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

Nicoletti, P., Carr, D.F., Barrett, S., McEvoy, L., Friedmann, P.S., Shear, N.H., Nelson, M.R., Chiriac, A.M., Blanca-López, N., Cornejo, J.A., Gaeta, F., Nakonechna, A., Torres, M.J., Caruso, C., Valluzzi, R.L., Floratos, A., Shen, Y., Pavlos, R.K., Phillips, E.J., Demoly, P., Romano, A., Blanca, M. and Pirmohamed, M. (2020) Beta-lactam-induced immediate hypersensitivity reactions: A genome-wide association study of a deeply phenotyped cohort. Journal of Allergy and Clinical Immunology . In Press.

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

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 (GWAS) 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

GWAS identified rs71542416 within the Class II HLA region as the top hit (P = 2x10-14); this was in linkage disequilibrium with HLA-DRB1*10:01 (OR = 2.93 P = 5.4x10-7) and HLA-DQA1*01:05 (OR=2.93, P=5.4x10-7). 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 (OR = 2.96 P=4.1x10-9). No association with HLA-DRB1*10:01 was identified in 268 patients with delayed hypersensitivity reactions to β-lactams.

Conclusion

HLA-DRB1*10:01 predisposed to immediate hypersensitivity reactions to penicillins. Further work to identify other predisposing HLA and non-HLA loci is required.

Clinical implications

This novel insight into the mechanisms of immediate reactions associated with penicillins may be of use in risk stratifying patients where penicillin cannot be excluded as an etiological agent.

Item Type:	Journal Article
Murdoch Affiliation(s):	Institute for Immunology and Infectious Diseases
Publisher:	Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology
Copyright:	© 2020 The Authors
URI:	http://researchrepository.murdoch.edu.au/id/eprint/58194

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