Coupling Genotyping and Computational Modeling in Prediction of Anti-epileptic Drugs that cause Stevens Johnson Syndrome and Toxic Epidermal Necrolysis for Carrier of HLA-B*15:02

Teh, Lay Kek; Selvaraj, Manikandan; Bannur, Zakaria; Ismail, Mohd Ikhwan Mohd; Rafia, Hanip; Law, Wan Chung; Sapuan, Sapiah; Puvanarajah, Santhi Datuk; Ali, Pakeer Shaik Syed; Salleh, Mohd Zaki

doi:10.18433/j38g7x

Cited by 10 publications

(9 citation statements)

References 33 publications

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“…These data suggest that drugs bind selectively to the HLA protein to activate the T cells that participate in the adverse event. Molecular docking studies support this concept; however, modeling data have to be interpreted with caution as the nature of the drug‐HLA protein interaction and the requirement for a specific peptide in the binding groove has not been determined. The most robust genetic associations are between HLA class I alleles and abacavir hypersensitivity, flucloxacillin liver injury (both HLA‐B*57:01), carbamazepine‐induced Stevens Johnson syndrome (HLA‐B*15:02), and allopurinol hypersensitivity (HLA‐B*58:01), and in each case, mechanistic studies have shown that CD8 + T cells are activated when the drug interacts with the relevant HLA protein .…”

Section: Introductionmentioning

confidence: 99%

Dapsone‐ and nitroso dapsone‐specific activation of T cells from hypersensitive patients expressing the risk allele HLA‐B*13:01

Zhao

Alhilali

Alzahrani

et al. 2019

Allergy

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Background Research into drug hypersensitivity associated with the expression of specific HLA alleles has focussed on the interaction between parent drug and the HLA with no attention given to reactive metabolites. For this reason, we have studied HLA‐B*13:01‐linked dapsone hypersensitivity to (a) explore whether the parent drug and/or nitroso metabolite activate T cells and (b) determine whether HLA‐B*13:01 is involved in the response. Methods Peripheral blood mononuclear cells (PBMC) from six patients were cultured with dapsone and nitroso dapsone, and proliferative responses and IFN‐γ release were measured. Dapsone‐ and nitroso dapsone‐specific T‐cell clones were generated and phenotype, function, HLA allele restriction, and cross‐reactivity assessed. Dapsone intermediates were characterized by mass spectrometry. Results Peripheral blood mononuclear cells from six patients and cloned T cells proliferated and secreted Th1/2/22 cytokines when stimulated with dapsone (clones: n = 395; 80% CD4+ CXCR3hiCCR4hi, 20% CD8+CXCR3hiCCR4hiCCR6hiCCR9hiCCR10hi) and nitroso dapsone (clones: n = 399; 78% CD4+, 22% CD8+ with same chemokine receptor profile). CD4+ and CD8+ clones were HLA class II and class I restricted, respectively, and displayed three patterns of reactivity: compound specific, weakly cross‐reactive, and strongly cross‐reactive. Nitroso dapsone formed dimers in culture and was reduced to dapsone, providing a rationale for the cross‐reactivity. T‐cell responses to nitroso dapsone were dependent on the formation of a cysteine‐modified protein adduct, while dapsone interacted in a labile manner with antigen‐presenting cells. CD8+ clones displayed an HLA‐B*13:01‐restricted pattern of activation. Conclusion These studies describe the phenotype and function of dapsone‐ and nitroso dapsone‐responsive CD4+ and CD8+ T cells from hypersensitive patients. Discovery of HLA‐B*13:01‐restricted CD8+ T‐cell responses indicates that drugs and their reactive metabolites participate in HLA allele‐linked forms of hypersensitivity.

