具有共享肽结合特异性的HLA - B等位基因决定了复方新诺明诱导的严重皮肤不良反应的全球风险。

HLA-B Alleles with Shared Peptide Binding Specificities Define Global Risk of Cotrimoxazole-induced SCAR.

作者信息

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

机构信息

Institute for Immunology and Infectious Diseases, Murdoch University, Western Australia, Australia.

Massachusetts Eye and Ear Institute, Harvard Medical School, Boston, MA, US.

出版信息

medRxiv. 2025 May 28:2025.05.28.25328237. doi: 10.1101/2025.05.28.25328237.

DOI:10.1101/2025.05.28.25328237

PMID:40492078

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12148054/

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-B13:01 and HLA-B38:02 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 (US) and South Africa (SA).

METHODS

We performed high-resolution HLA typing on dermatologist-adjudicated co-trimoxazole-induced SCAR patients in the US (n=63) and SA (n=26) compared to population controls. Peptide binding and docking analyses were performed using MHCcluster2.0 and CB-Dock2.

RESULTS

In a multiple logistic regression model, HLA-B44:03 (Pc<0.001, OR: 4.08), HLA-B38:01 (Pc<0.001, OR: 5.66), and HLA-C04:01 (Pc=0.003, OR: 2.50) were independently associated with co-trimoxazole-induced SJS/TEN in the US. HLA-B44:03 was also associated with co-trimoxazole-induced DRESS in SA (Pc=0.019, OR: 10.69). Distinct HLA-B variants with shared peptide binding specificities (SPBS) and HLA-C04:01 identified 94% and 78% of co-trimoxazole-induced SJS/TEN and DRESS in the US, respectively. The SEA risk allele HLA-B13:01, with SPBS to HLA-B*44:03, was identified in just 1/63 US SCAR patients.

CONCLUSION

HLA alleles with SPBS to SEA-related risk alleles including HLA-B44:03 (SPBS with HLA-B13:01) and HLA-B38:01 (SPBS with HLA-B38:02) but also HLA-C*04:01 predisposed to co-trimoxazole-induced SCAR in the US and SA. These findings provide biological plausibility and strategies for global risk prediction and diagnosis of co-trimoxazole-induced SCAR.

摘要

背景

复方新诺明是全球严重皮肤药物不良反应（SCAR）的主要诱因，包括史蒂文斯-约翰逊综合征/中毒性表皮坏死松解症（SJS/TEN）以及伴有嗜酸性粒细胞增多和全身症状的药物反应（DRESS）。在东南亚（SEA）人群中，复方新诺明诱发的SCAR与HLA I类等位基因相关，包括HLA - B13:01和HLA - B38:02。然而，这些关联在全球范围内的普遍性尚不清楚，但对于进行适合人群的风险分层和诊断至关重要。

目的

确定在美国（US）和南非（SA）人群中，与复方新诺明诱发的SJS/TEN和DRESS相关的HLA风险因素。

方法

我们对美国（n = 63）和南非（n = 26）经皮肤科医生判定为复方新诺明诱发的SCAR患者进行了高分辨率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。

结果

在多元逻辑回归模型中，HLA - B44:03（Pc<0.001，OR：4.08）、HLA - B38:01（Pc<0.001，OR：5.66）和HLA - C04:01（Pc = 0.003，OR：2.50）在美国与复方新诺明诱发的SJS/TEN独立相关。HLA - B44:03在南非也与复方新诺明诱发的DRESS相关（Pc = 0.019，OR：10.69）。具有共享肽结合特异性（SPBS）的不同HLA - B变体和HLA - C04:01分别在美国识别出94%和78%的复方新诺明诱发的SJS/TEN和DRESS。SEA风险等位基因HLA - B13:01，其与HLA - B*44:03具有SPBS，仅在1/63例美国SCAR患者中被识别出。

结论

与SEA相关风险等位基因具有SPBS的HLA等位基因，包括HLA - B44:03（与HLA - B13:01具有SPBS）、HLA - B38:01（与HLA - B38:02具有SPBS）以及HLA - C*04:01，在美国和南非易导致复方新诺明诱发的SCAR。这些发现为复方新诺明诱发的SCAR的全球风险预测和诊断提供了生物学合理性及策略。