HLA-B Alleles With Shared Peptide Binding Specificities Define Global Risk of Co-trimoxazole-Induced Severe Cutaneous Adverse Drug Reactions.

IF 6.6 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology-In Practice Pub Date : 2025-08-08 DOI:10.1016/j.jaip.2025.08.001

Yueran Li, Andrew Gibson, Hajirah N Saeed, Mohammadali Ashraf, Danmeng Li, David A Ostrov, Matthew S Krantz, Simon A Mallal, Eric Alves, Abha Chopra, Linda Choo, Roni P Dodiuk-Gad, Benjamin Kaffenberger, Aaron M Drucker, Michelle S Goh, Elizabeth Ergen, Robert Micheletti, Misha Rosenbach, Michelle D Martin-Pozo, Rama Gangula, Elizabeth A Williams, Alexis Yu, April O'Connor, Kelby Mahan, James T Kwan, Derek Metcalfe, Ramy Rashad, Swapna S Shanbhag, Mohammed Ali Tahboub, Sarah Pedretti, Phuti Choshi, Tafadzwa Chimbetete, Rose Selim, Ian James, Jason A Trubiano, Rannakoe Lehloenya, Jonny G Peter, Elizabeth J Phillips

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引用次数: 0

Abstract

Background: Co-trimoxazole is a leading global cause of severe cutaneous adverse drug reactions (SCAR) including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Co-trimoxazole-induced SCAR are associated with HLA class I alleles including HLA-B∗13:01 and HLA-B∗38:02 in Southeast Asian (SEA) populations. However, the global generalizability of these associations is unknown but critical for population-appropriate risk stratification and diagnosis.

Objective: To determine HLA risk factors associated with co-trimoxazole-induced SJS/TEN and DRESS in populations from the United States and South Africa.

Methods: We performed high-resolution HLA typing on dermatologist-adjudicated co-trimoxazole-induced patients with SCAR in the United States (n = 63) and South Africa (n = 26) compared with population controls. Peptide binding and docking analyses were performed using MHCcluster2.0 and CB-Dock2.

Results: In a multiple logistic regression model, HLA-B^∗44:03 (corrected P [Pc] < .001; odds ratio [OR] = 4.08), HLA-B^∗38:01 (Pc < .001; OR = 5.66), and HLA-C^∗04:01 (Pc = .003; OR = 2.50) were independently associated with co-trimoxazole-induced SJS/TEN in the United States. HLA-B^∗44:03 was also associated with co-trimoxazole-induced DRESS in South Africa (Pc = .019; OR = 10.69). Distinct HLA-B variants with shared peptide binding specificities (SPBS) and HLA-C^∗04:01 identified 94% and 78% of co-trimoxazole-induced SJS/TEN and DRESS in the United States, respectively. The SEA risk allele HLA-B^∗13:01, with SPBS to HLA-B^∗44:03, was identified in just one of 63 US patients with SCAR.

Conclusions: HLA alleles with SPBS to SEA-related risk alleles, including HLA-B^∗44:03 (SPBS with HLA-B^∗13:01) and HLA-B^∗38:01 (SPBS with HLA-B^∗38:02) but also HLA-C^∗04:01, predisposed to co-trimoxazole-induced SCAR in the United States and South Africa. These findings provide biological plausibility and strategies for global risk prediction and diagnosis of co-trimoxazole-induced SCAR.

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具有共享肽结合特异性的HLA-B等位基因定义了共新恶唑诱导的SCAR的整体风险。

背景：复方新诺明是严重皮肤药物不良反应（SCAR）的主要全球原因，包括史蒂文斯-约翰逊综合征/中毒性表皮坏死松解（SJS/TEN）和嗜酸性粒细胞增多和全身症状（DRESS）的药物反应。在东南亚（SEA）人群中，共新恶唑诱导的SCAR与HLA- b *13:01和HLA- b *38:02等HLA I类等位基因相关。然而，这些关联的全球普遍性尚不清楚，但对于适合人群的风险分层和诊断至关重要。目的：探讨美国（US）和南非（SA）人群中共新恶唑诱发SJS/TEN和DRESS的HLA危险因素。方法：我们对美国皮肤科医生判定的复方新恶唑诱导的SCAR患者（n=63）和SA患者（n=26）进行高分辨率HLA分型，并与人群对照进行比较。使用MHCcluster2.0和CB-Dock2进行肽结合和对接分析。结论：HLA- b *44:03（伴HLA- b *13:01）和HLA- b *38:01（伴HLA- b *38:02）以及HLA- c *04:01等HLA等位基因与sea相关的风险等位基因在美国和SA更易发生复方新恶唑诱导的SCAR。这些发现为共新恶唑诱导SCAR的全球风险预测和诊断提供了生物学上的可行性和策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Allergy and Clinical Immunology-In Practice ALLERGYIMMUNOLOGY-IMMUNOLOGY

CiteScore

11.10

自引率

9.60%

发文量

683

审稿时长

50 days

期刊介绍： JACI: In Practice is an official publication of the American Academy of Allergy, Asthma & Immunology (AAAAI). It is a companion title to The Journal of Allergy and Clinical Immunology, and it aims to provide timely clinical papers, case reports, and management recommendations to clinical allergists and other physicians dealing with allergic and immunologic diseases in their practice. The mission of JACI: In Practice is to offer valid and impactful information that supports evidence-based clinical decisions in the diagnosis and management of asthma, allergies, immunologic conditions, and related diseases. This journal publishes articles on various conditions treated by allergist-immunologists, including food allergy, respiratory disorders (such as asthma, rhinitis, nasal polyps, sinusitis, cough, ABPA, and hypersensitivity pneumonitis), drug allergy, insect sting allergy, anaphylaxis, dermatologic disorders (such as atopic dermatitis, contact dermatitis, urticaria, angioedema, and HAE), immunodeficiency, autoinflammatory syndromes, eosinophilic disorders, and mast cell disorders. The focus of the journal is on providing cutting-edge clinical information that practitioners can use in their everyday practice or to acquire new knowledge and skills for the benefit of their patients. However, mechanistic or translational studies without immediate or near future clinical relevance, as well as animal studies, are not within the scope of the journal.