Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions.

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Hung SI, Chung WH, Jee SH, Chen WC, Chang YT, Lee WR, Hu SL, Wu MT, Chen GS, Wong TW, Hsiao PF, Chen WH, Shih HY, Fang WH, Wei CY, Lou YH, Huang YL, Lin JJ, Chen YT

Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions.

Pharmacogenet Genomics. 2006 Apr;16(4):297-306.

PubMed ID

16538176 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Pharmaco-genomics

Drug	Interacting Gene/Enzyme	Allele name	Genotypes	Defining change(s)	Type(s)	Description	Details
Carbamazepine	HLA class I histocompatibility antigen, B-15 alpha chain Gene symbol: HLA-B UniProt: P30464	---	(T;T) / (G;T)	T allele (rs3130690)	ADR Directly Studied	Patients with this genotype have increased risk of cutaneous hypersensitivity reactions with carbamazepine.	Details
Carbamazepine	HLA class I histocompatibility antigen, A-31 alpha chain Gene symbol: HLA-A UniProt: P16189	---	(G;G) / (C;G)	G allele (rs1264511)	ADR Directly Studied	Patients with this genotype have increased risk of cutaneous hypersensitivity reactions with carbamazepine.	Details
Carbamazepine	Promotilin Gene symbol: MLN UniProt: P12872	---	(A;A) / (A;C)	A allele (rs2894342)	ADR Directly Studied	Patients with this genotype have increased risk of cutaneous hypersensitivity reactions with carbamazepine.	Details