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, Simon Mallal

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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.

Original languageEnglish
Pages (from-to)4180-4185
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number12
DOIs
Publication statusPublished - 23 Mar 2004
Externally publishedYes

Keywords

  • Ancestral haplotype
  • Human leukocyte antigen
  • Microsatellite
  • Single-nucleotide polymorphism

Cite this

Martin, Annalise M. ; Nolan, David ; Gaudieri, Silvana ; Almeida, Coral Ann ; Nolan, Richard ; James, Ian ; Carvalho, Filipa ; Phillips, Elizabeth ; Christiansen, Frank T. ; Purcell, Anthony W. ; McCluskey, James ; Mallal, Simon. / Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant. In: Proceedings of the National Academy of Sciences of the United States of America. 2004 ; Vol. 101, No. 12. pp. 4180-4185.
@article{4a05e810faf045ef8987b85a43686fd7,
title = "Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant",
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 = "Ancestral haplotype, Human leukocyte antigen, Microsatellite, Single-nucleotide polymorphism",
author = "Martin, {Annalise M.} and David Nolan and Silvana Gaudieri and Almeida, {Coral Ann} and Richard Nolan and Ian James and Filipa Carvalho and Elizabeth Phillips and Christiansen, {Frank T.} and Purcell, {Anthony W.} and James McCluskey and Simon Mallal",
year = "2004",
month = "3",
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doi = "10.1073/pnas.0307067101",
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Martin, AM, Nolan, D, Gaudieri, S, Almeida, CA, Nolan, R, James, I, Carvalho, F, Phillips, E, Christiansen, FT, Purcell, AW, McCluskey, J & Mallal, S 2004, 'Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant', Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 12, pp. 4180-4185. https://doi.org/10.1073/pnas.0307067101

Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant. / Martin, Annalise M.; Nolan, David; Gaudieri, Silvana; Almeida, Coral Ann; Nolan, Richard; James, Ian; Carvalho, Filipa; Phillips, Elizabeth; Christiansen, Frank T.; Purcell, Anthony W.; McCluskey, James; Mallal, Simon.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 12, 23.03.2004, p. 4180-4185.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant

AU - Martin, Annalise M.

AU - Nolan, David

AU - Gaudieri, Silvana

AU - Almeida, Coral Ann

AU - Nolan, Richard

AU - James, Ian

AU - Carvalho, Filipa

AU - Phillips, Elizabeth

AU - Christiansen, Frank T.

AU - Purcell, Anthony W.

AU - McCluskey, James

AU - Mallal, Simon

PY - 2004/3/23

Y1 - 2004/3/23

N2 - 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.

AB - 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.

KW - Ancestral haplotype

KW - Human leukocyte antigen

KW - Microsatellite

KW - Single-nucleotide polymorphism

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M3 - Article

VL - 101

SP - 4180

EP - 4185

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

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