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HLA-B Alleles With Shared Peptide Binding Specificities Define Global Risk of Co-trimoxazole-Induced Severe Cutaneous
Yueran Li1, Andrew Gibson1, Hajirah N Saeed2
1Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia.
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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