Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions
Journal
Pharmacogenetics and Genomics
Journal Volume
16
Journal Issue
4
Pages
297
Date Issued
2006-04
Author(s)
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*502 haplotype, and confirmed the association of B*1502 with SJS/TEN [Pc = 1.6 × 10-41, 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 = 2.2 × 10-3, 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. ? 2006 Lippincott Williams & Wilkins.
Subjects
Carbamazepine; Cutaneous adverse drug reactions; Genetic polymorphisms; Hypersensitivity syndrome; Major histocompatibility complex; Pharmacogenomics; Stevens-Johnson syndrome; Toxic epidermal necrolysis
SDGs
Other Subjects
carbamazepine; cytochrome P450 1A2; cytochrome P450 2B6; cytochrome P450 2C9; cytochrome P450 3A4; drug metabolizing enzyme; epoxide hydrolase; heat shock protein; HLA A antigen; HLA B antigen; HLA E antigen; major histocompatibility antigen class 2; microsatellite DNA; motilin; tumor necrosis factor alpha; adolescent; adult; aged; article; child; confidence interval; controlled study; drug eruption; drug fever; drug hypersensitivity; eosinophilia; female; gene expression; gene frequency; gene locus; genetic association; genetic susceptibility; genotype; haplotype; HLA typing; human; kidney dysfunction; liver dysfunction; lymphocytosis; maculopapular rash; major clinical study; major histocompatibility complex; male; matrix assisted laser desorption ionization time of flight mass spectrometry; phenotype; priority journal; risk assessment; single nucleotide polymorphism; skin disease; skin manifestation; statistical analysis; Stevens Johnson syndrome; toxic epidermal necrolysis; Anticonvulsants; Carbamazepine; Case-Control Studies; Drug Hypersensitivity; Epidermal Necrolysis, Toxic; Exanthema; Genetic Predisposition to Disease; Haplotypes; HLA-B Antigens; Humans; Stevens-Johnson Syndrome
Type
journal article