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Section: Introductionmentioning

confidence: 99%

Dapsone‐ and nitroso dapsone‐specific activation of T cells from hypersensitive patients expressing the risk allele HLA‐B*13:01

Zhao

Alhilali

Alzahrani

et al. 2019

Allergy

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“… 21 - 27 Of the 18 studies compiled for this analysis, 12 looked at participants between the ages of 18 and 55 years. 17 - 23 , 25 , 28 , 29 , 31 The studies that explicitly stated the amount of males versus females included in their patient population tended to have no significant difference between the 2 sexes. Only 4 studies included predominantly male patients, 18 - 21 , 25 , 29 while only 2 included predominantly female patients.…”

Section: Resultsmentioning

confidence: 99%

“…Of the studies that characterized participants with their diagnosis, 11 focused on schizophrenia, 15 - 21 , 24 , 27 , 29 - 30 while only 4 focused on bipolar 1 disorder. 19 , 22 , 28 , 32 Likewise, the effect of genetic changes on mood stabilizers and/or antipsychotic response was the focus of 12 out of 18 studies. Medications included sodium valproate, carbamazepine, lithium, and atypical antipsychotics such as clozapine, olanzapine, quetiapine, and risperidone.…”

Section: Resultsmentioning

confidence: 99%

The use of pharmacogenetic testing in patients with schizophrenia or bipolar disorder: A systematic review

Routhieaux

Keels

Tillery

2018

Mental Health Clinician

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Introduction:Pharmacogenetic testing may assist in identifying an individual's risk of developing a mental illness as well as predict an individual's response to treatment. The objective of this study is to report published outcomes of pharmacogenetic testing in patients with schizophrenia or bipolar disorder.Methods:A systematic review using PubMed and EBSCOhost through April 2017 was performed to identify articles that reported pharmacogenetic testing in adult patients with either bipolar disorder or schizophrenia using the keywords pharmacy, pharmacogenomics, pharmacogenetics, psychiatry, bipolar disorder, schizophrenia, mood stabilizer, and antipsychotic.Results:A total of 18 articles were included in the final literature review. A wide variety of genes amongst adult patients with varying ethnicities were found to be correlated with the development of schizophrenia or bipolar disorder as well as response to antipsychotics and mood stabilizers.Discussion:While current studies show a correlation between genetic variations and medication response or disease predisposition for patients with schizophrenia and bipolar disorder, research is unclear on the type of therapeutic recommendations that should occur based on the results of the pharmacogenetic testing. Hopefully interpreting pharmacogenetic results will one day assist with optimizing medication recommendations for individuals with schizophrenia and bipolar disorder.

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“…Molecular docking is being used increasingly commonly for investigating HLA-mediated ADRs ( Illing et al, 2012 ; Carr et al, 2017 ; Van Den Driessche and Fourches, 2017 ; Luo et al, 2015 ; Goldstein et al, 2014 ; Teh et al, 2016 ; Hirayama, 2017 ; Schotland et al, 2016 ; Isogai et al, 2013 ; Yang et al, 2015 ). The HLA structure presents unusual challenges for molecular docking protocols.…”

Section: Introductionmentioning

confidence: 99%

Critical assessment of approaches for molecular docking to elucidate associations of HLA alleles with adverse drug reactions

Ramsbottom

Carr

Jones

et al. 2018

Molecular Immunology

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HighlightsAll software assessed could dock Abacavir back into the risk allele structure but not always predict the exact binding mode.Most docking software assessed can distinguish between risk and control alleles.Docking performance can be degraded by using a homology model.Receptor flexibility can negatively affect the docking performance for complex HLA examples.Using AutoDockFR cannot compensate for the added difficulty of docking to the unbound target.

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Coupling Genotyping and Computational Modeling in Prediction of Anti-epileptic Drugs that cause Stevens Johnson Syndrome and Toxic Epidermal Necrolysis for Carrier of HLA-B*15:02

Cited by 10 publications

References 33 publications

Dapsone‐ and nitroso dapsone‐specific activation of T cells from hypersensitive patients expressing the risk allele HLA‐B*13:01

Dapsone‐ and nitroso dapsone‐specific activation of T cells from hypersensitive patients expressing the risk allele HLA‐B*13:01

The use of pharmacogenetic testing in patients with schizophrenia or bipolar disorder: A systematic review

Critical assessment of approaches for molecular docking to elucidate associations of HLA alleles with adverse drug reactions

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