Abstracts

Rationale: Despite significant advances in epilepsy therapeutic management, up to 40% of children with newly-diagnosed epilepsy will have persistent seizures. Genetic variation is known to play an integral role in a patient’s response to medication, however the precise risk factors of treatment-resistance remain largely unknown. In this study, we aimed to investigate the role of 82 genes involved in the metabolism and disposition of a variety of drugs (pharmacogenes) in the etiology of treatment-resistant epilepsy.Methods: For the identification of patients with treatment-resistant epilepsy, we developed a phenotyping algorithm with positive predictive value of 89% according to newly refined definitions by the ILAE, using electronic medical records (EMR). Sequencing of the 82 genes was performed using a custom-sequencing panel developed by the Pharmacogenomics Research Network (PGRN). GATK, BWA, and ANNOVAR were used for sequencing data processing. For gene-level analysis, we used three complementary algorithms: the Sequence Kernel Association Test, the Variant Threshold test and the Combined Multivariate and Collapsing test. Single variant analysis was also conducted using a Logistic Score Test.Results: 124 subjects identified with the EMR-based algorithm were sequenced, 37 African Americans and 87 European Americans (16 and 38 treatment-resistant subjects, respectively). No significant results were found in Europeans but in African Americans, both gene-based and single variant analysis demonstrated that CES2 is significantly associated (p=1.13E-05 and p-value=7.48E-05, respectively) with treatment resistance. CES2 encodes the Carboxylesterase 2, the major intestinal enzyme involved drug clearance and suggested to play a role in the blood-brain barrier system.Conclusions: We have identified a variant in CES2 associated with treatment-resistant epilepsy in African Americans. The identification of pharmacogenes in the etiology of non-lesional, treatment-resistant epilepsy of unknown cause can have a significant impact on an individual patient’s therapy as it may alter treatment choice and dosing, and can create novel targets.