Short communication SCN1AIVS5-91G>A polymorphism is associated with susceptibility to epilepsy but not with drug responsiveness Ritu Kumari a , Ram Lakhan a , Surendra Kumar a , R.K. Garg c , U.K. Misra b , J. Kalita b , Balraj Mittal a, * a Department of Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow 226014, India b Department of Neurology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India c Department of Neurology, King George’s Medical University, Lucknow 226003, India article info Article history: Received 4 June 2012 Accepted 4 February 2013 Available online 1 March 2013 Keywords: Antiepileptic drug Drug resistance Pharmacotherapy Voltage gated sodium channel abstract Sodium channel alpha subunit type 1 (SCN1A) is voltage gated ion channel which plays critical role in membrane excitability. A common SCN1A IVS5-91G>A (rs3812718) allele has been attributed to be a possible modifying factor for epilepsy susceptibility and therapeutic response. In the present study, we enrolled 485 epilepsy patients and 298 age-sex matched controls free of neurological deficits. Thera- peutic response of carbamazepine/oxcarbamazepine (CBZ/OXC) and other antiepileptic drugs were observed in terms of drug responsiveness and drug resistance. Genotyping of SCN1A IVS5-91G>A is done by Taqman custom designed assay; in a real time7500HT System. We observe highly significant asso- ciation [(P-values for GA (P ¼ 6.58  10 5 , OR ¼ 2.13, 95% CI ¼ 1.47e3.09) and AA (P ¼ 4.11  10 9 , OR ¼ 3.59, 95% CI ¼ 2.35e5.50)] at variant genotypes as well as A allele (P ¼ 6.92  10 11 ), OR ¼ 1.99, 95%, CI ¼ 1.62e2.45) in epilepsy patients versus control subjects. The relative risk for epilepsy suscep- tibility due to variant containing genotypes (GA þ AA) was also significant (P ¼ 1.64  10 5 ; OR ¼ 2.56; 95% CI ¼ 1.80e3.65) when compared with homozygous wild-type GG. The risk in recessive model (P ¼ 1.34  10 5 ; OR ¼ 2.12; 95% CI ¼ 1.51e2.97) was also apparent when compared with GA þ GG. In case-only analysis, we evaluated the effect of SCN1A IVS5-91G>A polymorphism with drug resistance of anti-epileptic drug therapies. However, we did not observe significant associations either with patients showing drug resistance to CBZ/OXC monotherapy or polytherapy. In conclusion, we report that SCN1AIVS5-91G>A polymorphism is associated with epilepsy susceptibility but not with drug respon- siveness in epilepsy patients from North India. Ó 2013 Elsevier Masson SAS. All rights reserved. 1. Introduction Epilepsy is clinically and genetically heterogeneous group of disorders characterized by an episode of excessive synchronized neuronal activity [1]. According to World Health Organization (WHO); worldwide eight per 1000 persons have epilepsy [2]. Earlier reports suggested that almost half of all epilepsies have some genetic predisposition which could directly or indirectly modulate seizure phenotype [3]. Studies indicate that different types of epilepsies can aggregate in families [4e6], suggesting the existence of shared genetic factors that increase susceptibility to different epilepsies [7]. The advances in pharmacogenetics have further revealed that genetic variations also determine clinical response of epilepsy patients to different drugs [8]. Therefore, genetic factors could be major determinants of individual suscep- tibility to epilepsy, and response to therapeutic compounds. Voltage-gated sodium channels (VGSCs) are responsible for neuronal depolarization as well as initiation and propagation of action potentials in neurons [9]. These are heterologous multi- subunit complexes that contain a large ‘a’ subunit and smaller ‘b’ subunits [10]. In fact, altered sodium channel transcript levels in human epilepsy have been found in brain tissues, suggesting a potential role for sodium channels in the pathophysiology of epi- lepsy. Along with other genetic variants of sodium channels, SCN1A IVS5-91G>A (rs3812718) allele has been attributed to be a possible modifying factor for epilepsy susceptibility and therapeutic response [11]. It has been suggested that the polymorphism in- fluences treatment response of carbamazepine in epilepsy patients [12e14], but results from replication studies have not been consistent. Therefore, we aimed to re-evaluate the role of SCN1AIVS5-91G>A gene polymorphism in epilepsy susceptibility as * Corresponding author. Tel.: þ91 522 2668700x2322; fax: þ91 522 2668017. E-mail addresses: balraj@sgpgi.ac.in, bml_pgi@yahoo.com (B. Mittal). Contents lists available at SciVerse ScienceDirect Biochimie journal homepage: www.elsevier.com/locate/biochi 0300-9084/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.biochi.2013.02.006 Biochimie 95 (2013) 1350e1353