Journal article
Genomic Risk Factors Driving Immune-Mediated Delayed Drug Hypersensitivity Reactions
Frontiers in Genetics, Vol.12, Art. 641905
2021
Abstract
Adverse drug reactions (ADRs) remain associated with significant mortality. Delayed hypersensitivity reactions (DHRs) that occur greater than 6 h following drug administration are T-cell mediated with many severe DHRs now associated with human leukocyte antigen (HLA) risk alleles, opening pathways for clinical prediction and prevention. However, incomplete negative predictive value (NPV), low positive predictive value (PPV), and a large number needed to test (NNT) to prevent one case have practically prevented large-scale and cost-effective screening implementation. Additional factors outside of HLA contributing to risk of severe T-cell-mediated DHRs include variation in drug metabolism, T-cell receptor (TCR) specificity, and, most recently, HLA-presented immunopeptidome-processing efficiencies via endoplasmic reticulum aminopeptidase (ERAP). Active research continues toward identification of other highly polymorphic factors likely to impose risk. These include those previously associated with T-cell-mediated HLA-associated infectious or auto-immune disease such as Killer cell immunoglobulin-like receptors (KIR), epistatically linked with HLA class I to regulate NK- and T-cell-mediated cytotoxic degranulation, and co-inhibitory signaling pathways for which therapeutic blockade in cancer immunotherapy is now associated with an increased incidence of DHRs. As such, the field now recognizes that susceptibility is not simply a static product of genetics but that individuals may experience dynamic risk, skewed toward immune activation through therapeutic interventions and epigenetic modifications driven by ecological exposures. This review provides an updated overview of current and proposed genetic factors thought to predispose risk for severe T-cell-mediated DHRs.
Details
- Title
- Genomic Risk Factors Driving Immune-Mediated Delayed Drug Hypersensitivity Reactions
- Authors/Creators
- Y. Li (Author/Creator)P. Deshpande (Author/Creator)R.J. Hertzman (Author/Creator)A.M. Palubinsky (Author/Creator)A. Gibson (Author/Creator)E.J. Phillips (Author/Creator)
- Publication Details
- Frontiers in Genetics, Vol.12, Art. 641905
- Publisher
- Frontiers
- Identifiers
- 991005541138907891
- Copyright
- © 2021 The Authors.
- Murdoch Affiliation
- Institute for Immunology and Infectious Diseases
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
- Domestic collaboration
- International collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.265 Dermatology - Skin Allergies
- 1.265.1140 Drug Hypersensitivity
- Web Of Science research areas
- Genetics & Heredity
- ESI research areas
- Molecular Biology & Genetics