title: Association of ABCB1, CYP3A4, EPHX1, FAS, SCN1A, MICA, and BAG6 polymorphisms with the risk of carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis in Chinese Han patients with epilepsy.
abstract: OBJECTIVE
  This study explored the association between the risk of carbamazepine (CBZ)-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and CBZ dose, dose-adjusted concentration, and ABCB1, CYP3A4, EPHX1, FAS, SCN1A, MICA, and BAG6 polymorphisms in patients of Han ethnicity with epilepsy who were living in northeastern China.
  
  
  METHODS
  We determined the genotypes of patients with CBZ-SJS/TEN and CBZ-tolerant patients, who were used as controls, for ABCB1, CYP3A4, EPHX1, FAS, SCN1A, MICA, and BAG6 polymorphisms by polymerase chain reaction (PCR) amplification and direct sequencing. We measured the steady-state serum CBZ concentrations using fluorescence polarization immunoassay for the control patients.
  
  
  RESULTS
  We observed statistically significant differences in EPHX1 c.337T>C polymorphisms between patients with CBZ-SJS/TEN and CBZ-tolerant controls in terms of allelic and genotypic frequencies (p = 0.011 and p = 0.007, respectively). The C allele and the C-G diplotype of EPHX1 may play important roles in increasing the risk of CBZ-SJS/TEN development (odds ratio [OR] 0.478, 95% confidence interval [CI] = 0.267-0.855, p = 0.011; OR = 0.213, 95% CI = 0.049-0.930, p = 0.025, respectively). We did not observe any significant associations between ABCB1, CYP3A4, EPHX1, FAS, SCN1A, MICA or BAG6 genes and CBZ dose or dose-adjusted concentration in CBZ-tolerant patients.
  
  
  CONCLUSIONS
  We found a significant association between EPHX1 c.337T>C polymorphisms and the development of CBZ-SJS/TEN in patients of Han ethnicity living in northeastern China. EPHX1 c.337T>C polymorphisms may contribute to the risk of severe CBZ-SJS/TEN by increasing the concentration of a CBZ metabolite, CBZ-10,11-epoxide, in patients with epilepsy.
authors.affiliation: Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, China; School of Pharmacy, China Medical University, Shenyang, China.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: He
authors.forename: Ling-Yan
authors.initials: LY
authors.lastname: Jian
authors.forename: Xiao-Lin
authors.initials: XL
authors.lastname: He
authors.forename: Man
authors.initials: M
authors.lastname: Tang
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Xu
authors.forename: Xiao-Jie
authors.initials: XJ
authors.lastname: Sun
authors.forename: Li-Mei
authors.initials: LM
authors.lastname: Zhao
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000483:Alleles; D000927:Anticonvulsants / Q000009:adverse effects; D044466:Asian People / Q000235:genetics*; D002220:Carbamazepine / Q000009:adverse effects*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics*; D004851:Epoxide Hydrolases / Q000235:genetics*; D005260:Female; D005838:Genotype; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones / Q000235:genetics; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D013262:Stevens-Johnson Syndrome / Q000175:diagnosis / Q000235:genetics*; D055815:Young Adult; D019014:fas Receptor / Q000235:genetics
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; C092009:BAG6 protein, human; C491901:FAS protein, human; D015395:Histocompatibility Antigens Class I; C099187:MHC class I-related chain A; D018832:Molecular Chaperones; D062550:NAV1.1 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human; D019014:fas Receptor; D002220:Carbamazepine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D004851:Epoxide Hydrolases; C522330:EPHX1 protein, human
keywords: EPHX1; SJS/TEN; carbamazepine