HLA-B Alleles With Shared Peptide Binding Specificities Define Global Risk of Co-trimoxazole-Induced Severe Cutaneous Adverse Drug Reactions.

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 and South Africa. 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. 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. 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.