Browse
Submit Data
Databases
API
Help

Dataset Information

26 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The Mechanistic Differences in HLA-Associated Carbamazepine Hypersensitivity.

ABSTRACT: Drug hypersensitivity reactions that resemble acute immune reactions are linked to certain human leucocyte antigen (HLA) alleles. Severe and life-threatening Stevens Johnson Syndrome and Toxic Epidermal Necrolysis following treatment with the antiepileptic and psychotropic drug Carbamazepine are associated with HLA-B*15:02; whereas carriers of HLA-A*31:01 develop milder symptoms. It is not understood how these immunogenic differences emerge genotype-specific. For HLA-B*15:02 an altered peptide presentation has been described following exposure to the main metabolite of carbamazepine that is binding to certain amino acids in the F pocket of the HLA molecule. The difference in the molecular mechanism of these diseases has not been comprehensively analyzed, yet; and is addressed in this study. Soluble HLA-technology was utilized to examine peptide presentation of HLA-A*31:01 in presence and absence of carbamazepine and its main metabolite and to examine the mode of peptide loading. Proteome analysis of drug-treated and untreated cells was performed. Alterations in sA*31:01-presented peptides after treatment with carbamazepine revealed different half-life times of peptide-HLA- or peptide-drug-HLA complexes. Together with observed changes in the proteome elicited through carbamazepine or its metabolite these results illustrate the mechanistic differences in carbamazepine hypersensitivity for HLA-A*31:01 or B*15:02 patients and constitute the bridge between pharmacology and pharmacogenetics for personalized therapeutics.

SUBMITTER: Simper GS

PROVIDER: S-EPMC6835980 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans.

Project description:BackgroundCarbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) in the Han Chinese and other Asian populations but not in European populations.MethodsWe performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3987 control subjects, all of European descent. We tested for an association between disease and HLA alleles through proxy single-nucleotide polymorphisms and imputation, confirming associations by high-resolution sequence-based HLA typing. We replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions.ResultsThe HLA-A*3101 allele, which has a prevalence of 2 to 5% in Northern European populations, was significantly associated with the hypersensitivity syndrome (P=3.5×10(-8)). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLA-A*3101 allele (P=1.1×10(-6)). Follow-up genotyping confirmed the variant as a risk factor for the hypersensitivity syndrome (odds ratio, 12.41; 95% confidence interval [CI], 1.27 to 121.03), maculopapular exanthema (odds ratio, 8.33; 95% CI, 3.59 to 19.36), and SJS-TEN (odds ratio, 25.93; 95% CI, 4.93 to 116.18).ConclusionsThe presence of the HLA-A*3101 allele was associated with carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry. The presence of the allele increased the risk from 5.0% to 26.0%, whereas its absence reduced the risk from 5.0% to 3.8%. (Funded by the U.K. Department of Health and others.).

| S-EPMC3113609 | biostudies-literature

HLA-A 31:01 and HLA-B 15:02 as genetic markers for carbamazepine hypersensitivity in children.

Project description:The occurrence of hypersensitivity reactions including rare but life-threatening Stevens-Johnson syndrome (SJS) and drug-induced hypersensitivity syndrome (HSS) limits the use of the anticonvulsant carbamazepine (CBZ). Human leukocyte antigen-B (HLA)-B 15:02 and HLA-A 31:01 have been identified as predictive genetic markers for CBZ hypersensitivity in Asian and European patients. To replicate these genetic associations in pediatric patients from North America with a diverse ethnic background, we investigated HLA-A 31:01 and HLA-B 15:02 in 42 children with CBZ hypersensitivity and 91 CBZ-tolerant children from across Canada. HLA-A 31:01 was significantly associated with CBZ-HSS (odds ratio (OR): 26.4, P = 0.0025) and maculopapular exanthema (MPE) (OR: 8.6, P = 0.0037) but not with CBZ-SJS. Conversely, HLA-B 15:02 was associated with CBZ-SJS (OR: 38.6, P = 0.002) but not HSS or MPE. This study is the first to demonstrate the association of HLA-A 31:01 with CBZ hypersensitivity in children, providing important replication of this association and highlighting the importance of HLA-A 31:01 as a predictive biomarker across various ancestries.

| S-EPMC3839910 | biostudies-literature

HLA alleles associated with asparaginase hypersensitivity in Chinese children.

