2 C>G gene polymorphism with disease susceptibility and drug

Acknowledgments

The study was supported by a grant received from the Department of Biotechnology (DBT) and fellowships provided by CSIR and DST, Government of India, New Delhi. We thankfully acknowledge support from Dr. NJ Gogtay, KEM hospital Mumbai, for drug level assays.

References (29)

  • G.J. Duncan et al.

    Cleaning up their act: the effects of marriage and cohabitation on licit and illicit drug use

    Demography

    (2006)
  • A.M. Hartz et al.

    Signaling to P-glycoprotein — a new therapeutic target to treat drug-resistant epilepsy?

    Drug News Perspect

    (2009)
  • R. Gandelman-Marton et al.

    Genetic aspects of epilepsy

    Harefuah

    (2008)
  • J.M. Fritschy

    Epilepsy, E/I balance and GABA(A) receptor plasticity

    Front Mol Neurosci

    (2008)
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