Premium
Drug‐resistant epilepsy classified by a phenotyping algorithm associates with NTRK2
Author(s) -
Almoguera Berta,
McGinnis Emily,
Abrams Debra,
Vazquez Lyam,
Cederquist Anna,
Sleiman Patrick M.,
Dlugos Dennis,
Hakonarson Hakon
Publication year - 2019
Publication title -
acta neurologica scandinavica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.967
H-Index - 95
eISSN - 1600-0404
pISSN - 0001-6314
DOI - 10.1111/ane.13115
Subject(s) - pharmacogenomics , epilepsy , drug resistant epilepsy , precision medicine , drug , medicine , pharmacology , biology , neuroscience , genetics
Objective Up to 40% of patients with epilepsy become drug resistant (DRE). Genetic factors are likely to play a role. While efforts have focused on the transporter and target hypotheses, neither of them fully explains the pan‐pharmacoresistance seen in DRE. Materials and methods In this study, we developed and used a phenotyping algorithm for the identification of DRE, responders, and epilepsy‐free controls that were sequenced using a gene panel developed by the Pharmacogenomics Research Network (PGRN), which includes 82 genes involved in drug response. We tested the transporter hypothesis of DRE, the association between drug resistance and variants in the ATP‐binding cassette family of genes previously associated with DRE, and also investigated potential new genetic factors. Results In the analysis of DRE vs controls, NTRK2 was significantly associated with DRE (rs76950094; P = 1.19 × 10 −7 and gene‐based P ‐value = 1.67 × 10 −4 ). NTRK2 encodes TrkB, which is involved in the development and maturation of the central nervous system, and increased activation of TrkB signaling is suggested to promote epilepsy. Conclusion Although the role of NTRK2 in DRE needs to be elucidated, these results support alternative mechanisms underlying DRE, complementary to the existing hypotheses, that should be evaluated.