Beta-lactam-induced immediate hypersensitivity reactions: A genome-wide association study of a deeply phenotyped cohort
Paola Nicoletti, Daniel F. Carr, Sarah Barrett, Laurence McEvoy, Peter S. Friedmann, Neil H. Shear, Matthew R. Nelson, Anca Mirela Chiriac, Natalia Blanca‐López, J.A. Cornejo‐García, Francesco Gaeta, Alla Nakonechna, Marı́a José Torres, Cristiano Caruso, Rocco Luigi Valluzzi, Aris Floratos, Yufeng Shen, Rebecca Pavlos, Elizabeth J. Phillips, Pascal Demoly, Antonino Romano, Miguel Blanca, Munir Pirmohamed
Abstract
Backgroundβ-lactam antibiotics are associated with a variety of immune-mediated or hypersensitivity reactions, including immediate (type I) reactions mediated by antigen-specific IgE.ObjectiveWe sought to identify genetic predisposing factors for immediate reactions to β-lactam antibiotics.MethodsPatients 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.ResultsGenome-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.ConclusionsHLA-DRB1∗10:01 predisposed to immediate hypersensitivity reactions to penicillins. Further work to identify other predisposing HLA and non-HLA loci is required. β-lactam antibiotics are associated with a variety of immune-mediated or hypersensitivity reactions, including immediate (type I) reactions mediated by antigen-specific IgE. We sought to identify genetic predisposing factors for immediate reactions to β-lactam antibiotics. 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. 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. HLA-DRB1∗10:01 predisposed to immediate hypersensitivity reactions to penicillins. Further work to identify other predisposing HLA and non-HLA loci is required.