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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

Author

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  • Shabeesh Balan
  • Sumitha Prameela Bharathan
  • Neetha Nanoth Vellichiramal
  • Sanish Sathyan
  • Vijai Joseph
  • Kurupath Radhakrishnan
  • Moinak Banerjee

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.

Suggested Citation

  • Shabeesh Balan & Sumitha Prameela Bharathan & Neetha Nanoth Vellichiramal & Sanish Sathyan & Vijai Joseph & Kurupath Radhakrishnan & Moinak Banerjee, 2014. "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," PLOS ONE, Public Library of Science, vol. 9(2), pages 1-10, February.
    • Handle: RePEc:plo:pone00:0089253
    DOI: 10.1371/journal.pone.0089253
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    Cited by:

    1. Mariana S Silva-Alves & Rodrigo Secolin & Benilton S Carvalho & Clarissa L Yasuda & Elizabeth Bilevicius & Marina K M Alvim & Renato O Santos & Claudia V Maurer-Morelli & Fernando Cendes & Iscia Lopes, 2017. "A Prediction Algorithm for Drug Response in Patients with Mesial Temporal Lobe Epilepsy Based on Clinical and Genetic Information," PLOS ONE, Public Library of Science, vol. 12(1), pages 1-15, January.

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