Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions.

Full Abstract

The anticonvulsant carbamazepine (CBZ) frequently causes cutaneous adverse drug reactions (cADRs), including maculopapular eruption (MPE), hypersensitivity syndrome (HSS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We reported that SJS/TEN caused by CBZ is strongly associated with the HLA-B*1502 gene in Han Chinese. Here, we extended our genetic study to different types of CBZ-cADRs (91 patients, including 60 patients with SJS/TEN, 13 patients with hypersensitivity syndrome and 18 with maculopapular exanthema versus 144 tolerant controls). We used MALDI-TOF mass spectrometry to screen the genetic association of 278 single nucleotide polymorphisms (SNPs), which cover the major histocompatibility complex (MHC) region, tumor necrosis factor-alpha, heat shock protein and CBZ-metabolic enzymes, including CYP3A4, 2B6, 2C8, 2C9, 1A2 and epoxide hydrolase 1. In addition, we genotyped 20 microsatellites in the MHC region and performed HLA-typing to construct the recombinant map. We narrowed the susceptibility locus for CBZ-SJS/TEN to within 86 kb flanking the HLA-B gene on the extended B*1502 haplotype, and confirmed the association of B*1502 with SJS/TEN [Pc=1.6x10, odds ratio (OR)=1357; 95% confidence interval (CI)=193.4-8838.3]. By contrast to CBZ-SJS/TEN, HLA-B*1502 association was not observed in the MPE or HSS groups: MPE was associated with SNPs in the HLA-E region and a nearby allele, HLA-A*3101 (Pc=2.2x10, OR=17.5; 95% CI=4.6-66.5), and HSS with SNPs in the motilin gene (Pc=0.0064, OR=7.11; 95% CI=3.1-16.5) located terminal to the MHC class II genes. No SNPs in genes involved in CBZ metabolism were associated with CBZ-induced cADRs. Our data suggest that HLA-B*1502 could contribute to the pathogenesis of CBZ-SJS/TEN, and that genetic susceptibility to CBZ-induced cADRs is phenotype-specific.

Author information

Author/s: Hung, Shuen-Iu (SI); Chung, Wen-Hung (WH); Jee, Shiou-Hwa (SH); Chen, Wen-Chieh (WC); Chang, Yun-Ting (YT); Lee, Woan-Ruoh (WR); Hu, Shu-Ling (SL); Wu, Meng-Tse (MT); Chen, Gwo-Shing (GS); Wong, Tak-Wah (TW); Hsiao, Pa-Fan (PF); Chen, Wei-Hsuan (WH); Shih, Han-Yu (HY); Fang, Wu-Hsiang (WH); Wei, Chun-Yu (CY); Lou, Yi-Hui (YH); Huang, Yau-Li (YL); Lin, Juei-Jueng (JJ); Chen, Yuan-Tsong (YT);

Affiliation: Institute of Biomedical Sciences, Academia Sinica, 128 Academia Road Section 2, Nankang, Taipei, Taiwan.

Journal and publication information

Publication Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't

Journal: Pharmacogenetics and genomics (Pharmacogenet Genomics), published in United States. (Language: eng)

Reference: 2006-Apr; vol 16 (issue 4) : pp 297-306

Dates: Created 2006/03/15; Completed 2006/07/27; Revised 2006/11/15;

PMID: 16538176, status: MEDLINE (last retrieval date: 2/18/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

External Links for this article
(including full text providers, if available):

Click Electronic Full-text Provider Links to see options for finding the electronic full text links to this article. Note there may be a subscription or fee required for access to the full text. See our FAQ for information on finding FREE full text articles.

This article may also be located in paper journal collections available in many libraries. Use the Journal and Publication Information above to find the full article.