Serious carbamazepine-induced hypersensitivity reactions associated with the HSP70 gene cluster.
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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ABSTRACT: In the recent decades, more and more new genes associated with disease susceptibility and drug response were identified. Interestingly, a differential allele frequency spectrum in human populations has been observed in some of those genes. This phenomenon could explain the differences of disease prevalence and drug responses in human populations. This study aimed to identify ancestry informative marker (AIM) and understand their roles on disease prevalence and drug response. We focused on single nucleotide variation (SNV) on chromosome 6 for individuals from four continental populations (African-, American-, East-Asian-, and European-descent individuals) in the 1000 Genomes Project. By analyzing whole-genome sequencing data in the 1000 Genomes Project – Phase I, we identified 219,027 candidate SNVs with a significant difference of allele frequency in populations. We investigated the role of the differential allele frequency spectrum on complex diseases and traits and found an AIM rs7748513 associated with a C-reactive protein (CRP). CRP is a systemic inflammation marker for predicting future cardiovascular risk, and serum CRP values have been routinely measured to monitor human diseases. Compared with other populations, African population has a higher frequency of G allele, and this allele is positively correlated to higher concentration of CRP and higher risk of cardiovascular diseases. We also investigated the role of AIMs in adverse drug reaction and drug response. Our analysis found AIM rs1142345 in TPMT gene and rs2227956 in HSPA1L gene associated with adverse drug reaction of Azathioprine and Carbamazepine, respectively and AIM rs1799971 in OPRM1 gene associated with drug response to morphine. All of these three AIMs showed significantly different distributions of allele frequency in populations. Previous studies showed that people who carry A allele of AIM rs1799971 in OPRM1 gene tend to have a better pain relief after using morphine. The allele frequency of A allele in East-Asian populations is considerably lower than other continental populations. In addition, we also summarized 67 drugs associated with the genes where the identified AIMs are located. The major function category of the drugs was antineoplastic agents (23.9%). In summary, this study illustrates the importance of AIMs in medical genomics and pharmacogenomics studies and provides insights into diverse disease prevalence and drug response in human populations.THE 2013 IASC SATELLITE FOR THE ISI WSC AND THE 8TH IASC-ARS CONFERENCE; 08/2013
- Personalized Medicine 03/2008; 5(2):123-131. · 1.13 Impact Factor
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ABSTRACT: Adverse reactions to antiepileptic drugs (AEDs) may lead to treatment failure, morbidity, and mortality. Drug hypersensitivity reactions (DHRs) are potentially fatal. AED DHRs present with a variety of clinical manifestations. The pathogenesis of AED DHRs has not been fully elucidated. Bioactivation, detoxification, covalent adduct formation, presentation to the immune system, and consequent formation of antibody and T-cell immune effectors have been suggested. This article summarizes the epidemiology, pathogenic mechanisms, risk factors, clinical features, and management of allergic reactions to the aromatic AEDs carbamazepine, phenytoin, and lamotrigine.Immunology and Allergy Clinics of North America 08/2014; · 2.22 Impact Factor