4.7 Article

Beta-lactam-induced immediate hypersensitivity reactions: A genome-wide association study of a deeply phenotyped cohort

期刊

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 147, 期 5, 页码 1830-+

出版社

MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2020.10.004

关键词

Type I hypersensitivity; beta-lactams; penicillins; cephalo-sporins; allergy; anaphylaxis; pharmacogenomics

资金

  1. International Serious Adverse Events Consortium (iSAEC)
  2. Abbott
  3. Amgen
  4. AstraZeneca
  5. Daiichi Sankyo
  6. GlaxoSmithKline
  7. Merck
  8. Novartis
  9. Pfizer
  10. Takeda
  11. Wellcome Trust
  12. Medical Research Council (MRC) Centre for Drug Safety Science [MR/L006758/1]
  13. iSAEC
  14. National Institutes of Health [1P50GM11530501, R21AI139021, R34AI136815, 1 R01 HG010863-01]
  15. National Health and Medical Research Council of Australia

向作者/读者索取更多资源

This study identified HLA-DRB1*10:01 as a genetic predisposing factor for immediate hypersensitivity reactions to beta-lactam antibiotics, particularly penicillins. Further research is needed to identify other predisposing HLA and non-HLA loci.
Background: beta-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 beta-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 x 10(-14)); this was in linkage disequilibrium with HLA-DRB1*10:01 (odds ratio, 2.93; P = 5.4 x 10(-7)) and HLA-DQA1*01:05 (odds ratio, 2.93, P = 5.4 x 10(-7)). Haplotype analysis identified that HLADRB1*10:01 was a risk factor even without the HLADQA1*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 x 10(-9)). No association with HLA-DRB1*10:01 was identified in 268 patients with delayed hypersensitivity reactions to beta-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.

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