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: 3.48). 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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    • "Like abacavir, HSP gene polymorphism was also found to be associated with severe CBZ hypersensitivity, but it was not clear whether the association was causal or related to linkage disequilibrium with another gene in MHC.[20] "
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    ABSTRACT: Drug hypersensitivity is an unpredictable, immunologically mediated adverse reaction, clustered in a genetically predisposed individual. The role of "hapten concept" in immune sensitization has recently been contested by the "pharmacological interaction" hypothesis. After completion of the "human genome project" and with the availability of high-resolution genotyping, genetic susceptibility to hypersensitivity for certain drugs has been proved beyond doubt though the trend is ethnicity and phenotype dependent. Application of this newly acquired knowledge may reduce or abolish the morbidity and mortality associated with cutaneous drug hypersensitivity.
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    • "Maculopapular exanthema has been associated with HLA-A*3101 and DRESS with the polymorphisms in the motilin gene in the Han Chinese population [36]. In Caucasians, DRESS has been associated with the ancestral haplotype HLA-B8.1 [61]. "
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    ABSTRACT: Drug-induced hypersensitivity reactions are of major concern and present a burden for national healthcare systems due to their often severe nature, high rate of hospital admissions and high mortality. They manifest with a wide range of symptoms and signs, and can be initiated by a wide range of structurally diverse chemical compounds. The pathophysiological mechanisms underlying hypersensitivity reactions are not well understood, but it is thought that they are immune mediated. MHC region on Chromosome 6 contains many genes with immune function. Classical MHC molecules are highly polymorphic cell surface glycoproteins whose function is to present peptide antigens to T cells. In addition to conferring protection from some diseases, HLA alleles are also associated with an increased risk of other diseases, including drug-induced hypersensitivity. Pharmacogenetic approach to predict the risk of drug-induced hypersensitivity has been established for several drugs. We will discuss the progress of hypersensitivity pharmacogenetics over the last few years and focus on current efforts of the international community to develop consortia which aim to standardize disease phenotypes and to identify affected individuals through international collaborations. In addition, we will discuss the clinical utility of HLA typing as predictive or diagnostic testing for drug-induced hypersensitivity.
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    • "There is growing evidence, however, that the role of regulatory genetic variants is likely to be highly context specific (11). For HSPA1A and HSPA1B, the question is of particular relevance given that these genes are heat shock inducible, and that polymorphism involving these genes or extended haplotypes over the MHC has been implicated in susceptibility to a number of infectious, inflammatory and autoimmune diseases (12–16) as well as malignancy (17–19) and drug hypersensitivity (20,21). "
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    ABSTRACT: The regulation of heat shock protein expression is of significant physiological and pathophysiological significance. Here we show that genetic diversity is an important determinant of heat shock protein 70 expression involving local, likely cis-acting, polymorphisms. We define DNA sequence variation for the highly homologous HSPA1A and HSPA1B genes in the major histocompatibility complex on chromosome 6p21 and establish quantitative and specific assays for determining transcript abundance. We show for lymphoblastoid cell lines established from individuals of African ancestry that following heat shock, expression of HSPA1B is associated with rs400547 (P 3.88 × 10−8) and linked single nucleotide polymorphisms (SNPs) located 62–93 kb telomeric to HSPA1B. This association was found to explain 31 and 29% of the variance in HSPA1B expression following heat shock or in resting cells, respectively. The associated SNPs show marked variation in minor allele frequency among populations, being more common in individuals of African ancestry, and are located in a region showing population-specific haplotypic block structure. The work illustrates how analysis of a heritable induced expression phenotype can be highly informative in defining functionally important genetic variation.
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