Genetic Association Analysis of ATP Binding Cassette Protein Family Reveals a Novel Association of ABCB1 Genetic Variants with Epilepsy Risk, but Not with Drug-Resistance

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.

Polymorphic Variants of SCN1A and EPHX1 Influence Plasma Carbamazepine Concentration, Metabolism and Pharmacoresistance in a Population of Kosovar Albanian Epileptic Patients

“…Previously, the impact of variants on a drug efflux transporter protein involved in the efflux of antiepileptic drugs, namely P-glycoprotein (Pgp; encoded by ABCB1 or MDR1), has been studied in different ethnic groups [ 46 , 47 ]. However, conflicting results have been reported, with some works indicating an impact on antiepileptic drug resistance [ 48 – 51 ], while others are in agreement with our observation, showing no effect of ABCB1 3435C>T on CBZ pharmacokinetic and drug response [ 52 – 55 ].…”

A Prediction Algorithm for Drug Response in Patients with Mesial Temporal Lobe Epilepsy Based on Clinical and Genetic Information

“…This limitation has been especially true for studies related to AED response in epilepsy. For instance, SNP rs1045642 (c.3435T>C), within ABCB1 , was initially associated with refractory epilepsy, but several other studies could not replicate the results [16, 17]. Indeed, our study showed that SNP rs1045642 presented low importance (MDA = 5.2), to the prediction model proposed (S5 Table).…”

“…However, subsequent studies did not replicate these findings [16, 17]. Similarly, SNPs in CYP2C9 (rs1799853 and rs1057910) have been associated with PHT dose requirement [18, 19], and SNPs in CYP2C19 (rs12248560) and CYP2D6 have been considered pharmacogenomic biomarkers for neurologic and psychiatric therapeutic drugs, including clobazam (CLB) and diazepam, receiving approval for use by the U.S. Food and Drug Administration (FDA) [19].…”

Role of ABC-Transporters in Epileptogenesis and Pharmacoresistant Epilepsy

“…All of them were residents of Kerala, south India, for more than three generations, of which 259 were RE (AED resistant), 201 were AED responsive, and the remaining 275 were non-epilepsy control subjects. Interestingly, this study concluded that variants in the ABCB1 and ABCG2 do not confer a significant risk to AED-resistance in the south Indian population of Kerala, but instead demonstrate an increased vulnerability to epilepsy and associated phenotypes [63].…”