Serious carbamazepine-induced hypersensitivity reactions associated with the HSP70 gene cluster.
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Alfirevic A, Mills T, Harrington P, Pinel T, Sherwood J, Jawaid A, Smith JC, March RE, Barratt BJ, Chadwick DW, Kevin Park B, Pirmohamed M
Serious carbamazepine-induced hypersensitivity reactions associated with the HSP70 gene cluster.
Pharmacogenet Genomics. 2006 Apr;16(4):287-96.
- PubMed ID
- 16538175 [ View in PubMed]
- Abstract
OBJECTIVES: The use of carbamazepine (CBZ), the most commonly prescribed antiepileptic drug, is hampered by the occurrence of severe, potentially lethal hypersensitivity reactions. The pathogenesis of hypersensitivity is not yet known, but immune mechanisms are involved. Predisposition to CBZ hypersensitivity is likely to be genetically determined, and genes within the major histocompatibility complex (MHC) have been implicated. The heat shock protein (HSP70) gene cluster is located in the MHC class III region. METHODS: Using a case-control study design, we compared 61 patients with CBZ hypersensitivity (22 with a severe reaction) to 44 patients on CBZ with no signs of hypersensitivity and 172 healthy controls. The genotyping strategy involved identification of common and rare single nucleotide polymorphisms (SNPs) within the HSP70 gene cluster by sequencing, estimation of linkage disequilibrium (LD) and haplotype structure, and thereafter, analysis of SNP/haplotype frequencies in the cases and controls. Population substructure was evaluated by genotyping of 34 microsatellites. RESULTS: Twenty-five SNPs were detected across the three HSP70 genes. Analyses revealed that alleles G, T and C at the SNPs HSPA1A +1911 C/G, HSPA1A +438 C/T and HSPA1L +2437 T/C, respectively, were associated with protection from serious hypersensitivity reactions to CBZ, with the associated alleles falling on a common haplotype. We were unable to detect the presence of population stratification in our patients and controls. CONCLUSIONS: Our data show that HSP70 gene variants are associated with serious CBZ hypersensitivity reactions, but whether this is causal or reflects LD with another gene within the MHC requires further study.
DrugBank Data that Cites this Article
- Pharmaco-genomics
Drug Interacting Gene/Enzyme Allele name Genotypes Defining change(s) Type(s) Description Details Carbamazepine Heat shock 70 kDa protein 1-like
Gene symbol: HSPA1L
UniProt: P34931--- (T;T) / (C;T) - T allele (rs2227956)
ADR Directly Studied Patients with this genotype have increased risk of cutaneous hypersensitivity reactions with carbamazepine. Details Carbamazepine Heat shock 70 kDa protein 1A/1B
Gene symbol: HSPA1A
UniProt: P08107--- (C;G) / (C;C) / (C;T) ADR Directly Studied Patients with this genotype have increased risk of cutaneous hypersensitivity reactions with carbamazepine. Details