title: Associations between HLA class I and cytochrome P450 2C9 genetic polymorphisms and phenytoin-related severe cutaneous adverse reactions in a Thai population.
abstract: BACKGROUND
  Phenytoin is one of the most common causative drugs of several types of severe cutaneous adverse reactions (SCAR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS). Genetic polymorphisms of the human leukocyte antigens (HLA) and cytochromes P450 (CYP) have been proposed as key elements for the susceptibility to phenytoin-related SCAR in certain ethnicities. This study investigated the associations between the genetic polymorphisms of HLA class I and CYP2C9 and phenytoin-related SCAR in a Thai population.
  
  
  METHODS
  Sixty phenytoin-related SCAR (i.e. 39 SJS/TEN and 21 DRESS) and 92 phenytoin-tolerant patients were enrolled in the study. The genotypes of HLA class I and CYP2C9 were determined.
  
  
  RESULTS
  Six HLA alleles including HLA-A*33:03, HLA-B*38:02, HLA-B*51:01, HLA-B*56:02, HLA-B*58:01, and HLA-C*14:02 were significantly associated with phenytoin-related SJS/TEN, whereas only the HLA-B*51:01 was significantly associated with phenytoin-related DRESS. The odds ratios of phenytoin-related SJS/TEN in the patients who carried one of these alleles ranged from 4- to 10-fold. The frequencies of patients who carried the HLA-B*15:02 in the SJS/TEN (12.82%) or the DRESS (9.52%) groups were not significantly different from that of the controls (14.13%). The higher risk of phenytoin-related SJS/TEN was observed in the patients with CYP2C9*3 (odds ratio=4.30, 95% confidence interval=1.41-13.09, P<0.05).
  
  
  CONCLUSIONS
  Neither SJS/TEN nor DRESS caused by phenytoin was significantly associated with the HLA-B*15:02. The CYP2C9*3 variant was significantly associated with phenytoin-related SJS/TEN, but not DRESS. Certain alleles of HLA, particularly HLA-B*56:02, were significantly associated with phenytoin-related SCAR in the study population.
authors.affiliation: aDepartment of Pharmacology bPharmacy Unit cDepartment of Medicine, Faculty of Medicine dIntegrated Epilepsy Research Group eFaculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen fDepartment of Pathology, Division of Pharmacogenomics and Personalized Medicine gLaboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC) hDepartment of Medicine, Division of Allergy Immunology and Rheumatology, Faculty of Medicine Ramathibodi Hospital, Mahidol University iPharmacy Unit, Police General Hospital, Bangkok jPharmacy Unit, Udon Thani Hospital, Udon Thani kDepartment of Medicine, Faculty of Medicine, Thammasat University, Pathumthani lMedical Genetics Center, Medical Life Sciences Institute, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand.
authors.forename: Wichittra
authors.initials: W
authors.lastname: Tassaneeyakul
authors.forename: Napat
authors.initials: N
authors.lastname: Prabmeechai
authors.forename: Chonlaphat
authors.initials: C
authors.lastname: Sukasem
authors.forename: Thachanan
authors.initials: T
authors.lastname: Kongpan
authors.forename: Parinya
authors.initials: P
authors.lastname: Konyoung
authors.forename: Pansu
authors.initials: P
authors.lastname: Chumworathayi
authors.forename: Somsak
authors.initials: S
authors.lastname: Tiamkao
authors.forename: Usanee
authors.initials: U
authors.lastname: Khunarkornsiri
authors.forename: Kongkiat
authors.initials: K
authors.lastname: Kulkantrakorn
authors.forename: Niwat
authors.initials: N
authors.lastname: Saksit
authors.forename: Nontaya
authors.initials: N
authors.lastname: Nakkam
authors.forename: Patompong
authors.initials: P
authors.lastname: Satapornpong
authors.forename: Suda
authors.initials: S
authors.lastname: Vannaprasaht
authors.forename: Alisara
authors.initials: A
authors.lastname: Sangviroon
authors.forename: Surakameth
authors.initials: S
authors.lastname: Mahasirimongkol
authors.forename: Nuanjun
authors.initials: N
authors.lastname: Wichukchinda
authors.forename: Ticha
authors.initials: T
authors.lastname: Rerkpattanapipat
authors.forename: Wongwiwat
authors.initials: W
authors.lastname: Tassaneeyakul
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D015235:HLA-B Antigens / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010672:Phenytoin / Q000009:adverse effects*; D020641:Polymorphism, Single Nucleotide; D013262:Stevens-Johnson Syndrome / Q000235:genetics*; D013785:Thailand; D055815:Young Adult
chemical_list: D015235:HLA-B Antigens; D010672:Phenytoin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9