Journal article
HLA-B Alleles with Shared Peptide Binding Specificities Define Global Risk of Co-trimoxazole-induced SCAR
The journal of allergy and clinical immunology. In practice, Vol.13(11), pp.3042-3053
2025
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 (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-B*44:03 (Pc<0.001, OR: 4.08), HLA-B*38:01 (Pc<0.001, OR: 5.66), and HLA-C*04:01 (Pc=0.003, OR: 2.50) were independently associated with co-trimoxazole-induced SJS/TEN in the US. HLA-B* 44:03 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-C*04:01 identified 94% and 78% of co-trimoxazole-induced SJS/TEN and DRESS in the US, respectively. The SEA risk allele HLA-B*13:01, with SPBS to HLA-B*44:03, was identified in just 1/63 US SCAR patient.
Conclusion
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 US and SA. These findings provide biological plausibility and strategies for global risk prediction and diagnosis of co-trimoxazole-induced SCAR.
Details
- Title
- HLA-B Alleles with Shared Peptide Binding Specificities Define Global Risk of Co-trimoxazole-induced SCAR
- Authors/Creators
- Yueran LiAndrew Gibson - Murdoch University, Personalised Medicine CentreHajirah N. Saeed - New York Eye and Ear InfirmaryMohammad Ali Tahboub - Harvard Medical SchoolDanmeng LiDavid A OstrovMatthew Krantz - Vanderbilt University Medical CenterSimon MallalEric Alves - The University of Western AustraliaAbha Chopra - Murdoch University, Personalised Medicine CentreLinda ChooRoni P Dodiuk-Gad - University of TorontoBenjamin Kaffenberger - The Ohio State University Wexner Medical CenterAaron M DruckerMichelle S.Y. Goh - Austin HealthElizabeth Ergen - University of Tennessee at KnoxvilleRobert Micheletti - University of PennsylvaniaMisha Rosenbach - University of PennsylvaniaMichelle D Martin-Pozo - Vanderbilt University Medical CenterRama Gangula - Vanderbilt University Medical CenterElizabeth A Williams - Vanderbilt University Medical CenterAlexis Yu - Vanderbilt UniversityApril O'Connor - Vanderbilt University Medical CenterKelby Mahan - Vanderbilt UniversityJames T Kwan - Harvard Medical SchoolDerek Metcalfe - Harvard Medical SchoolRamy Rashad - Harvard Medical SchoolSwapna S Shanbhag - L V Prasad Eye InstituteSarah Pedretti - University of Cape TownPhuti Choshi - University of Cape TownTafadzwa Chimbetete - University of Cape TownRose Selim - University of Cape TownIan JamesJason A. Trubiano - Austin HealthRannakoe J Lehloenya - University of Cape TownJonny G Peter - University of Cape TownElizabeth Phillips
- Publication Details
- The journal of allergy and clinical immunology. In practice, Vol.13(11), pp.3042-3053
- Publisher
- Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology
- Identifiers
- 991005803850307891
- Copyright
- © 2025 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology
- Murdoch Affiliation
- Institute for Immunology and Infectious Diseases; Personalised Medicine Centre
- Resource Type
- Journal article
- Note
- on behalf of the SJS Survivor Study
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