Predisposition to abacavir hypersensitivity conferred byHLA-B*5701and a haplotypicHsp70-Homvariant
Top Cited Papers
- 15 March 2004
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 101 (12), 4180-4185
- https://doi.org/10.1073/pnas.0307067101
Abstract
Susceptibility to a clinically significant drug hypersensitivity syndrome associated with abacavir use seems to have a strong genetic component. We have previously shown that the presence of HLA-B*5701 strongly predicts abacavir hypersensitivity and have identified a potential susceptibility locus within a 300-kb region between the MEGT1 and C4A6 loci in the central MHC. We now report the results of fine recombinant genetic mapping in an expanded patient population of 248 consecutive, fully ascertained, abacavir-exposed individuals in the Western Australian HIV Cohort Study, in which 18 cases of definite abacavir hypersensitivity (7.3%) and 230 tolerant controls were identified. Haplotype mapping within patients with allelic markers of the 57.1 ancestral haplotype suggests a susceptibility locus within the 14-kb Hsp70 gene cluster. HLA-B*5701 was present in 94.4% of hypersensitive cases compared with 1.7% of controls (odds ratio, 960; P < 0.00001). A haplotypic nonsynonymous polymorphism of Hsp70-Hom (HspA1L, resulting from the substitution of residue M493T in the peptide-binding subunit) was found in combination with HLA-B*5701 in 94.4% of hypersensitive cases and 0.4% of controls (odds ratio, 3,893; P < 0.00001). Individuals with abacavir hypersensitivity demonstrated increased monocyte tumor necrosis factor expression in response to ex vivo abacavir stimulation, which was abrogated with CD8+ T cell depletion. These data indicate that the concurrence of HLA-B*5701 and Hsp70-Hom M493T alleles is necessary for the development of abacavir hypersensitivity, which is likely to be mediated by an HLA-B*5701-restricted immune response to abacavir.Keywords
This publication has 34 references indexed in Scilit:
- Polymorphisms in lymphotoxin alpha and CD14 genes influence TNFα production induced by Gram-positive and Gram-negative bacteriaGenes & Immunity, 2003
- Haplotype-specific linkage disequilibrium patterns define the genetic topography of the human MHCHuman Molecular Genetics, 2003
- Heat shock protein 70 genotypes HSPA1B and HSPA1L influence cytokine concentrations and interfere with outcome after major injury*Critical Care Medicine, 2003
- The Structure of Haplotype Blocks in the Human GenomeScience, 2002
- Heat Shock Protein-chaperoned Peptides but Not Free Peptides Introduced into the Cytosol Are Presented Efficiently by Major Histocompatibility Complex I MoleculesJournal of Biological Chemistry, 2001
- High-resolution solution structure of the 18 kDa substrate-binding domain of the mammalian chaperone protein Hsc70 1 1Edited by P. E. WrightJournal of Molecular Biology, 1999
- HLA-restricted, processing- and metabolism-independent pathway of drug recognition by human alpha beta T lymphocytes.Journal of Clinical Investigation, 1998
- Heat shock proteins transfer peptides during antigen processing and CTL primingImmunogenetics, 1994
- Structure and expression of the three MHC-linked HSP70 genesImmunogenetics, 1990
- THE ESTIMATION AND SIGNIFICANCE OF THE LOGARITHM OF A RATIO OF FREQUENCIESAnnals of Human Genetics, 1956