title: 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.
authors.affiliation: Human Molecular Genetics Laboratory, Rajiv Gandhi Center for Biotechnology, Trivandrum, Kerala, India ; R. Madhavan Nayar Center for Comprehensive Epilepsy Care, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India.
authors.forename: Shabeesh
authors.initials: S
authors.lastname: Balan
authors.affiliation: Human Molecular Genetics Laboratory, Rajiv Gandhi Center for Biotechnology, Trivandrum, Kerala, India.
authors.forename: Sumitha Prameela
authors.initials: SP
authors.lastname: Bharathan
authors.affiliation: Human Molecular Genetics Laboratory, Rajiv Gandhi Center for Biotechnology, Trivandrum, Kerala, India.
authors.forename: Neetha Nanoth
authors.initials: NN
authors.lastname: Vellichiramal
authors.affiliation: Human Molecular Genetics Laboratory, Rajiv Gandhi Center for Biotechnology, Trivandrum, Kerala, India.
authors.forename: Sanish
authors.initials: S
authors.lastname: Sathyan
authors.affiliation: Department of Medicine, Memorial-Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Vijai
authors.initials: V
authors.lastname: Joseph
authors.affiliation: R. Madhavan Nayar Center for Comprehensive Epilepsy Care, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India.
authors.forename: Kurupath
authors.initials: K
authors.lastname: Radhakrishnan
authors.affiliation: Human Molecular Genetics Laboratory, Rajiv Gandhi Center for Biotechnology, Trivandrum, Kerala, India.
authors.forename: Moinak
authors.initials: M
authors.lastname: Banerjee
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000483:Alleles; D004351:Drug Resistance / Q000235:genetics*; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007194:India; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins