PMID- 33936169
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231111
IS  - 1664-8021 (Print)
IS  - 1664-8021 (Electronic)
IS  - 1664-8021 (Linking)
VI  - 12
DP  - 2021
TI  - Genomic Risk Factors Driving Immune-Mediated Delayed Drug Hypersensitivity 
      Reactions.
PG  - 641905
LID - 10.3389/fgene.2021.641905 [doi]
LID - 641905
AB  - 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.
CI  - Copyright (c) 2021 Li, Deshpande, Hertzman, Palubinsky, Gibson and Phillips.
FAU - Li, Yueran
AU  - Li Y
AD  - Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, 
      WA, Australia.
FAU - Deshpande, Pooja
AU  - Deshpande P
AD  - Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, 
      WA, Australia.
FAU - Hertzman, Rebecca J
AU  - Hertzman RJ
AD  - Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, 
      WA, Australia.
FAU - Palubinsky, Amy M
AU  - Palubinsky AM
AD  - Department of Medicine, Vanderbilt University Medical Centre, Nashville, TN, 
      United States.
FAU - Gibson, Andrew
AU  - Gibson A
AD  - Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, 
      WA, Australia.
FAU - Phillips, Elizabeth J
AU  - Phillips EJ
AD  - Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, 
      WA, Australia.
AD  - Department of Medicine, Vanderbilt University Medical Centre, Nashville, TN, 
      United States.
LA  - eng
GR  - R01 HG010863/HG/NHGRI NIH HHS/United States
PT  - Journal Article
PT  - Review
DEP - 20210416
PL  - Switzerland
TA  - Front Genet
JT  - Frontiers in genetics
JID - 101560621
PMC - PMC8085493
OTO - NOTNLM
OT  - T-cell receptor
OT  - delayed hypersensitivity
OT  - endoplasmic reticulum aminopeptidase
OT  - genetic risk
OT  - human leukocyte antigen
OT  - immune checkpoint
COIS- The reviewer AC declared a past co-authorship with the authors AG and EP to the 
      handling editor. EP was Drug Allergy Section Editor and receives royalties from 
      Uptodate and consulting fees from Biocryst, Janssen and Vertex. She is 
      co-director of IIID Pty Ltd that holds a patent for HLA-B*57:01 testing for 
      abacavir hypersensitivity, and she holds a patent for Detection of Human 
      Leukocyte Antigen-A*32:01 in connection with Diagnosing Drug Reaction with 
      Eosinophilia and Systemic Symptoms without any financial remuneration and not 
      directly related to the submitted work. Funders played no role in any aspect of 
      this Review. The remaining authors declare that the research was conducted in the 
      absence of any commercial or financial relationships that could be construed as a 
      potential conflict of interest.
EDAT- 2021/05/04 06:00
MHDA- 2021/05/04 06:01
PMCR- 2021/04/16
CRDT- 2021/05/03 06:12
PHST- 2020/12/15 00:00 [received]
PHST- 2021/03/08 00:00 [accepted]
PHST- 2021/05/03 06:12 [entrez]
PHST- 2021/05/04 06:00 [pubmed]
PHST- 2021/05/04 06:01 [medline]
PHST- 2021/04/16 00:00 [pmc-release]
AID - 10.3389/fgene.2021.641905 [doi]
PST - epublish
SO  - Front Genet. 2021 Apr 16;12:641905. doi: 10.3389/fgene.2021.641905. eCollection 
      2021.