title: Influence of genetic and non-genetic factors on phenytoin-induced severe cutaneous adverse drug reactions.
abstract: OBJECTIVE
  The purpose of this study was to investigate the association of genetic factors including variants in HLA-B and CYP2C genes and non-genetic factors with phenotype-specific phenytoin (PHT)-induced severe cutaneous adverse reactions (SCARs) in Thai patients.
  
  
  METHODS
  Thirty-six PHT-induced SCAR cases (15 Stevens-Johnson syndrome (SJS) and 21 drug rash with eosinophilia and systemic symptoms (DRESS)/drug hypersensitivity syndrome (DHS)) and 100 PHT-tolerant controls were studied. Variants in HLA-B, CYP2C9, and CYP2C19 genes were genotyped. Fisher's exact test and multiple logistic regression analysis were performed to test the association of genetic and non-genetic factors with specific type of SCARs.
  
  
  RESULTS
  Multiple logistic regression models showed that genetic and non-genetic factors associated with PHT-induced SCARs were specified to its phenotype. HLA-B*13:01, HLA-B*56:02/04, CYP2C19*3, and omeprazole co-medication were strong risk factors of DRESS/DHS (adjusted OR = 13.29, p = 0.0001; adjusted OR = 56.23, p = 0.0007; adjusted OR = 6.75, p = 0.0414; and adjusted OR = 9.21, p = 0.0020, respectively). While CYP2C9*3 and having Chinese ancestry were significant risk factors of SJS (adjusted OR = 10.41, p = 0.0042 and adjusted OR = 5.40, p = 0.0097, respectively). Combined genetic and non-genetic risk factors optimized sensitivity and increased specificity for predicting PHT-induced SCARs.
  
  
  CONCLUSIONS
  This study showed that distinct genetic markers were associated with phenotype-specific PHT-induced SCARs. Non-genetic factor, omeprazole co-medication, was strongly associated with PHT-induced DRESS/DHS in addition to variants in HLA-B and CYP2C genes. Combined markers may be better predictors for PHT-induced SCARs.
authors.affiliation: Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, 254 Phyathai Rd.,Wangmai, Patumwan, Bangkok, 10330, Thailand.
authors.forename: Kittika
authors.initials: K
authors.lastname: Yampayon
authors.affiliation: Division of Pharmacogenetics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.|Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand.
authors.forename: Chonlaphat
authors.initials: C
authors.lastname: Sukasem
authors.affiliation: Division of Medical Genetics, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Chanin
authors.initials: C
authors.lastname: Limwongse
authors.affiliation: Neurology Unit, Department of Internal Medicine, Phramongkutklao Hospital, Bangkok, Thailand.
authors.forename: Yotin
authors.initials: Y
authors.lastname: Chinvarun
authors.affiliation: Division of Dermatology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Therdpong
authors.initials: T
authors.lastname: Tempark
authors.affiliation: Division of Allergy Immunology and Rheumatology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Ticha
authors.initials: T
authors.lastname: Rerkpattanapipat
authors.affiliation: Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, 254 Phyathai Rd.,Wangmai, Patumwan, Bangkok, 10330, Thailand. pornpimol.k@chula.ac.th.
authors.forename: Pornpimol
authors.initials: P
authors.lastname: Kijsanayotin
mesh_terms: D000328:Adult; D000368:Aged; D000897:Anti-Ulcer Agents / Q000627:therapeutic use; D000927:Anticonvulsants / Q000009:adverse effects*; D044466:Asian People / Q000235:genetics; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D003875:Drug Eruptions / Q000235:genetics*; D005260:Female; D005838:Genotype; D015235:HLA-B Antigens / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D009853:Omeprazole / Q000627:therapeutic use; D010672:Phenytoin / Q000009:adverse effects*; D054328:Proton Pump Inhibitors / Q000627:therapeutic use
chemical_list: D000897:Anti-Ulcer Agents; D000927:Anticonvulsants; D015235:HLA-B Antigens; D054328:Proton Pump Inhibitors; D010672:Phenytoin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole
keywords: CYP2C; DRESS/DHS; HLA-B; Omeprazole; Phenytoin; SJS/TEN