Genetic variations in HLA-B region and hypersensitivity reactions to abacavir

Hetherington, Seth; Hughes, Arlene R.; Mosteller, Michael; Shortino, Denise; Baker, Katherine L; Spreen, William; Lai, Eric; Davies, Kirstie; Handley, Abigail R.; Dow, David; Fling, Mary E.; Stocum, Michael; Bowman, Clive; Thurmond, Linda M.; Roses, Allen D.

doi:10.1016/s0140-6736(02)08158-8

Cited by 747 publications

(412 citation statements)

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“…Hetherington et al 10 reported a strong association between ABC HSR and the HLA-B*5701 allele, which has been extensively reproduced. 17,18 We retrospectively assessed the likelihood that this region would have been identified had the genome-wide screen been conducted with a limited number of cases and population controls.…”

Section: Power Simulationsmentioning

confidence: 86%

“…We estimate power for both a genome-wide and a sequential genome-wide screening approach. We illustrate their use with abacavir-associated hypersensitivity (ABC HSR) cases 10 and population controls and demonstrate that the utilization of DNA samples collected in clinical trials paired with pregenotyped controls can enable near real-time screening for ADR genetic risk factors. This capability could allow genetics to contribute to the understanding and management of ADRs during the remainder of a drug's clinical development and post-approval patient care.…”

Section: Introductionmentioning

confidence: 99%

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Genome-wide approaches to identify pharmacogenetic contributions to adverse drug reactions

Bacanu

Mosteller

et al. 2008

Pharmacogenomics J

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Adverse drug reactions (ADRs) have a major impact on patients, physicians, health care providers, regulatory agencies and pharmaceutical companies. Identifying the genetic contributions to ADR risk may lead to a better understanding of the underlying mechanisms, identification of patients at risk and a decrease in the number of events. Technological advances have made the routine monitoring and investigation of the genetic basis of ADRs during clinical trials possible. We demonstrate through simulation that genome-wide genotyping, coupled with the use of clinically matched or population controls, can yield sufficient statistical power to permit the identification of strong genetic predictors of ADR risk in a prospective manner with modest numbers of ADR cases. The results of a 500 000 single nucleotide polymorphism analysis of abacavir-associated hypersensitivity reaction suggest that the known HLA-B gene region could be identified with as few as 15 cases and 200 population controls in a sequential analysis.

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Section: Power Simulationsmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Genome-wide approaches to identify pharmacogenetic contributions to adverse drug reactions

Bacanu

Mosteller

et al. 2008

Pharmacogenomics J

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show abstract

“…The HLA-B*57:01 allele is associated with slower HIV-1 disease progression 15,16,17,18,19 and autoimmune reactions, including hypersensitivity, to the anti-viral drug abacavir 20,21,22 . In HIV-1-infected individuals, the expressed HLA-B*57:01 allomorph elicits robust CD8 + T-cell responses that are thought to control viremia.…”

Section: Introductionmentioning

confidence: 99%

MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape

Pymm

Illing

Ramarathinam

et al. 2017

Nat Struct Mol Biol

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“…This defect could be genetically determined, as suggested by several examples of individual pharmacogenetic variability associated with specific adverse drug reactions. [4][5][6] More recently, several lines of evidence have accumulated to show that the final steps of the adverse drug reaction depend on an immunological process, that seems directed against the parent form of the drug more often than against a metabolite. 7 Azukizawa et al 8 generated transgenic mice in which ovalbumin was specifically expressed in keratinocytes.…”

Section: Introductionmentioning

confidence: 99%