Serious carbamazepine-induced hypersensitivity reactions associated with the HSP70 gene cluster

Department of Pharmacology and Therapeutics, The University of Liverpool, Sherrington Building, Ashton Street, Liverpool, UK.
Pharmacogenetics and Genomics (Impact Factor: 3.45). 05/2006; 16(4):287-96. DOI: 10.1097/01.fpc.0000189800.88596.7a
Source: PubMed

ABSTRACT 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.
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.
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.
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.

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    • "In addition, no other HLA-B allele, except for HLA-B*1502, was significantly associated with CBZ-induced SJS/TEN. Similar to previous reports (Hung et al., 2006; Locharernkul et al., 2008), the presence of HLA-B*1502 in our CBZ-tolerant controls supports the view that although HLA-B*1502 is necessary for the initiation of SJS/TEN induced by CBZ, there may also be other determinants involved in the etiology of these SCADR such as genetic polymorphisms of the tumor necrosis factor alpha (TNF-a) promoter (Pirmohamed et al., 2001), heat shock protein 70 (Alfirevic et al., 2006), or T-cell receptor (TCR) (Gerber & Pichler, 2006). "
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    • "Overall, these data suggest that genetic susceptibility may account for the much higher incidence of CBZ-induced SJS in Chinese compared with whites. The role of ethnicity in these reactions is emphasized by recent data confirming that an association between CBZ-induced SJS and the HLA-B * 1502 allele is present in Asians (Lonjou et al., 2006), but does not appear to occur in whites (Alfirevic et al., 2006a; Lonjou et al., 2006). As research in this area advances rapidly, it is likely that genetic testing will become an important tool to identify patients at risk for idiosyncratic reactions. "
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