title: Association between HLA-DRB1*0405, -DQB1*0401 and -DQA1*0303 alleles and lamotrigine-induced cutaneous adverse drug reactions. A pilot case-control study from Japan.
abstract: BACKGROUND
  Human leukocyte antigen (HLA) genotypes in lamotrigine -induced (LTG-induced) cutaneous adverse drug reactions (cADRs) have been described in several reports but controversy remains even for a given ethnic group. We attempted to clarify a possible association between LTG-induced cADRs and HLA alleles in Japanese patients.
  
  
  METHODS
  Sixteen subjects, including eight patients with LTG-induced cADRs and eight LTG-tolerant controls were included in this study. All eight patients with LTG-induced cADRs gave positive results in a drug-induced lymphocyte stimulation test (DLST) with LTG. We performed HLA-typing for HLA-A, -B, -C, -DRB1, -DQA1, -DQB1, -DPA1 and -DPB1, using PCR with sequence-specific oligonucleotide probes and multiple analyte profiling (xMAP) technology (Luminex System; Luminex Corporation, Austin, TX). We examined differences between allele frequencies in our two groups of subjects and the allele frequencies in the general Japanese population.
  
  
  RESULTS
  The frequencies of HLA-DRB1*0405, and HLA-DQB1*0401 alleles were higher in our LTG-cADRs patients than the reference frequencies in the general Japanese population. We also detected HLA-DQA1*0303 frequently in our LTG-cADRs patients, but data for this allele in the Japanese population was not available. Our observation was presumably due to the linkage disequilibrium among the three alleles. The haplotype frequency of HLA-DRB1*0405, DQB1*0401 and DQA1*0303 in our LTG-cADRs subjects was also different from the corresponding haplotype frequency in the database for the Japanese population and the difference was statistically significant. One patient with the HLA-DRB1*0405, -DQB1*0401 and DQA1*0303 haplotype was safely re-treated with LTG after results of a DLST with LTG ceased to be positive about 4 months after discontinuation of LTG.
  
  
  CONCLUSIONS
  Our analysis included only 16 patients. Associations between LTG-induced cADRs and specific HLA loci will have to be confirmed in larger studies.
  
  
  CONCLUSIONS
  LTG-induced cADRs are associated with HLA-DRB1*0405, -DQB1*0401 and -DQA1*0303.
authors.affiliation: Department of Dermatology, Faculty of Medicine, Oita University, Hasama, Yufu 879-5593, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Ito
authors.affiliation: Department of Dermatology, Faculty of Medicine, Oita University, Hasama, Yufu 879-5593, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Shimada
authors.affiliation: Department of Dermatology, Faculty of Medicine, Oita University, Hasama, Yufu 879-5593, Japan.
authors.forename: Kazushi
authors.initials: K
authors.lastname: Ishikawa
authors.affiliation: Department of Dermatology, Faculty of Medicine, Oita University, Hasama, Yufu 879-5593, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Takeo
authors.affiliation: Department of Dermatology, Faculty of Medicine, Oita University, Hasama, Yufu 879-5593, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hatano
authors.affiliation: Department of Dermatology, Faculty of Medicine, Oita University, Hasama, Yufu 879-5593, Japan.
authors.forename: Kazumoto
authors.initials: K
authors.lastname: Katagiri
authors.affiliation: Department of Neuropsychiatry, Faculty of Medicine, Oita University, Hasama, Yufu 879-5593, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Kohno
authors.affiliation: Department of Neuropsychiatry, Faculty of Medicine, Oita University, Hasama, Yufu 879-5593, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Araki
authors.affiliation: Department of Neuropsychiatry, Faculty of Medicine, Oita University, Hasama, Yufu 879-5593, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Terao
authors.affiliation: HLA Foundation Laboratory, Kyoto, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kojima
authors.affiliation: Unit of Human Disease Genomics, Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Chikashi
authors.initials: C
authors.lastname: Terao
authors.affiliation: Department of Biostatistics, Faculty of Medicine, Oita University, Hasama, Yufu 879-5593, Japan.
authors.forename: Nobuoki
authors.initials: N
authors.lastname: Eshima
authors.affiliation: Department of Dermatology, Faculty of Medicine, Oita University, Hasama, Yufu 879-5593, Japan. Electronic address: fujiwara@oita-u.ac.jp.
authors.forename: Sakuhei
authors.initials: S
authors.lastname: Fujiwara
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D059848:HLA-DQ alpha-Chains / Q000235:genetics*; D059866:HLA-DQ beta-Chains / Q000235:genetics*; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006239:Haplotypes; D006650:Histocompatibility Testing; D006801:Humans; D007564:Japan; D000077213:Lamotrigine; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D014227:Triazines / Q000009:adverse effects*
chemical_list: D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen; D059811:HLA-DRB1 Chains; C493960:HLA-DRB1*04:05 antigen; D014227:Triazines; D000077213:Lamotrigine
keywords: Cutaneous adverse drug reactions; Drug lymphocyte stimulation test; Human leukocyte antigen; Lamotrigine; MHC class II antigen