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Preprint
HLA-B Alleles with Shared Peptide Binding Specificities Define Global Risk of Cotrimoxazole-induced SCAR
medRxiv
Cold Spring Harbor Laboratory Press, 1.1
28/05/2025
PMID: 40492078
Abstract
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.
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).
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.
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 patients.
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.
HLA alleles including HLA-B*13:01 and HLA-B*38:02 are risk factors for co-trimoxazole-induced SCAR in Asian populations. However, the generalizability of these associations to other global populations is unknown but critical for population-appropriate risk stratification and diagnosis.
HLA alleles with shared peptide binding specificities (SPBS) to Asian-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 South Africa.
HLA alleles previously associated with co-trimoxazole-induced SCAR do not identify risk across populations. However, HLA alleles with SPBS provide biological plausibility and strategies for global and population-appropriate clinical risk stratification and diagnosis of cotrimoxazole-induced SCAR.
Details
- Title
- HLA-B Alleles with Shared Peptide Binding Specificities Define Global Risk of Cotrimoxazole-induced SCAR
- Authors/Creators
- Yueran Li - Institute for Immunology and Infectious Diseases, Murdoch UniversityAndrew Gibson - Murdoch University, Personalised Medicine CentreHajirah N Saeed - New York Eye and Ear InfirmaryMohammad Ali Tahboub - Harvard Medical SchoolDanmeng Li - Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of FloridaDavid A Ostrov - Department of Pathology, Immunology and Laboratory Medicine, University of FloridaMatthew S Krantz - Vanderbilt UniversitySimon A Mallal - Vanderbilt UniversityEric Alves - Institute for Immunology and Infectious Diseases, Murdoch UniversityAbha Chopra - Murdoch University, Personalised Medicine CentreLinda Choo - Institute for Immunology and Infectious Diseases, Murdoch UniversityRoni P Dodiuk-Gad - University of TorontoBenjamin Kaffenberger - The Ohio State University Wexner Medical CenterAaron M Drucker - Department of Medicine and Women’s College Research and Innovation Institute, Women’s College HospitalMichelle S Goh - Alfred 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 UniversityKelby 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 James - Institute for Immunology and Infectious Diseases, Murdoch UniversityJason A Trubiano - AntibioticRannakoe Lehloenya - University of Cape TownJonny G Peter - University of Cape TownElizabeth J Phillips - Vanderbilt UniversitySJS Survivor Study
- Publication Details
- medRxiv
- Publisher
- Cold Spring Harbor Laboratory Press
- Edition
- 1.1
- Number of pages
- 43
- Identifiers
- 991005786083907891
- Copyright
- The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
- Murdoch Affiliation
- Personalised Medicine Centre
- Language
- English
- Resource Type
- Preprint
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