Beta-lactam-induced immediate hypersensitivity reactions: A genome-wide association study of a deeply phenotyped cohort,Journal of Allergy and Clinical Immunology

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Beta-lactam-induced immediate hypersensitivity reactions: A genome-wide association study of a deeply phenotyped cohort
Journal of Allergy and Clinical Immunology ( IF 14.2 ) Pub Date : 2020-10-13 , DOI: 10.1016/j.jaci.2020.10.004
Paola Nicoletti ₁ , Daniel F Carr ₂ , Sarah Barrett ₂ , Laurence McEvoy ₂ , Peter S Friedmann ₃ , Neil H Shear ₄ , Matthew R Nelson ₅ , Anca M Chiriac ₆ , Natalia Blanca-López ₇ , José A Cornejo-García ₈ , Francesco Gaeta ₉ , Alla Nakonechna ₁₀ , Maria J Torres ₁₁ , Cristiano Caruso ₉ , Rocco L Valluzzi ₁₂ , Aris Floratos ₁₃ , Yufeng Shen ₁₄ , Rebecca K Pavlos ₁₅ , Elizabeth J Phillips ₁₆ , Pascal Demoly ₁₇ , Antonino Romano ₁₈ , Miguel Blanca ₁₉ , Munir Pirmohamed ₂₀

Affiliation

Icahn School of Medicine at Mount Sinai, New York, NY; Sema4, Stamford, Conn.
Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
Dermatology Unit, Sir Henry Wellcome Research Laboratories, School of Medicine, University of Southampton, Southampton, United Kingdom.
Division of Dermatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Division of Dermatology, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
Deerfield, New York, NY.
Division of Allergy, Hôpital Arnaud de Villeneuve, University Hospital of Montpellier, Montpellier, France.
Infanta Leonor University Hospital, Madrid, Spain.
Allergy Research Group, Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, ARADyAL, Malaga, Spain.
Allergy Unit, Columbus Hospital, Fondazione Policlinico Universitario Agostino Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.
Liverpool University Hospitals Foundation National Health Service Trust, Liverpool, United Kingdom.
Allergy Research Group, Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, ARADyAL, Malaga, Spain; Allergy Unit, Hospital Regional Universitario de Málaga, Malaga, Spain.
Division of Allergy, University Department of Pediatrics, Pediatric Hospital Bambino Gesù, Rome, Italy.
Department of Systems Biology, New York, NY; Department of Biomedical Informatics, Columbia University, New York, NY.
Department of Systems Biology, New York, NY.
Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, University of Western Australia, Nedlands, Australia.
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn; Centre for Clinical Pharmacology and Infectious Diseases, Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia.
Division of Allergy, Hôpital Arnaud de Villeneuve, University Hospital of Montpellier, Montpellier, France; Unité Mixte de Recherche en Santé (UMR-S) 1136 Institut National de la Santé et de la Recherche Médicale-Sorbonne Université, Equipe Epidemiology of allergic and respiratory diseases (EPAR)- Louis d'Epidémiologie et de Santé Publique (IPLESP), Paris, France.
Istituto di Ricovero e Cura a Carattere Scientifico Oasi Maria SS, Troina, Italy; Fondazione Mediterranea GB Morgagni, Catania, Italy.
Allergy Unit, Hospital Regional Universitario de Málaga, Malaga, Spain.
Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom; Liverpool University Hospitals Foundation National Health Service Trust, Liverpool, United Kingdom.

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.

中文翻译：

β-内酰胺诱导的即刻超敏反应：深度表型队列的全基因组关联研究

背景

β-内酰胺类抗生素与多种免疫介导或超敏反应有关，包括由抗原特异性 IgE 介导的即时（I 型）反应。

客观的

我们试图确定对β-内酰胺类抗生素产生即时反应的遗传易感因素。

方法

从过敏诊所招募对青霉素或头孢菌素有即时超敏反应临床史的患者，这些患者经免疫学证实。对 662 名诊断为立即超敏反应的患者（发现队列）进行了全基因组关联研究，主要发现在 98 名西班牙病例队列中重复，使用与发现队列相同的诊断标准招募。

结果

全基因组关联研究将 II 类 HLA 区域内的 rs71542416 确定为最高命中（P = 2 × 10 ^-14）；这与HLA-DRB1∗10:01（优势比，2.93；P = 5.4 × 10 ^-7）和HLA-DQA1∗01:05（优势比，2.93，P = 5.4 × 10 ^-7）处于连锁不平衡状态。单倍型分析发现，即使没有HLA-DQA1∗01:05等位基因，HLA-DRB1∗10:01也是一个危险因素。与HLA-DRB1∗10:01的关联在另一个队列中被复制，发现和复制队列的荟萃分析表明HLA-DRB1∗10:01在全基因组水平上增加立即超敏反应的风险（优势比，2.96；P = 4.1 × 10 ^-9）。在 268 名对 β-内酰胺类有迟发性超敏反应的患者中，未发现与HLA-DRB1∗10:01相关。