Project description:Asparaginase is an important drug to treat childhood haematological malignancies. Data on the association between human leukocyte antigens (HLA) and asparaginase hypersensitivity among Chinese are lacking. We conducted a retrospective study to identify HLA alleles associated with asparaginase hypersensitivity among Chinese children with acute lymphoblastic leukaemia (ALL), mixed phenotype leukaemia and non-Hodgkin lymphoma (NHL), who received asparaginases with HLA typing performed between 2009 and 2019. 107 Chinese patients were analysed. 66.3% (71/107) developed hypersensitivity to at least one of the asparaginases. HLA-B*46:01 (OR 3.8, 95% CI 1.4-10.1, p < 0.01) and DRB1*09:01 (OR 4.3, 95% CI 1.6-11.4, p < 0.01) were significantly associated with L-asparaginase hypersensitivities, which remained significant after adjustment for age, gender and B cell ALL [HLA-B*46:01 (adjusted OR 3.5, 95% 1.3-10.5, p = 0.02) and DRB1*09:01 (OR 4.4, 95% CI 1.6-13.3, p < 0.01)].

| S-EPMC8557538 | biostudies-literature

Shared Genetic Risk Factors Across Carbamazepine-Induced Hypersensitivity Reactions.

Project description:Carbamazepine (CBZ) causes life-threating T-cell-mediated hypersensitivity reactions, including serious cutaneous adverse reactions (SCARs) and drug-induced liver injury (CBZ-DILI). In order to evaluate shared or phenotype-specific genetic predisposing factors for CBZ hypersensitivity reactions, we performed a meta-analysis of two genomewide association studies (GWAS) on a total of 43 well-phenotyped Northern and Southern European CBZ-SCAR cases and 10,701 population controls and a GWAS on 12 CBZ-DILI cases and 8,438 ethnically matched population controls. HLA-A*31:01 was identified as the strongest genetic predisposing factor for both CBZ-SCAR (odds ratio (OR) = 8.0; 95% CI 4.10-15.80; P = 1.2 × 10-9 ) and CBZ-DILI (OR = 7.3; 95% CI 2.47-23.67; P = 0.0004) in European populations. The association with HLA-A*31:01 in patients with SCAR was mainly driven by hypersensitivity syndrome (OR = 12.9; P = 2.1 × 10-9 ) rather than by Stevens-Johnson syndrome/toxic epidermal necrolysis cases, which showed an association with HLA-B*57:01. We also identified a novel risk locus mapping to ALK only for CBZ-SCAR cases, which needs replication in additional cohorts and functional evaluation.

| S-EPMC7156285 | biostudies-literature

HLA-A*3101 and Carbamazepine-Induced Hypersensitivity Reactions in Europeans

Project description:Based on the prior knowledge of involvement of the human leukocyte antigen locus in Han Chinese patients with carbamazepine-induced Stevens-Johnson syndrome, we imputed the HLA types for each case and control subject from the array of SNPs in the Human610-Quad GWAS platform (NCBI Build 36.1). We then performed a genome-wide association test which included the imputed HLA alleles as markers.

| EGAS00000000036 | EGA

Polymorfism Of CYP2C9 And 3A5 and carbamazepine hypersensitivity reactions in Brazilian subjects

Project description: Not available

| S-EPMC4128306 | biostudies-literature

Carbamazepine-induced hypersensitivity reactions in Europeans

Project description:An antiepileptic drug carbamazepine is well tolerated by the majority of patients, but can cause severe and potentialy fatal hypersensitivity reactions in a small number of individuals. The aim of this study was to identify genetic predictors of hypersensitivity reactions to carbamazepine. We undertook a genome-wide association study (GWAS) in 22 patients of European ancestry with carbamazepine-induced hypersensitivity syndrome (HSS) and compared our data with genotypes from a healthy population within the WTCCC. We performed imputation of classical HLA alleles according to a recently described method (Science. 2010 Dec 10;330(6010):1551-7. Epub 2010 Nov 4). GWAS statistical analysis was performed using logistic regression with an additive model of inheritance.

| EGAS00000000037 | EGA

Drug Induced Hypersensitivity and the HLA Complex

Project description:Drug-induced hypersensitivity reactions are of major concern and present a burden for national healthcare systems due to their often severe nature, high rate of hospital admissions and high mortality. They manifest with a wide range of symptoms and signs, and can be initiated by a wide range of structurally diverse chemical compounds. The pathophysiological mechanisms underlying hypersensitivity reactions are not well understood, but it is thought that they are immune mediated. MHC region on Chromosome 6 contains many genes with immune function. Classical MHC molecules are highly polymorphic cell surface glycoproteins whose function is to present peptide antigens to T cells. In addition to conferring protection from some diseases, HLA alleles are also associated with an increased risk of other diseases, including drug-induced hypersensitivity. Pharmacogenetic approach to predict the risk of drug-induced hypersensitivity has been established for several drugs. We will discuss the progress of hypersensitivity pharmacogenetics over the last few years and focus on current efforts of the international community to develop consortia which aim to standardize disease phenotypes and to identify affected individuals through international collaborations. In addition, we will discuss the clinical utility of HLA typing as predictive or diagnostic testing for drug-induced hypersensitivity.

| S-EPMC4052542 | biostudies-literature

Abacavir induces loading of novel self-peptides into HLA-B*57: 01: an autoimmune model for HLA-associated drug hypersensitivity.

Project description:BACKGROUND:Abacavir drug hypersensitivity in HIV-treated patients is associated with HLA-B57:01 expression. To understand the immunochemistry of abacavir drug reactions, we investigated the effects of abacavir on HLA-B57:01 epitope-binding in vitro and the quality and quantity of self-peptides presented by HLA-B57:01 from abacavir-treated cells. DESIGN AND METHODS:An HLA-B57:01-specific epitope-binding assay was developed to test for effects of abacavir, didanosine or flucloxacillin on self-peptide binding. To examine whether abacavir alters the peptide repertoire in HLA-B57:01, a B-cell line secreting soluble human leucocyte antigen (sHLA) was cultured in the presence or absence of abacavir, peptides were eluted from purified human leucocyte antigen (HLA), and the peptide epitopes comparatively mapped by mass spectroscopy to identify drug-unique peptides. RESULTS:Abacavir, but not didansosine or flucloxacillin, enhanced binding of the FITC-labeled self-peptide LF9 to HLA-B57:01 in a dose-dependent manner. Endogenous peptides isolated from abacavir-treated HLA-B57:01 B cells showed amino acid sequence differences compared with peptides from untreated cells. Novel drug-induced peptides lacked typical carboxyl (C) terminal amino acids characteristic of the HLA-B57:01 peptide motif and instead contained predominantly isoleucine or leucine residues. Drug-induced peptides bind to soluble HLA-B57:01 with high affinity that was not altered by abacavir addition. CONCLUSION:Our results support a model of drug-induced autoimmunity in which abacavir alters the quantity and quality of self-peptide loading into HLA-B57:01. Drug-induced loading of novel self-peptides into HLA, possibly by abacavir either altering the binding cleft or modifying the peptide-loading complex, generates an array of neo-antigen peptides that drive polyclonal T-cell autoimmune responses and multiorgan systemic toxicity.

| S-EPMC4155923 | biostudies-literature

HLA alleles associated with asparaginase hypersensitivity in childhood ALL: a report from the DFCI Consortium.

Project description:Aim: To evaluate the association between human leukocyte antigen (HLA) alleles and native Escherichia coli asparaginase hypersensitivity (AH) in children with acute lymphoblastic leukemia (ALL) who received Dana-Farber Cancer Institute treatment protocols. Patients & methods: HLA-DQA1, HLA-DRB1 and HLA-DQB1 alleles were retrieved from available whole exome sequencing data of a subset of childhood ALL patients from Quebec ALL cohort and analyzed for an association with AH. PCR assay was developed to analyze associated alleles in the entire discovery and replication cohorts. Results: Two alleles in linkage disequilibrium (HLA-DRB1*07:01 and DQA1*02:01) were associated with AH. Additional analyses, performed to distinguish between HLA-DRB1*07:01 haplotypes with and without DQB1*02:02 allele, showed that the association was dependent on the presence of DQB1*02:02. Conclusion: This study confirms the implication of HLA-DRB1*07:01, DQA1*02:01 and DQB1*02:02 alleles in developing AH in childhood ALL.

| S-EPMC7299187 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data