title: Genotype-phenotype association between HLA and carbamazepine-induced hypersensitivity reactions: strength and clinical correlations.
abstract: BACKGROUND
  Increasing studies reported genetic susceptibility to drug hypersensitivity reactions, as exemplified by the HLA-A*31:01 and HLA-B*15:02 association with carbamazepine (CBZ)-induced hypersensitivity reactions, such as maculopapular exanthema (MPE), drug rash with eosinophilia and systemic symptoms (DRESS), and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN).
  
  
  OBJECTIVE
  To carry out a comprehensive analysis on the clinical spectrum and HLA genotype-phenotype correlations in CBZ-induced hypersensitivity reactions.
  
  
  METHODS
  We analyzed the clinical information of 194 patients with CBZ hypersensitivity (51 MPE, 23 DRESS, 112 SJS/TEN, and 8 cases with other phenotypes), and 152 CBZ-tolerant controls. All are Han Chinese. We examined the HLA-A/HLA-B genotypes, gene dosage, and drug dosage effects.
  
  
  RESULTS
  CBZ-SJS/TEN showed the strongest association with the HLA-B*15:02 allele (Pc=5.8×10(-43); odds ratio (OR) (95% CI)=97.6(42.0-226.8)), in which HLA-B*15:02 was identified in all patients (25/25) with SJS/TEN with >5% body surface area (BSA) skin detachment, but lost its 100% association (85.1%, 74/87) in SJS with <5% BSA detachment. In contrast, HLA-B*40:01 showed negative association with CBZ-induced SJS/TEN ((Pc=8.3×10(-5); OR (95% CI)=0.22(0.1-0.4)). By comparison, CBZ-induced MPE/DRESS had no association with HLA-B*15:02, but linked to HLA-A*31:01 (Pc=2.7×10(-3); OR (95% CI)=6.86(2.4-19.9), and HLA-B*51:01 (Pc=0.01; OR (95% CI)=4.56(2.0-10.5)). No gene dosage or CBZ dosage effects was observed.
  
  
  CONCLUSIONS
  This study reported the different strength of HLA association with CBZ hypersensitivity in Han Chinese. With the increasing application of pharmacogenetic markers, the HLA genotype-phenotype correlations and the results of the test need to be carefully interpreted for CBZ-induced hypersensitivity reactions.
authors.affiliation: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospitals, Taipei, Linkou and Keelung, Taiwan.
authors.forename: Yi-Hsin
authors.initials: YH
authors.lastname: Hsiao
authors.affiliation: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospitals, Taipei, Linkou and Keelung, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Rosaline Chung-Yee
authors.initials: RC
authors.lastname: Hui
authors.affiliation: College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Neurology, Chang Gung Memorial Hospital, Taipei, Linkou, Taiwan.
authors.forename: Tony
authors.initials: T
authors.lastname: Wu
authors.affiliation: Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Wan-Chun
authors.initials: WC
authors.lastname: Chang
authors.affiliation: College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Neurology, Chang Gung Memorial Hospital, Taipei, Linkou, Taiwan.
authors.forename: Mo-Song
authors.initials: MS
authors.lastname: Hsih
authors.affiliation: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospitals, Taipei, Linkou and Keelung, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chih-Hsun
authors.initials: CH
authors.lastname: Yang
authors.affiliation: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospitals, Taipei, Linkou and Keelung, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Hsin-Chun
authors.initials: HC
authors.lastname: Ho
authors.affiliation: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospitals, Taipei, Linkou and Keelung, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Ya-Ging
authors.initials: YG
authors.lastname: Chang
authors.affiliation: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospitals, Taipei, Linkou and Keelung, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Ming-Jing
authors.initials: MJ
authors.lastname: Chen
authors.affiliation: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospitals, Taipei, Linkou and Keelung, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Jing-Yi
authors.initials: JY
authors.lastname: Lin
authors.affiliation: Department of Laboratory Medicine, Chang-Gung Memorial Hospital, Taoyuan County, Taiwan; Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan County, Taiwan.
authors.forename: Ding-Ping
authors.initials: DP
authors.lastname: Chen
authors.affiliation: Department of Laboratory Medicine, Chang-Gung Memorial Hospital, Taoyuan County, Taiwan; Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan County, Taiwan.
authors.forename: Pi-Yueh
authors.initials: PY
authors.lastname: Chang
authors.affiliation: Department of Laboratory Medicine, Chang-Gung Memorial Hospital, Taoyuan County, Taiwan; Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan County, Taiwan.
authors.forename: Tsu-Lan
authors.initials: TL
authors.lastname: Wu
authors.affiliation: Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan. Electronic address: sihung@ym.edu.tw.
authors.forename: Shuen-Iu
authors.initials: SI
authors.lastname: Hung
authors.affiliation: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospitals, Taipei, Linkou and Keelung, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan. Electronic address: chung1@cgmh.org.tw.
authors.forename: Wen-Hung
authors.initials: WH
authors.lastname: Chung
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000009:adverse effects*; D002220:Carbamazepine / Q000009:adverse effects*; D002648:Child; D002681:China; D015331:Cohort Studies; D004342:Drug Hypersensitivity / Q000235:genetics*; D004802:Eosinophilia / Q000235:genetics; D005076:Exanthema / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D005787:Gene Frequency; D056726:Genetic Association Studies; D006680:HLA Antigens / Q000235:genetics*; D015234:HLA-A Antigens / Q000235:genetics; D059910:HLA-B15 Antigen / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010597:Pharmacogenetics; D013262:Stevens-Johnson Syndrome / Q000235:genetics; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D006680:HLA Antigens; D015234:HLA-A Antigens; C506273:HLA-A*31:01 antigen; C483536:HLA-B*15:02 antigen; D059910:HLA-B15 Antigen; D002220:Carbamazepine
keywords: BSA; CBZ; CI; Carbamazepine; DIHS; DRESS; Drug rash with eosinophilia and systemic symptoms; EM; FDE; HLA; Human leukocyte antigens; MPE; Maculopapular exanthema; OR; SJS; Stevens–Johnson syndrome; TEN; body surface area; carbamazepine; confidence interval; drug induced hypersensitivity syndrome; drug rash with eosinophilia and systemic symptoms; erythema multiforme; fixed drug eruption; human leukocyte antigen; maculopapular exanthema; odds ratio; toxic epidermal necrolysis