title: A candidate gene study of antiepileptic drug tolerability and efficacy identifies an association of CYP2C9 variants with phenytoin toxicity.
abstract: OBJECTIVE
  It is widely acknowledged that individual response to antiepileptic drugs (AEDs) is influenced by genetic factors. However, most of the underlying genes and genetic variants remain unidentified to date. The purpose of this study is to examine the role of common variants in a number of candidate genes in the response to commonly prescribed AEDs.
  
  
  METHODS
  We recruited 495 patients with epilepsy. Patients were classified according to their response to several AEDs. We genotyped 104 polymorphisms in 17 candidate genes for AED response. We looked for statistically significant associations between these polymorphisms and well-defined AED response phenotypes.
  
  
  RESULTS
  We identified significant associations of CYP2C9 variant alleles with presence of phenytoin (PHT) adverse drug reactions (ADRs) and of GSTM1 copy number variation with the presence of carbamazepine ADRs. The latter association could not be confirmed in a replication study.
  
  
  CONCLUSIONS
  Our study is the first comprehensive candidate gene association study in epilepsy pharmacogenetics. Our results confirm the role of CYP2C9 variants in PHT toxicity. No other definite associations were identified. Large-scale efforts are needed to unravel the genetic determinants of AED response.
authors.affiliation: Laboratory of Experimental Neurology Department of Neurology, Hôpital Erasme, Université Libre de Bruxelles, Brussels DNAvision, Gosselies, Belgium. Chantal.Depondt@erasme.ulb.ac.be
authors.forename: C
authors.initials: C
authors.lastname: Depondt
authors.forename: P
authors.initials: P
authors.lastname: Godard
authors.forename: R S
authors.initials: RS
authors.lastname: Espel
authors.forename: A L
authors.initials: AL
authors.lastname: Da Cruz
authors.forename: P
authors.initials: P
authors.lastname: Lienard
authors.forename: M
authors.initials: M
authors.lastname: Pandolfo
mesh_terms: D000927:Anticonvulsants / Q000009:adverse effects*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D004827:Epilepsy / Q000188:drug therapy; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010672:Phenytoin / Q000009:adverse effects*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide
chemical_list: D000927:Anticonvulsants; D010672:Phenytoin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases