Beta-lactam-induced immediate hypersensitivity reactions: A genome-wide association study of a deeply phenotyped cohort - 05/05/21
Abstract |
Background |
β-lactam antibiotics are associated with a variety of immune-mediated or hypersensitivity reactions, including immediate (type I) reactions mediated by antigen-specific IgE.
Objective |
We sought to identify genetic predisposing factors for immediate reactions to β-lactam antibiotics.
Methods |
Patients with a clinical history of immediate hypersensitivity reactions to either penicillins or cephalosporins, which were immunologically confirmed, were recruited from allergy clinics. A genome-wide association study was conducted on 662 patients (the discovery cohort) with a diagnosis of immediate hypersensitivity and the main finding was replicated in a cohort of 98 Spanish cases, recruited using the same diagnostic criteria as the discovery cohort.
Results |
Genome-wide association study identified rs71542416 within the Class II HLA region as the top hit (P = 2 × 10−14); this was in linkage disequilibrium with HLA-DRB1∗10:01 (odds ratio, 2.93; P = 5.4 × 10−7) and HLA-DQA1∗01:05 (odds ratio, 2.93, P = 5.4 × 10−7). Haplotype analysis identified that HLA-DRB1∗10:01 was a risk factor even without the HLA-DQA1∗01:05 allele. The association with HLA-DRB1∗10:01 was replicated in another cohort, with the meta-analysis of the discovery and replication cohorts showing that HLA-DRB1∗10:01 increased the risk of immediate hypersensitivity at a genome-wide level (odds ratio, 2.96; P = 4.1 × 10−9). No association with HLA-DRB1∗10:01 was identified in 268 patients with delayed hypersensitivity reactions to β-lactams.
Conclusions |
HLA-DRB1∗10:01 predisposed to immediate hypersensitivity reactions to penicillins. Further work to identify other predisposing HLA and non-HLA loci is required.
Le texte complet de cet article est disponible en PDF.Key words : Type I hypersensitivity, β-lactams, penicillins, cephalosporins, allergy, anaphylaxis, pharmacogenomics
Abbreviations used : BL, OR, QTL, SNP
Plan
| This work was supported by the International Serious Adverse Events Consortium (iSAEC). The iSAEC is a nonprofit organization dedicated to identifying and validating DNA variants useful in predicting the risk of drug-related serious adverse events. The iSAEC brings together the pharmaceutical industry, regulatory authorities, and academic centers to address clinical and scientific issues associated with the genetics of drug-related serious adverse events. The iSAEC’s funding members included: Abbott, Amgen, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Merck, Novartis, Pfizer, Takeda, and the Wellcome Trust. M.P. is a National Institute for Health Research Senior Investigator. M.P. and D.F.C. thank the Medical Research Council (MRC) Centre for Drug Safety Science for support (MR/L006758/1). P.N. was supported by the iSAEC. E.J.P. receives funding from the National Institutes of Health (grants 1P50GM115305-01, R21AI139021, R34AI136815, and 1 R01 HG010863-01) and the National Health and Medical Research Council of Australia. The views expressed are those of the author(s) and not of any of their funders. The funders played no role in the analysis of the data and interpretation of the findings. |
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| Disclosure of potential conflict of interest: P. Nicoletti is an employee of Sema4, a Mount Sinai venture. M.R. Nelson was an employee of GlaxoSmithKline at the time the work was undertaken. M. Pirmohamed receives research funding from various organizations including the MRC, National Institute for Health Research, European Union Commission, and Health Education England. He has also received partnership funding for the following: MRC Clinical Pharmacology Training Scheme (cofunded by MRC and Roche, UCB, Eli Lilly, and Novartis); a PhD studentship jointly funded by Engineering and Physical Sciences Research Council, and AstraZeneca; and grant funding from Vistagen Therapeutics. He also has unrestricted educational grant support for the UK Pharmacogenetics and Stratified Medicine Network from Bristol Myers Squibb and UCB. He has developed an HLA genotyping panel with MC Diagnostics, but does not benefit financially from this. None of the funding declared above has been used for the current paper. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 147 - N° 5
P. 1830 - mai 2021 Retour au numéro
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