Abstract
Epilepsy constitutes a heterogeneous group of disorders that is characterized by recurrent unprovoked seizures due to widely different etiologies. Multidrug resistance remains a major issue in clinical epileptology, where one third of patients with epilepsy continue to have seizures. Role of efflux transporters in multidrug resistant epilepsy has been attributed to drug-resistant epilepsy although, with discrepant observation in genetic studies. These discrepancies could be attributed to variety of factors such as variable definition of the anti-epileptic drug (AED)-resistance, variable epilepsy phenotypes and ethnicities among the studies. In the present study we inquired the role of multidrug transporters ABCB1 and ABCG2 variants in determining AED-resistance and susceptibility to epilepsy in three well-characterized cohorts comprising of mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) (prototype for AED-resistant epilepsy); juvenile myoclonic epilepsy (JME) (prototype for AED-responsive epilepsy); and healthy non-epileptic controls, in 738 subjects of Malayalam speaking south Indian ancestry. ABCB1 and ABCG2 variants were not found to be associated with drug resistance when AED-resistant and AED-responsive cohorts were compared. However, a significant association was observed between ABCB1 (C3435T) rs1045642 and risk of having epilepsy (MTLE-HS and JME pooled cohort; genotypic p-value = 0.0002; allelic p-value = 0.004). This association was seen persistent with MTLE-HS (genotypic p-value = 0.0008; allelic p-value = 0.004) and also with JME (genotypic p-value = 0.01; allelic p-value = 0.05) cohort individually. In-silico functional prediction indicated that ABCB1 rs1045642 has a deleterious impact on protein coding function and in splicing regulation. We conclude that the ABCB1 and ABCG2 variants do not confer to AED-resistance in the study population. However, ABCB1 rs1045642 increases vulnerability to epilepsy with greater tendency for MTLE-HS in south Indian ancestry from Kerala.
Highlights
Epilepsy constitutes a heterogeneous group of disorders characterized by recurrent unprovoked seizures due to widely different etiologies
We assessed the role of ABCB1 and ABCG2 variants in anti-epileptic drug (AED) resistance by comparing a uniform cohort of AED resistant mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) epilepsy patients with AED responsive juvenile myoclonic epilepsy (JME) epilepsy patients
The genotypic and allelic frequencies of ABCG2 variants did not differ significantly when the AED resistant patient group was compared with the AED responsive group (Table 2)
Summary
Epilepsy constitutes a heterogeneous group of disorders characterized by recurrent unprovoked seizures due to widely different etiologies. Role of efflux transporters in multidrug resistant epilepsy has been attributed from the studies which reported overexpression of the major blood–brain barrier transporter Pglycoprotein (P-gp) in epileptic tissue from patients with drugresistant epilepsy [4]. This was further complemented by the over expression of other associated efflux proteins in the epileptogenic tissues both in human and animal models [5,6], supporting the notion that efflux activity limits the AED availability to the targets
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.