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Report
HLA-B58:01 and Risk of Allopurinol-Induced Severe Cutaneous Adverse Reactions in the US
JAMA dermatology (Chicago, Ill.), Vol.161(12), pp.1258-1263
American Medical Association
2025
PMID: 41160012
Abstract
Importance
Carriage of HLA-B*58:01 has been shown to be associated with allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) in many populations globally; however, there is a critical need to investigate whether this is generalizable to populations of mixed ancestry, such as those in the US.
Objective
To assess the association of human leukocyte antigen (HLA) class I and II in a cohort of US patients who received a diagnosis of allopurinol-induced SJS/TEN or DRESS compared with allopurinol-tolerant and population control participants.
Design, Setting, and Participants
This genetic association study included consenting individuals who had specialist-adjudicated allopurinol-induced SJS/TEN or DRESS (collectively allopurinol-induced severe cutaneous adverse reactions [SCARs]) between January 1, 2015, and December 31, 2024. HLA carriage in these individuals was compared with allopurinol-tolerant and population control participants identified through the Vanderbilt University Medical Center biobank, which includes 94 489 individuals with imputed HLA class I and II typing from genotyping array data. Data were analyzed from January 2025 to August 2025.
Main Outcomes and Measures
The main outcome measure was the association of HLA class I and II alleles with allopurinol-induced SCARs. HLA class I and II conditional logistic regression case-control analyses were performed between patients with allopurinol-induced SCARs and both population control and allopurinol-tolerant control participants matched on age, sex, and self-identified race. Odds ratios (ORs) and 95% CIs were reported, with Bonferroni-corrected P < .05.
Results
This genetic association study used conditional logistic regression analyses and included 16 patients with allopurinol-induced SCAR (mean [SD] age, 61.1 [12.6] years; 9 female patients [56.25%] and 7 male patients [43.75%]) and 160 allopurinol-tolerant control participants matched 10:1. Two HLA class I alleles were found to be independently associated with increased risk of allopurinol-induced SCAR: HLA-B*58:01 (OR, 28.0 [95% CI, 8.6-100.6]) and HLA-A*34:02 (OR, 20.6 [95% CI, 3.3-131.1]). No HLA class II alleles meeting the Bonferroni-corrected P < .05 level of significance were identified.
Conclusions and Relevance
These findings suggest that although HLA-B*58:01 was found to be associated with allopurinol-induced SCARs, generalizing findings from previous studies, the allele was absent in more than one-third of the patient cohort and is therefore an incomplete indicator of risk. Importantly, in the US allopurinol-induced SCAR cohort, HLA-A*34:02 was found to be a second independent genetic risk factor for allopurinol-induced SCARs. These findings underscore the need to conduct population-based studies that both reproduce known and uncover novel HLA associations to reduce harm through contributions to screening, risk stratification, and diagnosis.
Details
- Title
- HLA-B58:01 and Risk of Allopurinol-Induced Severe Cutaneous Adverse Reactions in the US
- Authors/Creators
- Chelsea N Campbell - Vanderbilt University Medical CenterMatthew S Krantz - Vanderbilt University Medical CenterAlexis Yu - Vanderbilt University Medical CenterElizabeth J Phillips - Vanderbilt University Medical CenterStevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) Survivor Study Collaborators
- Publication Details
- JAMA dermatology (Chicago, Ill.), Vol.161(12), pp.1258-1263
- Publisher
- American Medical Association
- Identifiers
- 991005884935707891
- Copyright
- © 2025 Campbell CN et al.
- Murdoch Affiliation
- Research and Innovation Office; Institute for Immunology and Infectious Diseases
- Language
- English
- Resource Type
- Report
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