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

• Published in: PloS one Vol. 9; no. 2; p. e89253
• Main Authors: Balan, Shabeesh, Bharathan, Sumitha Prameela, Vellichiramal, Neetha Nanoth, Sathyan, Sanish, Joseph, Vijai, Radhakrishnan, Kurupath, Banerjee, Moinak
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21.02.2014; Public Library of Science (PLoS)
• Subjects: Adolescent; Adult; Alleles; Anticonvulsants; Association analysis; ATP Binding Cassette Transporter, Subfamily B - genetics; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters - genetics; Biology; Biotechnology; Blood-brain barrier; Brain research; Convulsions & seizures; Development and progression; Drug resistance; Drug Resistance - genetics; Drug therapy; Efflux; Epilepsy; Epilepsy - drug therapy; Epilepsy - genetics; Etiology; Female; Gene Frequency; Genetic Association Studies; Genetic diversity; Genetic Predisposition to Disease; Genetic variance; Genetic Variation; Genetics; Genotype; Haplotypes; Hippocampus; Humans; India; Laboratories; Male; Medicine; Meta-analysis; Microbial drug resistance; Multidrug resistance; Neoplasm Proteins - genetics; Population studies; Protein binding; Proteins; Schizophrenia; Sclerosis; Seizures; Seizures (Medicine); Splicing; Studies; Temporal lobe; Young Adult; New York; United States > US; India
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0089253

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.