Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant
- Annalise M. Martin†,
- David Nolan†,
- Silvana Gaudieri†,‡,
- Coral Ann Almeida†,
- Richard Nolan§,
- Ian James†,
- Filipa Carvalho†,
- Elizabeth Phillips¶,
- Frank T. Christiansen§,∥,
- Anthony W. Purcell††,
- James McCluskey††, and
- Simon Mallal†,§,‡‡
- †Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Perth 6000, Australia; ∥School of Surgery and Pathology and ‡School of Anatomy and Human Biology, University of Western Australia, Crawley 6009, Australia; §Department of Clinical Immunology and Biochemical Genetics, Royal Perth Hospital, Perth 6000, Australia; ¶Divisions of Clinical Pharmacology and Infectious Diseases, Sunnybrook and Women's College Health Sciences Centre, Toronto, ON, Canada M4N 3M5; and ††Department of Microbiology and Immunology, University of Melbourne, Parkville 3052, Australia
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Edited by Jacques F. A. P. Miller, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia (received for review October 31, 2003)
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.
Footnotes
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↵ ‡‡ To whom correspondence should be addressed at: Centre for Clinical Immunology and Biomedical Statistics, Second Floor, North Block, Royal Perth Hospital, Perth 6000, Australia. E-mail: s.mallal{at}murdoch.edu.au.
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This paper was submitted directly (Track II) to the PNAS office.
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Abbreviations: AH, ancestral haplotype; TNF, tumor necrosis factor; HLA, human leukocyte antigen; LD, linkage disequilibrium; SNP, single-nucleotide polymorphism; OR, odds ratio; PBMC, peripheral blood mononuclear cell.
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Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. AY559729–AY559746).
- Copyright © 2004, The National Academy of Sciences
