HLA-B Alleles With Shared Peptide Binding Specificities Define Global Risk of Co-trimoxazole-Induced Severe Cutaneous Adverse Drug Reactions.
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Li Yueran, Gibson Andrew, Saeed Hajirah N, Ashraf Mohammadali, Li Danmeng, Ostrov David A, Krantz Matthew S, Mallal Simon A, Alves Eric, Chopra Abha, Choo Linda, Dodiuk-Gad Roni P, Kaffenberger Benjamin, Drucker Aaron M, Goh Michelle S, Ergen Elizabeth, Micheletti Robert, Rosenbach Misha, Martin-Pozo Michelle D, Gangula Rama, Williams Elizabeth A, Yu Alexis, O'Connor April, Mahan Kelby, Kwan James T, Metcalfe Derek, Rashad Ramy, Shanbhag Swapna S, Tahboub Mohammed Ali, Pedretti Sarah, Choshi Phuti, Chimbetete Tafadzwa, Selim Rose, James Ian, Trubiano Jason A, Lehloenya Rannakoe, Peter Jonny G, Phillips Elizabeth J, SJS Survivor Study
Аннотация
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.