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J Dermatol Sci. 2014 Feb;73(2):101-9. doi: 10.1016/j.jdermsci.2013.10.003. Epub 2013 Oct 22.

Genotype-phenotype association between HLA and carbamazepine-induced hypersensitivity reactions: strength and clinical correlations.

Author information

1
Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospitals, Taipei, Linkou and Keelung, Taiwan.
2
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.
3
College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Neurology, Chang Gung Memorial Hospital, Taipei, Linkou, Taiwan.
4
Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
5
Department of Laboratory Medicine, Chang-Gung Memorial Hospital, Taoyuan County, Taiwan; Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan County, Taiwan.
6
Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan. Electronic address: sihung@ym.edu.tw.
7
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.

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.

CONCLUSION:

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.

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

PMID:
24268988
DOI:
10.1016/j.jdermsci.2013.10.003
[Indexed for MEDLINE]
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